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Abstract

Understanding body weight regulation will aid in the development of new strategies to combat obesity. This review examines energy homeostasis and food intake behaviors, specifically with regards to hormones, peptides, and neurotransmitters in the periphery and central nervous system, and their potential role in obesity. Dysfunction in feeding signals by the brain is a factor in obesity. The hypothalamic (arcuate nucleus) and brainstem (nucleus tractus solitaris) areas integrate behavioral, endocrine, and autonomic responses via afferent and efferent pathways from and to the brainstem and peripheral organs. Neurons present in the arcuate nucleus express pro-opiomelanocortin, Neuropeptide Y, and Agouti Related Peptide, with the former involved in lowering food intake, and the latter two acutely increasing feeding behaviors. Action of peripheral hormones from the gut, pancreas, adipose, and liver are also involved in energy homeostasis. Vagal afferent neurons are also important in regulating energy homeostasis. Peripheral signals respond to the level of stored and currently available fuel. By studying their actions, new agents maybe developed that disable orexigenic responses and enhance anorexigenic signals. Although there are relatively few medications currently available for obesity treatment, a number of agents are in development that work through these pathways.

Keywords

food intake energy homeostasis appetite gut hormones lipostatic hypothesis

‘. . . obesity is an imbalance between energy expenditure and energy intake with a relative greater prolonged energy intake than energy expenditure leading to excessive energy storage.’

Obesity is a growing epidemic not just in the United States but also worldwide. Globally, more than 2 billion adults and children are classified based on body mass index (BMI) as overweight (BMI 25.0 to 29.9 kg/m²) or obese (BMI ≥ 30.0 kg/m²).¹ In the United States, more than two thirds have a BMI greater than 25.0 kg/m² and nearly one half are obese.² These alarming statistics are apparent across nearly all demographic groups. Furthermore, it is predicted that by 2020 nearly 75% of adults in the United States will be overweight or obese.³ In its simplest form, obesity is an imbalance between energy expenditure and energy intake with a relative greater prolonged energy intake than energy expenditure leading to excessive energy storage. The health ramifications of obesity include, but are not limited to, type 2 diabetes, cardiovascular disease, certain types of cancer, osteoarthritis, mobility limitations, poor mental health, and all-cause mortality.^4,5 Unfortunately, current treatments, with the exception of bariatric surgeries, are mostly ineffective.⁶ Because bariatric surgeries are mostly irreversible with possible long-term complications, and large costs, their use for the masses are implausible. Therefore, new strategies need to be developed. This review examines energy homeostasis and food intake behaviors, specifically with regards to hormones, peptides, and neurotransmitters in the periphery and central nervous system (CNS), and their potential role in obesity. Afferent and efferent signals regulate both components of energy balance—energy intake and energy expenditure.

However, further understanding of body weight control, specifically with regard to feeding behaviors, is needed. A number of regulatory processes are discussed in this article, including the lipostatic theory, which is based on the release of leptin from adipocytes and its signaling cascade in the brain. This is an example of the peripheral signals integrating with the brain to regulate food intake and energy expenditure. Altering a body’s net energy balance leads to opposing changes in energy expenditure and/or food intake to minimize body weight changes.⁷ The “set-point” hypothesis was derived from these observations, which suggests that physiological systems alter food intake and energy expenditure to regulate body weight. Alternatively, the “settling-point” states that external environmental factors (ie, diet and lifestyle) determine body weight regulation. There is continuing debate among these 2 theories.⁸ Whereas the physiological factors of hormones and neural innervation are the basis for this article, the mention of the nonregulatory approach is added for context. Based on the epidemic outbreak of obesity, body weight regulation is not strictly regulated. Manipulating the environment such as with portion size, energy density of the food, or the social situation leads to changes in food intake. However, total compensation for these manipulations do not occur, at least acutely.⁹ For example, omitting breakfast does not lead to overconsumption of subsequent meals and snacks during the day as total daily intake is reduced when breakfast is skipped.⁹ Therefore, according to the “settling-point” hypothesis, altering the environment may be the key to treating and/or preventing obesity.

Role of the Brain

Body weight regulation is based on the ability of the brain, particularly the hypothalamus, to integrate behavioral, endocrine, and autonomic responses via afferent and efferent pathways from and to the brainstem and peripheral organs.^10,11 In addition to the CNS, a number of peripheral organs and organ systems are involved in energy balance, including the liver, pancreas, adipose, gut, and muscle. A diverse range of neural and hormonal messages from these organs regarding the body’s energy status—both stored and recently ingested—are presented to the brain and the brain interprets this information.¹² Energy consumption, energy expenditure, and metabolism of nutrients are thus influenced by these signals. Ultimately, this control is required by the body to ensure adequacy of nutrient availability for current needs and for stored energy during times when energy intake is limited.¹³ Dysfunction in generating signals or in the interpretation of these signals by the brain is a factor in obesity as well as undernourishment from eating disorders.

Work from the 1950s demonstrated the importance of the action of the brain in energy homeostasis. Depending on the location, specific lesions of nuclei in the hypothalamus caused either profound increases or decreases in food intake and body weight.^14,15 In addition to the hypothalamus, the brainstem, which includes the nucleus tractus solitaris, area postrema, and dorsal vagal nucleus, has a critical role in body weight regulation. Specifically, the nucleus tractus solitaris behaves as a relay center and passes on the signals received from the periphery, in the form of neural inputs or circulating factors, to the hypothalamus. The area postrema, lying near the nucleus tractus solitaris, detects circulating hormones and nutrients and then provides this information to the hypothalamus by both efferent and afferent projections, thus allowing it to moderate food intake based on nutritional needs.^16,17 The amygdala in the limbic system, which is the integrative center for emotions and emotional behavior, has high levels of neurotransmitters with anorexigenic and orexigenic actions.^18-20

The area of the hypothalamus that appears to be most critical in the integration of signals regarding energy flux is the arcuate nucleus. It receives proximal satiation signals, which interact with adiposity derived signals. The arcuate nucleus contains melanocortin system neurons that express pro-opiomelanocortin (POMC), which is a precursor for a number of peptides, including α-melanocyte stimulating hormone (α-MSH), endorphins, and adrenocorticotropic hormone, among others.^21-24 The primary receptor for α-MSH is melanocortin 4 receptor (MC4R), and it is present in the arcuate nucleus as well as several other brain areas.^25-28 Binding of either α-MSH or an agonist to MC4R activates catabolic pathways and leads to hypophagia, thermogenesis, and weight loss,^29-33 whereas MC4R antagonists elicit hyperphagia and weight gain.³⁴ Mice devoid of MC4R are obese with hyperphagia, and excessive fat mass.^35-37 Furthermore, a mutation in human MC4R is the most common monogenic form of human obesity, present in 1% to 2.5% of humans with a BMI above 30.0 kg/m².^31,38,39

Lying adjacent to the POMC catabolic neuron, the arcuate nucleus also houses anabolic neurons. These neurons synthesize Neuropeptide Y (NPY) and Agouti Related Peptide (AgRP).^21-23,40 NPY binds to Y receptors to acutely increase food intake, leading to subsequent weight gain.^41,42 Consistent with this action, NPY secretion in the hypothalamus increases during fasting.⁴³ Additionally, hypothalamic administration of NPY increases food intake.⁴⁴ AgRP, a reverse agonist to MC4R receptors, competes with α-MSH for binding to the receptor, leading to increases in food intake and weight gain.^11,42,45-49 AgRP is expressed only in neurons in the arcuate nucleus that also produce NPY.^48,50

Other hypothalamic areas involved in feeding behaviors that communicate with the arcuate nucleus are the paraventricular nucleus, the dorsomedial nucleus, and the lateral nucleus. The paraventricular nucleus is activated by neurons from the arcuate nucleus and express peptides that are primarily catabolic (nesfatin, oxytocin, thyroid releasing hormone, corticotropin releasing hormone).^51,52 On the other hand, the dorsomedial nucleus receives inputs from the anabolic NPY and AgRP neurons that originate in the arcuate nucleus.^18,53 Neurons with melanin concentrating hormone are present in the lateral nucleus of the hypothalamus. They express MC4R and integrate POMC, NPY, and AgRP neurons.^54-56 POMC neurons that project to the spinal cord are also involved in energy homeostasis by stimulating adaptive thermogenesis in brown adipose tissue through the MC4R sympathetic preganglionic neurons.⁴⁹

A number of centrally acting neurotransmitters are involved in energy homeostasis through regulating food intake and/or energy expenditure. Gamma amino benzoic acid (GABA) is a neurotransmitter produced by the action of NPY and AgRP, and GABA regulates energy balance in the parabrachial nucleus, actions residing outside the hypothalamus.^57,58 Its role in obesity is evident in that removing the vesicular transporter for GABA in AgRP neurons leads to resistance to obesity induced by a high-fat diet, independent of alterations in the consumption of food.⁵⁷ Another neurotransmitter involved in regulating food intake and energy expenditure is serotonin, which is present in selected arcuate POMC neurons.^59-61 These POMC serotonin receptors are involved in regulating energy homeostasis through changes in feeding behavior, independent of energy expenditure.^61,62 Oxytocin is a centrally acting neurotransmitter and hormone with a growing interest as an antiobesity target based on its involvement in energy homeostasis.^63-66 Mice with deficiency in either oxytocin or oxytocin receptors display an obesity phenotype.^67,68 Long-term administration of oxytocin either peripherally or centrally leads to inhibition of food intake, increased energy expenditure, and weight loss in diet-induced obesity and genetically obese rodent models.^63-66,69-72 Interestingly, this effect on energy balance with oxytocin is not solely confined to rodent models as chronic administration of oxytocin to diet-induced obese rhesus monkeys reduced body weight, lowered food intake, and increased energy expenditure.⁷³ The primary site of oxytocin production in the brain is neurons located in parvocellular paraventricular nucleus, with less produced in the anterior hypothalamus and medial amygdala.⁷⁴ Projections from these locations go to the brainstem, including the nucleus solitaris tract and spinal cord.^75,76 Although its mechanism is not totally understood, oxytocin appears to be a downstream effector of anorexigenic signals in the arcuate nucleus and brainstem.^51,64,74,77

Whereas the blood brain barrier serves as a protective structure for the brain to prevent damage from unwanted molecules, this brain structure is permeable to peripheral metabolic signals and allows their communication with areas of the brain that regulate energy homeostasis. The arcuate nucleus is adjacent to the median eminence, which has an incomplete blood-brain barrier with fenestrated capillaries.⁷⁸ The lack of the traditional blood-brain barrier in this hypothalamic area increases the permeability of molecules from the blood to the brain.^79-81 Furthermore, circulating factors may influence areas in the brainstem such as the nucleus tractus solitaries since the area postrema is a circumventricular organ that is adjacent to the nucleus tractus solitaries. Hormones and nutrients thus may bypass the blood-brain barrier and gain access to the 2 key areas handling energy homeostasis—the brainstem and hypothalamus.

Peripheral Signals

A number of signals originate in the peripheral organs and are in response to level of stored and currently available fuel in selected tissues.¹² These signals include both neural and hormonal messages. For the latter type, leptin and insulin reflect energy stores and have been extensively investigated. Gut peptides provide further information on current food consumption and they modify electrical activity of the vagal afferent sensory pathway by attaching to receptors on these neurons that extend into the digestive tract mucosa. These intestinal derived signals are sent via the vagus to the nucleus tractus solitaris of the brainstem, with further projection of the message to hypothalamic regions.⁸²

Leptin

Hormone signals from adipose tissue were first proposed in the lipostatic hypothesis as early as the mid-1950s.⁸³ Kennedy observed that rats alter food intake as a homeostatic adjustment to keep body fat stores stable. For example, food intake increased with a rise in energy expenditure, which maintained constant body fat stores. Thus, Kennedy hypothesized that a circulating metabolite exerts its action on the hypothalamic region; this was supported as damage to the hypothalamus allowed the animal to overeat and to subsequently become obese.⁸³ This homeostatic theory of hunger allows the brain to monitor energy storage in the body. The proposed circulating metabolic factor was subsequently identified over 40 years later in 1994 as leptin.⁸⁴ Leptin is produced primarily by white adipose tissue and released into the general circulation. Plasma levels of leptin are positively correlated with total body fat as higher levels of plasma leptin are seen in those with higher body fat. However, leptin’s secretion is tightly coupled to energy status as leptin levels decrease by nearly two thirds after 1 week of energy restriction.⁸⁵ Thus, plasma leptin concentrations decrease faster than the rate of reduction of adipose tissue. Furthermore, leptin is more highly correlated with subcutaneous than visceral adiposity.^86,87 Soluble leptin receptor is the main binding protein for leptin in blood and it can affect the bioavailability and effects of leptin.^88,89 High levels of the soluble receptor reduces biologically active leptin and inhibits leptin signaling.⁹⁰ Low levels of soluble receptor also indicate low leptin activity as this may reflect low expression of the membrane bound leptin receptor, indicating leptin resistance.⁹¹

Early studies in obese animal models demonstrated that leptin decreases food consumption and increases energy expenditure. Animals with leptin deficiency show increased food intake, lower energy expenditure, and develop severe obesity.^92-94 Leptin exerts its action through binding to the membrane bound leptin receptor, triggering the Janus Activated Kinases (JAK) and the transcription factor signal transducer and activators of transcription (STAT) signaling cascades, among others.^30,95-97 Leptin communicates directly with the brain and acts predominately in the hypothalamus in the areas of the arcuate nucleus, ventromedial hypothalamus, and lateral hypothalamic by passing through the sparse blood-brain barrier near the hypothalamus via a saturable transporter.^21,98,99 Leptin receptors are expressed on both POMC and NPY/AgRP neurons and are highest for these neurons in the arcuate nucleus.⁹⁸ As discussed above, neuropeptides from these neurons regulate energy homeostasis.^100-104 In the arcuate nucleus, leptin stimulates gene expression and the firing rate of POMC neurons^30,105-107 and inhibits activity of NPY and AgRP neurons.^{84,98,108,109} The activation of POMC neurons leads to increased production of α-MSH and binding with its receptor, MC4R, to reduce feeding behaviors.^110-112 Consistent with this mechanism, use of MC4R antagonists abolishes the effects of leptin.^113,114 Furthermore, selective deletion of leptin receptors in the CNS also eliminates the effect of leptin.

Administering leptin to rodents and humans with congenital leptin deficiency resolved obesity through decreasing food intake.^92,115-119 The implication of leptin for treating human obesity is questioned, however, as only a small fraction of humans are leptin deficient; most humans are refractory to leptin, that is, leptin resistant. This term refers to states of obesity that demonstrate hyperleptinemia as well as a lowered response to leptin. In diet-induced obese mice and in the vast majority of humans, providing leptin is inefficient in treating obesity.¹¹⁹ Further supporting the concept of leptin resistance in humans are data showing that individuals that are more likely to regain weight after weight loss have higher leptin levels, consistent with lower leptin sensitivity, than those with successful weight maintenance.¹²⁰ Importantly, the causes of leptin resistance have been an active area of research with several mechanisms identified, including a dysfunction in transporting leptin into the CNS,^99,121-124 a defect in leptin signaling,^125,126 endoplasmic reticulum stress,^127-129 and alterations in the operation of the leptin receptor.^130,131 One well-studied leptin signaling pathway has been Suppressor of Cytokine Signaling (SOCS3). Interestingly, leptin signaling is attenuated by SOCS3.¹³² In a negative feedback mechanism, leptin increases SOCS3 expression.^132,133 By studying this and other signaling pathways, possible therapeutic treatments may be developed for combatting leptin resistance and the obesity phenotype observed with leptin resistance.

We and others have demonstrated alterations in plasma leptin with behavioral and surgical weight loss interventions. In post Roux-en-Y gastric bypass surgery patients, leptin decreased serially up to the 6-month follow-up time point.¹³⁴ Circulating values dropped by 70% from baseline with a 30% decrease in body weight 6 months postsurgery.¹³⁴ In this morbidly obese cohort, leptin was correlated with body mass index at baseline (r = .78) and remained significantly correlated at 6 months (r = .79). Behavioral obesity treatment encompassing dietary energy restriction and exercise training also reduced leptin levels in older adults for up to 18 months, even with moderate weight loss of 5% to 10%.¹³⁵ Interestingly, change in body weight was statistically related to change in leptin over 18 months of weight loss intervention in older adults.¹³⁵

Insulin

In addition to the well-known peripheral actions of insulin in maintaining glucose homeostasis, insulin signaling in the brain is also important for energy balance.^30,136-138 Similar to leptin, pancreatic beta cell insulin secretion occurs in response to changes in energy flux,¹³⁹ and insulin levels are proportional to body fat, for both fasting and 24-hour insulin levels.^140,141 With actions that mimic leptin, insulin decreases food intake and lower insulin levels increase food intake.^22,142-144 Insulin is critical for the integration of several peripheral metabolic signals. This is accomplished through insulin’s action to inhibit NPY and stimulate POMC neurons. Insulin receptors in the blood-brain barrier facilitates its presence in the CNS. The hypothalamus, particularly the arcuate nucleus, which is rich in insulin receptors, is the gateway for insulin’s access to the CNS.¹⁴⁵ Acute infusion of insulin into the CNS reduces food intake and body weight through binding of insulin to specific receptors on neurons in the hypothalamus, hindbrain, and other locations.^137,146,147 In contrast, chronic administration has little effect on obesity due to the development of insulin resistance.¹³ Administration of insulin receptor agonists into the CNS also reduces food intake and body weight in rodents on a high-fat diet.¹⁴⁸ Supporting this role for insulin in feeding behaviors and subsequent body weight maintenance, mice lacking insulin receptors in the CNS are insulin resistant with increased food intake and development of diet-induced obesity.¹⁴⁹ In contrast to leptin, circulating levels of insulin are more highly correlated with visceral than subcutaneous fat.^13,150-152

In addition to the lipostatic hypothesis that illustrates hormonal signals originating from white adipose tissue, this high-energy storage depot also has afferent sensory input that is received by spinal neurons and project to the brainstem, hypothalamus, and paraventricular nucleus. All of these central areas are important in sympathetic nervous system outflow.¹⁵³ The importance of this sensory signal in energy homeostasis was apparent when denervation of sensory neurons from white adipose tissue led to increased fat pad weight.¹⁵⁴ Furthermore, the electrical outflow in the sensory neuron of white adipose tissue is increased with leptin injection into this tissue,¹⁵² suggesting that this hormone may be responsible for the afferent signaling discharge. However, others demonstrated that increased adipose afferent reflex was still apparent in leptin resistance.^155,156 Furthermore, the leptin injection raised CNS sympathetic outflow to other white adipose tissue, brown adipose tissue, adrenal medulla, and liver.^157,158

Gut Hormones

Over the past several decades, the importance of signals originating from the intestines has become apparent for energy homeostasis. Enteroendocrine cells sense nutrient content in the intestinal lumen and regulate the release of gut derived hormones. After diffusion into the hepatic portal vein, these hormones spread into the systemic circulation and alter neuronal signaling in the brain to modulate feeding.¹⁵⁹ The blood-brain barrier in the brainstem allows gut hormones to access the area postrema, which then communicates with the nucleus tractus solitaris. Additionally, gut hormones signal the brain by directly stimulating vagal afferent neurons.^160-163 This section will review a number of these gut hormones and their action with energy homeostasis.

CCK

Cholecystokinin (CCK) is released into the circulation from the endocrine I cells in the duodenum and jejunum in response to saturated fatty acids, long-chain fatty acids, amino acids, and small peptides.^164,165 The hormone increases the release of pancreatic enzymes and bile salts into the duodenum that promotes the digestion of fats and proteins.^166,167 The level of CCK secretion is proportional to the lipid and protein content in the meal. Actions for CCK related to the digestion and absorption of nutrients includes slowing down gastric emptying and stimulating gallbladder secretion. In its role of appetite regulation, CCK inhibits food intake and decreases meal size.^168-173 Low circulating levels of CCK are related to increased hunger and decreased fullness.¹⁷⁴ However, animals without CCK have normal food intake and body weight, suggesting that this signaling molecule is not essential for normal regulation of energy status.¹³ CCK binds to vagal neurons that activate the hindbrain, which is responsible for integrating satiation and adiposity signals with nutrient levels, hedonic signals, and social factors¹⁷⁵ and relaying the information to other areas of the brain, including the hypothalamus and the reward center.¹³ Support for CCK’s action through the vagal afferent nerve is from work showing that lesions to the vagus nerve eliminates the CCK-induced reduction in food intake.¹⁷³ Interestingly, manipulating CCK satiation signals with pharmacological agents influences eating through affecting meal size but not the initiation of a meal.^176,177 Furthermore, early work with CCK showed that intraperitoneal administration of CCK in rats reduced meal size, but increased the number of meals such that there was no difference in total daily food intake or growth rate in rats after 6 days of treatment.¹⁷⁸ Leptin’s involvement in CCK signaling is apparent as leptin enhances the vagal sensitivity to CCK.¹⁷⁹

Ghrelin

Working through the vagal afferent pathway and the nucleus tractus solitaris, ghrelin—the hunger hormone—activates NPY and AgRP neurons and suppresses POMC neurons in the arcuate to stimulate appetite.^180-185 Inhibiting gastric vagal afferent signals¹⁸² and blocking the NPY neuron activation mitigates ghrelin-induced feeding.^186-188 The receptor for ghrelin, growth hormone secretagogue receptor, is found centrally in similar locations to the leptin receptor.^183,184,189 The interaction between leptin and ghrelin is also seen as ghrelin reverses the inhibition of NPY and AgRP neurons by leptin and leptin antagonizes the increased food intake by ghrelin.¹⁸⁷ Its action requires GABA, as this neurotransmitter is released from the NPY and AgRP neurons with the binding of ghrelin to its receptor.¹⁹⁰ As information is received from ghrelin by the vagal afferent pathway, the orexigenic signal is transmitted to norepinephrine neurons of the nucleus tractus solitaris. This promotes norepinephrine secretion from the hypothalamus.¹⁸²

Administration of ghrelin centrally and peripherally stimulates appetite, food intake, and weight gain.^191-194 Mice who are selectively deficient in the ghrelin receptor are hypophagic and lean when fed a high-fat diet.¹⁹⁵ In mice with an isolated defect in GABA transport, the orexigenic effect of ghrelin was dampened as these mice have a normal weight phenotype on a high-fat diet.¹⁹⁶ The orexigenic signal is then dispersed to other parts of the hypothalamus and nonhypothalamic regions by axons of POMC and NPY and AgRP neurons reaching to the dorsomedial nucleus, lateral nucleus, paraventricular nucleus, and the ventromedial nucleus. Ghrelin also modifies appetite through binding on visceral vagal afferent neurons. Both leptin and insulin dampen ghrelin-induced activation of NPY neurons.¹⁹⁷ Ghrelin’s action in the periphery, specifically the intestine, includes increases in motility and gastric emptying.^198,199 As expected for the hunger hormone, ghrelin peaks in fasted state and before a meal and is lower following a meal, suggesting it is acting more as a meal initiator and not controlling meal size.²⁰⁰ Levels of ghrelin are lower in obese than normal weight individuals,¹⁹⁴ and those with higher body fat, insulin, and leptin have lower ghrelin.^194,201 Circulating levels of ghrelin are higher following weight loss.^201-203

PYY

Pancreatic Tyrosine Tyrosine (PYY_3-36) is a posttranslational modified truncated form of PYY_1-36 that interacts with specific Y receptors on vagal afferent neurons.²⁰⁴ This gut peptide induces satiety and is involved in energy expenditure.^30,205-207 PYY_3-36 also reduces gastric emptying, intestinal motility, pancreatic secretions, and absorption of fluids and electrolytes from the ileum.^208-210 Circulating levels of PYY_3-36 are lowest during fasting, increase to a peak within 1 to 2 hours postprandial, and remain elevated for 6 hours.²¹¹ PYY_3-36 activates POMC neurons and suppresses NPY in the arcuate nucleus.²⁰⁷ Actions of PYY_3-36 also occur through vagal stimulation in the brainstem.²¹² Peripheral administration of PYY_3-36 decreases food intake.^{207,211,213-215} Consistent with this action, obese have lower circulating levels than lean individuals.^207,211 Interestingly, resistance to PYY is not thought to be present in obesity.

GLP-1

An incretin produced by the L cells of the intestine, glucagon like peptide 1 (GLP-1) is formed from the posttranslational modification of the proglucagon peptide. The increased glucose-stimulated insulin release occurs following binding of GLP-1 to specific receptors on pancreatic beta cells in response to glucose.^216,217 Increased initial GLP-1 release occurs in response to neural reflex or circulating factors.^218,219 A subsequent second phase of release ensues from the presence of food in the distal gut.^220,221 The levels peak by 90 minutes and the rise in plasma GLP-1 is proportional to calories consumed.^160,222 In addition to enhancing glucose stimulated insulin secretion with insulinotropic and glucagonostatic actions,²²³ GLP-1 slows gastric emptying and inhibits gastric acid secretion.^224,225 By slowing gastric emptying, the need for insulin is lowered as the rate of glucose appearance in the blood is reduced.²²⁶ The ileal brake resulting from the appearance of undigested carbohydrates, lipids, and protein in the ileum leads to GLP-1 and PYY release. This braking slows intestinal motility to allow more efficient digestion and nutrient absorption. Central neurons with GLP-1 receptors are found in the brainstem, including the nucleus of the solitary tractus and ventrolateral medulla.²²⁷ There are projections to hunger centers in the lateral hypothalamus and periventricular areas.²²⁸ The paraventricular hypothalamus and arcuate nucleus are also rich in GLP-1 receptors.^162,163 GLP-1 reduces food intake, increases satiety, and promotes weight loss through its peripheral and central actions.^229-232 Acute intracerebroventricular administration of GLP-1 inhibits food intake, and antagonists to the GLP-1 receptor increases food intake, even in satiated rats.^230,233 Direct administration of GLP-1 into the paraventricular nucleus has a strong inhibition of food intake, suggesting it is the primary site for brain-derived GLP-1 satiation^234,235; however GLP-1 also produces anorexic effects in the arcuate nucleus as POMC neurons express GLP-1 receptors.²³⁵ Furthermore, GLP-1 is lower in obese than lean individuals.²³⁶ As satiation signals like CCK and GLP-1 are produced during food consumption neural circuits are activated and food intake decreases, ending the meal. Long-term central and subcutaneous injections of GLP-1 reduces weight gain and leads to weight loss.²³⁷

Oxyntomodulin

The gut peptide oxyntomodulin is also secreted from intestinal L cells in response to food ingestion and it is a product of preproglucagon. Oxyntomodulin delays gastric emptying and lowers gastric acid secretion.²³⁸ It is known to lower food intake²³⁹ and chronic preprandial peripheral administration of oxyntomodulin increased weight loss in humans.²⁴⁰ Part of the weight loss may be attributed to increased energy expenditure as oxyntomodulin increased activity related energy expenditure in pair-fed rats.^239,241,242

Obestatin

Obestatin originates in the gastric mucosa of the stomach, the small intestine, and the pancreas, and is a posttranslational product of preproghrelin. Obestatin’s function with energy homeostasis is to inhibit food intake, prevent body weight gain, and reduce gut motility.²⁴³ Obestatin does not appear to affect expression in the brain of NPY, AgRP, and POMC, but it did inhibit ghrelin-induced expression of NPY and NPY receptors.²⁴³

Nesfatin

Nesfatin is found in the gut and hypothalamus as a neuropeptide. Its expression in the stomach and duodenum, as well as exogenous peripheral administration of the hormone, activates vagal afferent neurons to reduce food intake.^244-246

As is evident, physiological actions for these molecules include altering feeding behaviors through central and peripheral actions. Much of this work has been shown in genetically altered animal models. Interestingly though, acute and/or chronic administration of these hormones as pharmacologic agents to increase their levels and actions may alter feeding behaviors, but several have inherent limitations reducing their application for obesity treatment in their current state. As described, CCK reduces meal size but demonstrates compensatory increases in meal frequency with no change in total daily food intake. Tolerance also develops with repeated CCK administration,²⁴⁷ which may undermine its clinical utility. Furthermore, leptin administration to non–leptin-deficient animals, including humans, even at supraphysiological levels, is mostly ineffective in altering food intake and reducing body weight.²⁴⁸ In some treatment programs with these hormones, nausea and gut distress accompanies their use.^161,249 A recent publication did show promise as a 10-hour subcutaneous infusion of a combination of GLP-1, PYY, and oxyntomodulin in obese adults decreased total daily ad libitum food intake by about 32% with no difference in sensations of hunger, amount to eat, and fullness as compared to a saline infusion.²⁵⁰ Optimism for the use of gut hormone–derived treatments comes from specific targets of appetite controlling systems and less likelihood of adverse side effects than current drugs.²⁵¹

Altered Pathways in Obesity

Obesity and diabetes are commonly associated with resistance to or diminished production of peripheral and central regulators of energy homeostasis, including energy expenditure and food intake.²⁵² Disturbances in metabolic, neural, or hormone signals can occur with a number of metabolic disorders, such as obesity, anorexia nervosa, and diabetes. Vagal nerve actions are altered via neuropathy present in obesity and diabetes.²⁵³ Research shows a reduction in responses to CCK and leptin at the vagal nerve in mice fed a high-fat diet.²⁵⁴ The inflammation present in obesity may spread to the vagus nerve and then to the hypothalamus.^255,256 As circulating signals (glucose, triglycerides, hormones, and cytokines) are altered with obesity, this influences a number of factors that have a dysfunctional effect on fuel metabolism and energy homeostasis. These include central and leptin signaling and blood-brain barrier permeability.^149,257-260 With these altered responses to food intake signals, obesity may worsen.

Levels of gut peptides following a meal are attenuated in obese individuals, suggesting a dampened satiety response with eating.^236,261 Leptin resistance is characterized by high leptin levels and is apparent in obesity. There is a lower response to leptin’s action in the arcuate nucleus, namely, with the POMC, NPY, and AgRP neurons.^262-264 This impaired function of leptin occurs experimentally with sustained exposure to high-fat diets.^265,266 During high-fat feeding, up to one fourth of the POMC neuronal population is lost,²⁶⁶ leading to a dampened response to leptin and increased susceptibility to obesity. An upregulation of leptin receptor mRNA is observed with extended high-fat diet consumption.^265,267,268 Over time, desensitization of leptin signaling pathway occurs and leads to higher food intake and obesity.²⁶⁵ Interestingly, administering melanocortin agonists makes mice with diet-induced obesity hyperresponsive, indicating that the melanocortin system is functioning properly downstream of the arcuate nucleus.²⁶²

Obesity Therapeutics

Intensive lifestyle treatments lead to about a clinically significant 7% to 10% weight loss at 1 year.²⁶⁹ However, weight loss in primary care settings do not always achieve clinical significance (>5% weight loss). Sustaining behavior change for long-term weight loss maintenance is difficult based on biological and environmental challenges imposed. Thus, adjunctive therapy, such as including pharmacotherapy, may be necessary. Patients who have a history of unsuccessful prior attempts at weight loss and meet label indications are candidates for obesity pharmacotherapy. Ultimately, the initial goal with adjunctive pharmacotherapy to diet and exercise is to help patients achieve a weight loss of 5% or more, which has been shown to be sufficient in reducing significant health risk such as hypertension, impaired glucose tolerance, and nonalcoholic fatty liver disease.²⁷⁰

Soon after leptin was characterized, there was great interest in its potential use in treating human obesity. However, because congenital deficiency is rare in humans,²⁷¹ this excitement has waned. In the scarce cases of congenital leptin deficiency, individuals present with morbid obesity, profound hyperphagia, and type 2 diabetes.²⁷² For these individuals, daily leptin use lowers food intake, reduces body weight, and their diabetes is resolved, essentially reversing morbid obesity.¹¹⁶ Unfortunately, research does not support the use of leptin alone for antiobesity therapy in obese individuals with leptin resistance.²⁴⁸ However, a number of agents that restore leptin sensitivity have been investigated for their long-term effectiveness in obesity treatment. These pharmacological agents have targeted pathways that are known to affect leptin sensitivity: reducing endoplasmic reticulum stress, reversal of SOCS3 inhibition, and enhancing expression of leptin receptors.²⁷³ Although these monotherapy approaches have not been highly effective, they do underscore the complexities with energy homeostasis and the regulation of feeding behaviors and energy expenditure. Promising results are found though when leptin is combined with other hormonal therapy, including CCK, amylin, and GLP-1; these polytherapies provide greater reduction in food intake and body weight than leptin alone.^274-277 Use of agents that improve leptin sensitivity along with leptin may also be a future therapy for obesity treatment.²⁷⁸ Furthermore, antagonists to molecules that serve as endogenous negative regulators of leptin are being investigated to improve leptin sensitivity.^278-282

Current Food and Drug Administration–approved medications for long-term treatment of obesity have demonstrated limited success in research trials. There are 4 medications with mechanisms that target central and peripheral hormonal and neural responses. Available agents for obesity treatment include lorcaserin, a selective 2C serotonin receptor agonist; liraglutide, an analogue of human GLP-1; and 2 combination preparations: phentermine, an adrenergic agonist, and topiramate ER, a neurostabilizer (Qysmia); and naltrexone ER, an opioid receptor antagonist, and burpropion SR, a dopamine and norepinephrine reuptake inhibitor (Contrave). Lorcaserin, which stimulates POMC neurons, showed in a 2-year follow-up a placebo-subtracted weight loss of over 3 kg.²⁸³ Importantly, more patients lost at least 10% of initial body weight with lorcaserin than placebo.²⁸⁴ Phentermine is available either alone or with topiramate and it works centrally through a catecholamine agonist (norepinephrine and dopamine). A low-dose version of phentermine (Lomaira) is marketed to curb evening appetite with minimal impact on sleep. Topiramate’s weight loss action is unknown.²⁸⁵ Bupropion inhibits the reuptake of dopamine and norepinephrine and reduces appetite through stimulating POMC neurons. Naltrexone blocks the effect of beta-endorphins secreted from POMC neurons.²⁷⁰ The placebo-subtracted weight loss was nearly 9 kg for phentermine and topiramate combination and 5 kg (4.8%) for the bupropion and naltrexone combination.²⁸³ Liraglutide affects food intake through a central action of increased stimulation of POMC, and peripherally by increased vagal afferent stimulation.^286,287 More than a 5 kg (5.4%) difference in weight loss between placebo and liraglutide treatment groups have been shown.²⁸³ Other agents that also are agonists to the GLP-1 receptor are being developed.^288,289 As is apparent, significant, albeit modest, reductions in weight are observed with current Food and Drug Administration–approved medications. Additionally, health care providers generally have inadequate training to utilize and counsel their patients on these medications.²⁹⁰

Several promising studies have utilized oxytocin as an antiobesity medication.²⁹¹ Administering oxytocin peripherally activates vagal afferent neurons and suppresses food intake through action on the nucleus tractus solitaris.²⁹² Therapeutically, receptor antagonists to melanin concentrating hormone have been studied in rodent models for potential antiobesity medication.^293,294 These antagonists show potential promise for an antiobesity medication as they lead to reduced food intake, lower consumption of palatable foods, and body weight loss in diet-induced obese mice and rats.^293,294

Off-label use of medications for obesity prevention or treatment include bupropion, metformin, zonisamide, and pramlintide. Bupropion is a norepinephrine and dopamine reuptake inhibitor and it showed an average of an additional 2.8 kg of weight loss relative to placebo after 6 to 12 months of monotherapy treatment.²⁹⁵ Metformin, the insulin sensitizer medication shows small, but a sustained 2% greater weight loss than placebo. Its use as an adjuvant to prevent or reduce weight gain with antipsychotic drugs shows promise.²⁹⁶ Zonisamide, which is used to treat epilepsy, produced a greater than 3% weight loss than placebo at 12 months, but adverse side effects likely limit its general use.²⁹⁷ The analogue of human amylin, pramlintide, showed an additional 2.2 kg of weight loss relative to placebo.²⁹⁸

Mice and humans with a deficiency or defect in MC4R demonstrate hyperphagia and obesity.^31,33 Conversely, exogenous agonists of MC4R, including setmelanotide, are being used in clinical studies as potential antiobesity therapy.^299,300 MC4Rs are involved in both sides of energy homeostasis with MC4Rs in the paraventricular hypothalamus and the amygdala involved in food intake control and neurons with these receptors in other locations of the brain regulate energy expenditure.³⁰¹ A recent study showed that an MC4R agonist increased resting energy expenditure in obese individuals, but did not affect exercise energy expenditure or the thermic effect of food.²⁹⁹ In this short 3-day study, no adverse effects on blood pressure was observed, providing optimism for its long-term use in selected obese individuals.

Other centrally acting agents are being developed and tested for safety and efficacy. Mechanisms of action for these include antagonists to the NPY receptors and altering dopamine, serotonin, and norepinephrine with varying degrees of success.^300,302,303 Additional drugs and drug combinations that work either peripherally or with both central and peripheral actions are in various stages of research. These include drugs that (1) interfere with the digestion of nutrients (fats and carbohydrate), (2) alter the absorption of glucose from the intestine and the reabsorption of glucose in renal tubules, (3) inhibit production of capillaries in adipose tissue, (4) downregulating growth factors involved in fat storage, (5) increasing AMP activated protein kinase, (6) stimulators of the beta2 adrenergic receptor, and (7) mimetics of PYY, oxyntomodulin, and amylin and antagonists for ghrelin.^{249,270,300,304-309}

Summary

Regions of the brain, primarily the hypothalamus and brain stem, integrate neural and hormonal signals from the periphery and other brain areas, to elicit feeding behaviors. These diverse messages from the periphery are in response to the body’s energy status. As dysfunctions in these signals become apparent, especially observed in experimental animal models, obesity and eating disorders can ensue. The catabolic and anabolic neurons in the CNS, including NPY, AgRP, and POMC, are important in this process. The discovery of leptin opened the door to understanding how adipose tissue communicates with the CNS. Similarly, a number of gut hormones have been researched with promising results in manipulating their actions to help treat obesity. Although current therapies with pharmacologic agents have been mostly disappointing, further research in this area will likely lead to better agents with fewer side effects and greater efficacy.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Popkin

Adair

SW.

Global nutrition transition and the pandemic of obesity in developing countries. Nutr Rev. 2012;70:3-21.

Ogden

Carroll

Kit

Flegal

KM.

Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014;311:806-814.

Wang

McPherson

Marsh

Gortmaker

Brown

Health and economic burden of the projected obesity trends in the USA and the UK. Lancet. 2011;378:815-825.

Kolotkin

Meter

Williams

GR.

Quality of life and obesity. Obes Rev. 2001;2:219-229.

Jensen

Ryan

Apovian

, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129(25 suppl 2):S102-S138. doi:10.1161/01.cir.0000437739.71477.ee.

Sjostrom

Review of the key results from the Swedish Obese Subjects (SOS) trial: a prospective controlled intervention study of bariatric surgery. J Intern Med. 2013;273:219-234.

Leibel

Rosenbaum

Hirsch

Changes in energy expenditure resulting from altered body weight. N Eng J Med. 1995;332:621-628.

Levitsky

DA.

The non-regulation of food intake in humans: hope for reversing the epidemic of obesity. Physiol Behav. 2005;86:623-632.

Levitsky

DA.

Putting behavior back into feeding behavior: a tribute to George Collier. Appetite. 2002;38:143-148.

10.

Elmquist

Coppari

Balthasar

Ichinose

Lowell

BB.

Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol. 2005;493:63-71.

11.

Flier

JS.

Obesity wars: molecular progress confronts an expanding epidemic. Cell. 2004;116:337-350.

12.

Seeley

Woods

SC.

Monitoring of stored and available fuel by the CNS: implications for obesity. Nat Rev Neurosci. 2003;4:901-909.

13.

Woods

SC.

The control of food intake: behavioral versus molecular perspectives. Cell Metab. 2009;9:489-498.

14.

Stellar

The physiology of motivation. Psychol Rev. 1954;61:5-22.

15.

Anand

Brobeck

JR.

Hypothalamic control of food intake in rats and cats. Yale J Biol Med. 1951;24:123-140.

16.

Orskov

Poulsen

Møller

Holst

JJ.

Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I. Diabetes. 1996;45:832-835.

17.

Shapiro

Miselis

RR.

The central neural connections of the area postrema of the rat. J Comp Neurol. 1985;234:344-364.

18.

Renner

Puskás

Dobolyi

Palkovits

Glucagon-like peptide-1 of brainstem origin activates dorsomedial hypothalamic neurons in satiated rats. Peptides. 2012;35:14-22.

19.

Puskás

Papp

Gallatz

Palkovits

Interactions between orexin-immunoreactive fibers and adrenaline or noradrenaline-expressing neurons of the lower brainstem in rats and mice. Peptides. 2010;31:1589-1597.

20.

Ricardo

Koh

ET.

Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Res. 1978;153:1-26.

21.

Schwartz

Porte

Diabetes, obesity, and the brain. Science. 2005;307:375-379.

22.

Woods

Seeley

Porte

Schwartz

MW.

Signals that regulate food intake and energy homeostasis. Science. 1998;280:1378-1383.

23.

Fan

Boston

Kesterson

Hruby

Cone

RD.

Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature. 1997;385:165-168.

24.

Park

Lee

Song

Bose

Shin

Kim

HJ.

Efficacy and safety of mixed oriental herbal medicines for treating human obesity: a systematic review of randomized clinical trials. J Med Food. 2012;15:589-597.

25.

Mountjoy

KG.

Functions for pro-opiomelanocortin-derived peptides in obesity and diabetes. Biochem J. 2010;428:305-324.

26.

Pritchard

Turnbull

White

Pro-opiomelanocortin processing in the hypothalamus: impact on melanocortin signalling and obesity. J Endocrinol. 2002;172:411-421.

27.

Gantz

Miwa

Konda

, et al. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J Biol Chem. 1993;268:15174-15179.

28.

Kishi

Aschkenasi

Lee

Mountjoy

Saper

Elmquist

JK.

Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J Comp Neurol. 2003;457:213-235.

29.

Näslund

Hellström

PM.

Appetite signaling: from gut peptides and enteric nerves to brain. Physiol Behav. 2007;92:256-262.

30.

Williams

Scott

Elmquist

JK.

Modulation of the central melanocortin system by leptin, insulin, and serotonin: coordinated actions in a dispersed neuronal network. Eur J Pharmacol. 2011;660:2-12.

31.

Farooqi

Keogh

Yeo

GSH

Lank

Cheetham

O’Rahilly

Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348:1085-1095.

32.

Rossi

Balthasar

Olson

, et al. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab. 2011;13:195-204.

33.

Huszar

Lynch

Fairchild-Huntress

, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88:131-141.

34.

Lindqvist

Baelemans

Erlanson-Albertsson

Effects of sucrose, glucose and fructose on peripheral and central appetite signals. Regul Pept. 2008;150:26-32.

35.

Butler

Kesterson

Khong

, et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology. 2000;141:3518-3521.

36.

Sutton

Trevaskis

Hulver

, et al. Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or -4 receptors. Endocrinology. 2006;147:2183-2196.

37.

Butler

Marks

Fan

Kuhn

Bartolome

Cone

RD.

Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci. 2001;4:605-611.

38.

Farooqi

O’Rahilly

Genetics of obesity in humans. Endocr Rev. 2006;27:710-718.

39.

Barsh

Farooqi

O’Rahilly

Genetics of body-weight regulation. Nature. 2000;404:644-651.

40.

Yeo

GSH

Heisler

LK.

Unraveling the brain regulation of appetite: lessons from genetics. Nat Neurosci. 2012;15:1343-1349.

41.

Beck

Neuropeptide Y in normal eating and in genetic and dietary-induced obesity. Philos Trans R Soc Lond B Biol Sci. 2006;361:1159-1185.

42.

Nijenhuis

Oosterom

Adan

RA.

AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor. Mol Endocrinol. 2001;15:164-171.

43.

Kalra

Dube

Sahu

Phelps

Kalra

PS.

Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc Natl Acad Sci U S A. 1991;88:10931-10935.

44.

Stanley

Kyrkouli

Lampert

Leibowitz

SF.

Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides. 1986;7:1189-1192.

45.

Srinivasan

Lubrano-Berthelier

Govaerts

, et al. Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans. J Clin Invest. 2004;114:1158-1164.

46.

Ollmann

Wilson

Yang

, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997;278:135-138.

47.

Broberger

Johansen

Johansson

Schalling

Hökfelt

The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc Natl Acad Sci U S A. 1998;95:15043-15048.

48.

Hahn

Breininger

Baskin

Schwartz

MW.

Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci. 1998;1:271-272.

49.

Xie

Neurotrophic factor control of satiety and body weight. Nat Rev Neurosci. 2016;17:282-292.

50.

Chen

Haskell-Luevano

Cone

Smith

MS.

Altered expression of agouti-related protein and its colocalization with neuropeptide Y in the arcuate nucleus of the hypothalamus during lactation. Endocrinology. 1999;140:2645-2650.

51.

Maejima

Sedbazar

Suyama

, et al. Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway. Cell Metab. 2009;10:355-365.

52.

Arletti

Benelli

Bertolini

Influence of oxytocin on feeding behavior in the rat. Peptides. 1989;10:89-93.

53.

Renner

Szabó-Meltzer

Puskás

Tóth

Dobolyi

Palkovits

Activation of neurons in the hypothalamic dorsomedial nucleus via hypothalamic projections of the nucleus of the solitary tract following refeeding of fasted rats. Eur J Neurosci. 2010;31:302-314.

54.

Shimada

Tritos

Lowell

Flier

Maratos-Flier

Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature. 1998;396:670-674.

55.

Date

Ueta

Yamashita

, et al. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci U S A. 1999;96:748-753.

56.

Sakurai

Amemiya

Ishii

, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92:573-585.

57.

Aponte

Atasoy

Sternson

SM.

AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci. 2011;14:351-355.

58.

Palmiter

RD.

GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism. Eur J Pharmacol. 2011;660:21-27.

59.

Nonogaki

Strack

Dallman

Tecott

LH.

Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med. 1998;4:1152-1156.

60.

Berglund

Sohn

, et al. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver. Nat Neurosci. 2010;13:1457-1459.

61.

Jones

Kohno

, et al. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron. 2008;60:582-589.

62.

Raji

Becker

, et al. Obesity is linked with lower brain volume in 700 AD and MCI patients. Neurobiol Aging. 2010;31:1326-1339.

63.

Deblon

Veyrat-Durebex

Bourgoin

, et al. Mechanisms of the anti-obesity effects of oxytocin in diet-induced obese rats. PLoS One. 2011;6:e25565.

64.

Maejima

Iwasaki

Yamahara

Kodaira

Sedbazar

Yada

Peripheral oxytocin treatment ameliorates obesity by reducing food intake and visceral fat mass. Aging (Albany NY). 2011;3:1169-1177.

65.

Morton

Thatcher

Reidelberger

, et al. Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats. Am J Physiol Endocrinol Metab. 2012;302:E134-E144.

66.

Zhang

Bai

Zhang

, et al. Neuropeptide exocytosis involving synaptotagmin-4 and oxytocin in hypothalamic programming of body weight and energy balance. Neuron. 2011;69:523-535.

67.

Camerino

Low sympathetic tone and obese phenotype in oxytocin-deficient mice. Obesity (Silver Spring). 2009;17:980-984.

68.

Takayanagi

Kasahara

Onaka

Takahashi

Kawada

Nishimori

Oxytocin receptor-deficient mice developed late-onset obesity. Neuroreport. 2008;19:951-955.

69.

Kublaoui

Gemelli

Tolson

Wang

Zinn

AR.

Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice. Mol Endocrinol. 2008;22:1723-1734.

70.

Altirriba

Poher

Caillon

, et al. Divergent effects of oxytocin treatment of obese diabetic mice on adiposity and diabetes. Endocrinology. 2014;155:4189-4201.

71.

Zhang

Cai

Circadian intervention of obesity development via resting-stage feeding manipulation or oxytocin treatment. Am J Physiol Endocrinol Metab. 2011;301:E1004-E1012.

72.

Blevins

Thompson

Anekonda

, et al. Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization. Am J Physiol Regul Integr Comp Physiol. 2016;310:R640-R658.

73.

Blevins

Graham

Morton

, et al. Chronic oxytocin administration inhibits food intake, increases energy expenditure, and produces weight loss in fructose-fed obese rhesus monkeys. Am J Physiol Regul Integr Comp Physiol. 2015;308:R431-R438.

74.

Blevins

JM.

Role of oxytocin signaling in the regulation of body weight. Rev Endocr Metab Disord. 2013;14:311-329.

75.

Rinaman

Oxytocinergic inputs to the nucleus of the solitary tract and dorsal motor nucleus of the vagus in neonatal rats. J Comp Neurol. 1998;399:101-109.

76.

Sawchenko

Swanson

LW.

Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in the rat. J Comp Neurol. 1982;205:260-272.

77.

Vrang

Larsen

Kristensen

Tang-Christensen

Central administration of cocaine-amphetamine-regulated transcript activates hypothalamic neuroendocrine neurons in the rat. Endocrinology. 2000;141:794-801.

78.

Peruzzo

Pastor

Blázquez

, et al. A second look at the barriers of the medial basal hypothalamus. Exp Brain Res. 2000;132:10-26.

79.

Ciofi

The arcuate nucleus as a circumventricular organ in the mouse. Neurosci Lett. 2011;487:187-190.

80.

Rodríguez

Blázquez

Guerra

The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid. Peptides. 2010;31:757-776.

81.

Shaver

Pang

Wainman

Wall

Gross

PM.

Morphology and function of capillary networks in subregions of the rat tuber cinereum. Cell Tissue Res. 1992;267:437-448.

82.

Berthoud

HR.

The vagus nerve, food intake and obesity. Regul Pept. 2008;149:15-25.

83.

Kennedy

GC.

The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond B Biol Sci. 1953;140:578-596.

84.

Zhang

Proenca

Maffei

Barone

Leopold

Friedman

JM.

Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425-432.

85.

Wisse

Campfield

Marliss

Morais

Tenenbaum

Gougeon

Effect of prolonged moderate and severe energy restriction and refeeding on plasma leptin concentrations in obese women. Am J Clin Nutr. 1999;70:321-330.

86.

Goldstone

Brynes

Thomas

, et al. Resting metabolic rate, plasma leptin concentrations, leptin receptor expression, and adipose tissue measured by whole-body magnetic resonance imaging in women with Prader-Willi syndrome. Am J Clin Nutr. 2002;75:468-475.

87.

Cnop

Landchild

Vidal

, et al. The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations: distinct metabolic effects of two fat compartments. Diabetes. 2002;51:1005-1015.

88.

Lammert

Kiess

Bottner

Glasow

Kratzsch

Soluble leptin receptor represents the main leptin binding activity in human blood. Biochem Biophys Res Commun. 2001;283:982-988.

89.

Yang

Boucher

Modulation of direct leptin signaling by soluble leptin receptor. Mol Endocrinol. 2004;18:1354-1362.

90.

Schaab

Kausch

Klammt

, et al. Novel regulatory mechanisms for generation of the soluble leptin receptor: implications for leptin action. PLoS One. 2012;7:e34787.

91.

Schaab

Kratzsch

The soluble leptin receptor. Best Pract Res Clin Endocrinol Metab. 2015;29:661-670.

92.

Tartaglia

Dembski

Weng

, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263-1271.

93.

Chen

Charlat

Tartaglia

, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 1996;84:491-495.

94.

Berglund

Vianna

Donato

, et al. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J Clin Invest. 2012;122:1000-1009.

95.

Ste-Marie

Kaelin

Barsh

GS.

Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding. Endocrinology. 2007;148:72-80.

96.

Bates

Stearns

Dundon

, et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature. 2003;421:856-859.

97.

Kwon

Kim

MS.

Leptin signalling pathways in hypothalamic neurons. Cell Mol Life Sci. 2016;73:1457-1477.

98.

Schwartz

Peskind

Raskind

Boyko

Porte

Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med. 1996;2:589-593.

99.

Caro

Kolaczynski

Nyce

, et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet. 1996;348:159-161.

100.

Golden

Maccagnan

Pardridge

WM.

Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J Clin Invest. 1997;99:14-18.

101.

Korner

Chua

Williams

Leibel

Wardlaw

SL.

Regulation of hypothalamic proopiomelanocortin by leptin in lean and obese rats. Neuroendocrinology. 1999;70:377-383.

102.

Lee

Verma

Simonds

, et al. Leptin stimulates neuropeptide Y and cocaine amphetamine-regulated transcript coexpressing neuronal activity in the dorsomedial hypothalamus in diet-induced obese mice. J Neurosci. 2013;33:15306-15317.

103.

Meister

Control of food intake via leptin receptors in the hypothalamus. Vitam Horm. 2000;59:265-304.

104.

Mercer

Stuart

Attard

Otero-Corchon

Nillni

Low

MJ.

Temporal changes in nutritional state affect hypothalamic POMC peptide levels independently of leptin in adult male mice. Am J Physiol Endocrinol Metab. 2014;306:E904-E915.

105.

Barsh

Schwartz

MW.

Genetic approaches to studying energy balance: perception and integration. Nat Rev Genet. 2002;3:589-600.

106.

Cowley

Smart

Rubinstein

, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411:480-484.

107.

Williams

Margatho

Lee

, et al. Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J Neurosci. 2010;30:2472-2479.

108.

Cowley

Pronchuk

Fan

Dinulescu

Colmers

Cone

RD.

Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron. 1999;24:155-163.

109.

Pinto

Roseberry

Liu

, et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science. 2004;304:110-115.

110.

Mizuno

Kleopoulos

Bergen

Roberts

Priest

Mobbs

CV.

Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and [corrected] in ob/ob and db/db mice, but is stimulated by leptin. Diabetes. 1998;47:294-297.

111.

Schwartz

Seeley

Woods

, et al. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes. 1997;46:2119-2123.

112.

Thornton

Cheung

Clifton

Steiner

RA.

Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology. 1997;138:5063-5066.

113.

Benoit

Air

Coolen

, et al. The catabolic action of insulin in the brain is mediated by melanocortins. J Neurosci. 2002;22:9048-9052.

114.

Seeley

Yagaloff

Fisher

, et al. Melanocortin receptors in leptin effects. Nature. 1997;390:349.

115.

Halaas

Gajiwala

Maffei

, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269:543-546.

116.

Farooqi

Jebb

Langmack

, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341:879-884.

117.

Pelleymounter

Cullen

Baker

, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269:540-543.

118.

Ramachandrappa

Farooqi

IS.

Genetic approaches to understanding human obesity. J Clin Invest. 2011;121:2080-2086.

119.

Halaas

Boozer

Blair-West

Fidahusein

Denton

Friedman

JM.

Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A. 1997;94:8878-8883.

120.

Crujeiras

Goyenechea

Abete

, et al. Weight regain after a diet-induced loss is predicted by higher baseline leptin and lower ghrelin plasma levels. J Clin Endocrinol Metab. 2010;95:5037-5044.

121.

Knight

Hannan

Greenberg

Friedman

JM.

Hyperleptinemia is required for the development of leptin resistance. PLoS One. 2010;5:e11376.

122.

Van Heek

Compton

France

, et al. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest. 1997;99:385-390.

123.

Banks

DiPalma

Farrell

CL.

Impaired transport of leptin across the blood-brain barrier in obesity. Peptides. 1999;20:1341-1345.

124.

El-Haschimi

Pierroz

Hileman

Bjørbaek

Flier

JS.

Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest. 2000;105:1827-1832.

125.

Björnholm

Münzberg

Leshan

, et al. Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. J Clin Invest. 2007;117:1354-1360.

126.

Zabolotny

Bence-Hanulec

Stricker-Krongrad

, et al. PTP1B regulates leptin signal transduction in vivo. Dev Cell. 2002;2:489-495.

127.

Hosoi

Sasaki

Miyahara

Hashimoto

Matsuo

Yoshii

Ozawa

Endoplasmic reticulum stress induces leptin resistance. Mol Pharmacol. 2008;74:1610-1619.

128.

Ozcan

Ergin

, et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009;9:35-51.

129.

Won

Jang

Namkoong

, et al. Central administration of an endoplasmic reticulum stress inducer inhibits the anorexigenic effects of leptin and insulin. Obesity (Silver Spring). 2009;17:1861-1865.

130.

Wilsey

Scarpace

PJ.

Caloric restriction reverses the deficits in leptin receptor protein and leptin signaling capacity associated with diet-induced obesity: role of leptin in the regulation of hypothalamic long-form leptin receptor expression. J Endocrinol. 2004;181:297-306.

131.

Zhang

Scarpace

PJ.

The role of leptin in leptin resistance and obesity. Physiol Behav. 2006;88:249-256.

132.

Starr

Willson

Viney

, et al. A family of cytokine-inducible inhibitors of signalling. Nature. 1997;387:917-921.

133.

Bjorbaek

Elmquist

Frantz

Shoelson

Flier

JS.

Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell. 1998;1:619-625.

134.

Miller

Nicklas

Fernandez

Serial changes in inflammatory biomarkers after Roux-en-Y gastric bypass surgery. Surg Obes Relat Dis. 2011;7:618-624.

135.

Miller

Nicklas

Davis

Ambrosius

Loeser

Messier

SP.

Is serum leptin related to physical function and is it modifiable through weight loss and exercise in older adults with knee osteoarthritis?

Int J Obes Relat Metab Disord. 2004;28:1383-1390.

136.

Hill

Elias

Fukuda

, et al. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab. 2010;11:286-297.

137.

Woods

Lotter

McKay

Porte

Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature. 1979;282:503-505.

138.

Spanswick

Smith

Mirshamsi

Routh

Ashford

ML.

Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci. 2000;3:757-758.

139.

Newgard

Jensen

, et al. Stimulus/secretion coupling factors in glucose-stimulated insulin secretion: insights gained from a multidisciplinary approach. Diabetes. 2002;51(suppl 3):S389-S393.

140.

Polonsky

Given

Van Cauter

Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest. 1988;81:442-448.

141.

Polonsky

Given

Hirsch

, et al. Quantitative study of insulin secretion and clearance in normal and obese subjects. J Clin Invest. 1988;81:435-441.

142.

Schwartz

Woods

Porte

Jr Seeley

Baskin

DG.

Central nervous system control of food intake. Nature. 2000;661-671.

143.

Air

Benoit

Blake Smith

Clegg

Woods

SC.

Acute third ventricular administration of insulin decreases food intake in two paradigms. Pharmacol Biochem Behav. 2002;72:423-439.

144.

Chavez

Seeley

Woods

SC.

A comparison between effects of intraventricular insulin and intraperitoneal lithium chloride on three measures sensitive to emetic agents. Behav Neurosci. 1995;109:547-550.

145.

Baskin

Schwartz

Sipols

D’Alessio

Goldstein

White

MF.

Insulin receptor substrate-1 (IRS-1) expression in rat brain. Endocrinology. 1994;134:1952-1955.

146.

Banks

WA.

The blood-brain barrier as a regulatory interface in the gut-brain axes. Physiol Behav. 2006;89:472-476.

147.

Woods

Seeley

Baskin

Schwartz

MW.

Insulin and the blood-brain barrier. Curr Pharm Des. 2003;9:795-800.

148.

Air

Strowski

Benoit

, et al. Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity. Nat Med. 2002;8:179-183.

149.

Brüning

Gautam

Burks

, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289:2122-2125.

150.

Wajchenberg

BL.

Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev. 2000;21:697-738.

151.

Dua

Hennes

Hoffmann

, et al. Leptin: a significant indicator of total body fat but not of visceral fat and insulin insensitivity in African-American women. Diabetes. 1996;45:1635-1637.

152.

Pouliot

Després

Nadeau

, et al. Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes. 1992;41:826-834.

153.

Bartness

Shrestha

Vaughan

Schwartz

Song

CK.

Sensory and sympathetic nervous system control of white adipose tissue lipolysis. Mol Cell Endocrinol. 2010;318:34-43.

154.

Shi

Bartness

TJ.

White adipose tissue sensory nerve denervation mimics lipectomy-induced compensatory increases in adiposity. Am J Physiol Regul Integr Comp Physiol. 2005;289:R514-R520.

155.

Morgan

Anderson

Mark

AL.

Renal sympathetic nerve activity is increased in obese Zucker rats. Hypertension. 1995;25:834-838.

156.

Carlson

Shelton

White

Wyss

JM.

Elevated sympathetic activity contributes to hypertension and salt sensitivity in diabetic obese Zucker rats. Hypertension. 2000;35:403-408.

157.

Niijima

Afferent signals from leptin sensors in the white adipose tissue of the epididymis, and their reflex effect in the rat. J Auton Nerv Syst. 1998;73:19-25.

158.

Niijima

Reflex effects from leptin sensors in the white adipose tissue of the epididymis to the efferent activity of the sympathetic and vagus nerve in the rat. Neurosci Lett. 1999;262:125-128.

159.

Engelstoft

Egerod

Holst

Schwartz

TW.

A gut feeling for obesity: 7TM sensors on enteroendocrine cells. Cell Metab. 2008;8:447-449.

160.

Batterham

Bloom

SR.

The gut hormone peptide YY regulates appetite. Ann N Y Acad Sci. 2003;994:162-168.

161.

Halatchev

Cone

RD.

Peripheral administration of PYY(3-36) produces conditioned taste aversion in mice. Cell Metab. 2005;1:159-168.

162.

Richards

Parker

Adriaenssens

, et al. Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes. 2014;63:1224-1233.

163.

Secher

Jelsing

Baquero

, et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest. 2014;124:4473-4488.

164.

Moran

Robinson

Goldrich

McHugh

PR.

Two brain cholecystokinin receptors: implications for behavioral actions. Brain Res. 1986;362:175-179.

165.

Buchan

Polak

Solcia

Capella

Hudson

Pearse

AG.

Electron immunohistochemical evidence for the human intestinal I cell as the source of CCK. Gut. 1978;19:403-407.

166.

Liddle

Goldfine

Rosen

Taplitz

Williams

JA.

Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction. J Clin Invest. 1985;75:1144-1152.

167.

Rehfeld

Bungaard

Friis-Hansen

Goetze

JP.

On the tissue-specific processing of procholecystokinin in the brain and gut: a short review. J Physiol Pharmacol. 2003;54(suppl 4):73-79.

168.

Kissileff

Pi-Sunyer

Thornton

Smith

GP.

C-terminal octapeptide of cholecystokinin decreases food intake in man. Am J Clin Nutr. 1981;34:154-160.

169.

Ballinger

McLoughlin

Medbak

Clark

Cholecystokinin is a satiety hormone in humans at physiological post-prandial plasma concentrations. Clin Sci. 1995;89:375-381.

170.

Schwartz

GJ.

The role of gastrointestinal vagal afferents in the control of food intake: current prospects. Nutrition. 2000;16:866-873.

171.

Gibbs

Young

Smith

GP.

Cholecystokinin decreases food intake in rats. J Comp Physiol Psychol. 1973;84:488-495.

172.

Smith

GP.

Cholecystokinin and treatment of meal size: proof of principle. Obesity (Silver Spring). 2006;14(suppl 4):168S-170S.

173.

Noble

Wank

Crawley

, et al. International Union of Pharmacology. XXI. Structure, distribution, and functions of cholecystokinin receptors. Pharmacol Rev. 1999;51:745-781.

174.

French

Murray

Rumsey

Sepple

Read

NW.

Is cholecystokinin a satiety hormone? Correlations of plasma cholecystokinin with hunger, satiety and gastric emptying in normal volunteers. Appetite. 1993;21:95-104.

175.

Berthoud

HR.

Interactions between the “cognitive” and “metabolic” brain in the control of food intake. Physiol Behav. 2007;91:486-498.

176.

Moran

TH.

Gut peptides in the control of food intake: 30 years of ideas. Physiol Behav. 2004;82:175-180.

177.

Strader

Woods

SC.

Gastrointestinal hormones and food intake. Gastroenterology. 2005;128:175-191.

178.

West

Fey

Woods

SC.

Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am J Physiol. 1984;246:R776-R787.

179.

Peters

Ritter

Simasko

SM.

Leptin and CCK selectively activate vagal afferent neurons innervating the stomach and duodenum. Am J Physiol Regul Integr Comp Physiol. 2006;290:R1544-R1549.

180.

Nakazato

Murakami

Date

, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194-198.

181.

Date

Shimbara

Koda

, et al. Peripheral ghrelin transmits orexigenic signals through the noradrenergic pathway from the hindbrain to the hypothalamus. Cell Metab. 2006;4:323-331.

182.

Date

Murakami

Toshinai

, et al. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology. 2002;123:1120-1128.

183.

Horvath

Diano

Sotonyi

Heiman

Tschöp

Minireview: ghrelin and the regulation of energy balance—a hypothalamic perspective. Endocrinology. 2001;142:4163-4169.

184.

Zigman

Elmquist

JK.

Minireview: From anorexia to obesity: the yin and yang of body weight control. Endocrinology. 2003;144:3749-3756.

185.

Kojima

Hosoda

Date

Nakazato

Matsuo

Kangawa

Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656-660.

186.

Asakawa

Inui

Kaga

, et al. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology. 2001;120:337-345.

187.

Nakazato

Murakami

Date

, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194-198.

188.

Shintani

Ogawa

Ebihara

, et al. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes. 2001;50:227-232.

189.

Arvat

Di Vito

Broglio

, et al. Preliminary evidence that ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans. J Endocrinol Invest. 2000;23:493-495.

190.

Boyle

Palmiter

RD.

Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell. 2009;137:1225-1234.

191.

Wren

Seal

Cohen

, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86:5992.

192.

Lawrence

Snape

Baudoin

FMH

Luckman

SM.

Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology. 2002;143:155-162.

193.

Wren

Small

Ward

, et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology. 2000;141:4325-4328.

194.

Tschöp

Smiley

Heiman

ML.

Ghrelin induces adiposity in rodents. Nature. 2000;407:908-913.

195.

Zigman

Nakano

Coppari

, et al. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest. 2005;115:3564-3572.

196.

Tong

Jones

Elmquist

Lowell

BB.

Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci. 2008;11:998-1000.

197.

Kohno

Yada

Arcuate NPY neurons sense and integrate peripheral metabolic signals to control feeding. Neuropeptides. 2012;46:315-319.

198.

Edholm

Levin

Hellström

Schmidt

PT.

Ghrelin stimulates motility in the small intestine of rats through intrinsic cholinergic neurons. Regul Pept. 2004;121:25-30.

199.

Levin

Edholm

Ehrström

, et al. Effect of peripherally administered ghrelin on gastric emptying and acid secretion in the rat. Regul Pept. 2005;131:59-65.

200.

Cummings

Purnell

Frayo

Schmidova

Wisse

Weigle

DS.

A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50:1714-1719.

201.

Shiiya

Nakazato

Mizuta

, et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab. 2002;87:240-244.

202.

Ariyasu

Takaya

Tagami

, et al. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab. 2001;86:4753-4758.

203.

Cummings

Weigle

Frayo

, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346:1623-1630.

204.

Michel

Beck-Sickinger

Cox

, et al. XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev. 1998;50:143-150.

205.

Baldock

Allison

Lundberg

, et al. Novel role of Y1 receptors in the coordinated regulation of bone and energy homeostasis. J Biol Chem. 2007;282:19092-19102.

206.

Sainsbury

Schwarzer

Couzens

, et al. Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice. Proc Natl Acad Sci U S A. 2002;99:8938-8943.

207.

Batterham

Cowley

Small

, et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature. 2002;418:650-654.

208.

Al-Saffar

Hellström

Nylander

Correlation between peptide YY-induced myoelectric activity and transit of small-intestinal contents in rats. Scand J Gastroenterol. 1985;20:577-582.

209.

Savage

Adrian

Carolan

Chatterjee

Bloom

SR.

Effects of peptide YY (PYY) on mouth to caecum intestinal transit time and on the rate of gastric emptying in healthy volunteers. Gut. 1987;28:166-170.

210.

Symersky

Biemond

Frolich

Masclee

AAM

. Effect of peptide YY on pancreatico-biliary secretion in humans. Scand J Gastroenterol. 2005;40:944-949.

211.

Batterham

Cohen

Ellis

, et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med. 2003;349:941-948.

212.

Sam

Troke

Tan

Bewick

GA.

The role of the gut/brain axis in modulating food intake. Neuropharmacology. 2012;63:46-56.

213.

Challis

Pinnock

Coll

Carter

Dickson

O’Rahilly

Acute effects of PYY3-36 on food intake and hypothalamic neuropeptide expression in the mouse. Biochem Biophys Res Commun. 2003;311:915-919.

214.

Chelikani

Haver

Reidelberger

RD.

Intravenous infusion of peptide YY(3-36) potently inhibits food intake in rats. Endocrinology. 2005;146:879-888.

215.

Vrang

Madsen

Tang-Christensen

Hansen

Larsen

PJ.

PYY(3-36) reduces food intake and body weight and improves insulin sensitivity in rodent models of diet-induced obesity. Am J Physiol Regul Integr Comp Physiol. 2006;291:R367-R375.

216.

Vilsbøll

Holst

JJ.

Incretins, insulin secretion and Type 2 diabetes mellitus. Diabetologia. 2004;47:357-366.

217.

MacDonald

El-Kholy

Riedel

Salapatek

AMF

Light

Wheeler

MB.

The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes. 2002;51(suppl 3):S434-S442.

218.

Elliott

Morgan

Tredger

Deacon

Wright

Marks

Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns. J Endocrinol. 1993;138:159-166.

219.

Nauck

Siemsglüss

Orskov

Holst

JJ.

Release of glucagon-like peptide 1 (GLP-1 [7-36 amide]), gastric inhibitory polypeptide (GIP) and insulin in response to oral glucose after upper and lower intestinal resections. Z Gastroenterol. 1996;34:159-166.

220.

Pilichiewicz

Chaikomin

Brennan

, et al. Load-dependent effects of duodenal glucose on glycemia, gastrointestinal hormones, antropyloroduodenal motility, and energy intake in healthy men. Am J Physiol Endocrinol Metab. 2007;293:E743-E753.

221.

Pilichiewicz

Papadopoulos

Brennan

, et al. Load-dependent effects of duodenal lipid on antropyloroduodenal motility, plasma CCK and PYY, and energy intake in healthy men. Am J Physiol Regul Integr Comp Physiol. 2007;293:R2170-R2178.

222.

Todd

Edwards

Ghatei

Mather

Bloom

SR.

Subcutaneous glucagon-like peptide-1 improves postprandial glycaemic control over a 3-week period in patients with early type 2 diabetes. Clin Sci. 1998;95:325-329.

223.

Orskov

Glucagon-like peptide-1, a new hormone of the entero-insular axis. Diabetologia. 1992;35:701-711.

224.

Holst

JJ.

The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87:1409-1439.

225.

Naslund

Bogefors

Skogar

, et al. GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans. Am J Physiol. 1999;277:R910-R916.

226.

Nauck

Niedereichholz

Ettler

, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 1997;273:E981-E988.

227.

Merchenthaler

Lane

Shughrue

Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J Comp Neurol. 1999;403:261-280.

228.

Jin

Han

Simmons

Towle

Lauder

Lund

PK.

Distribution of glucagonlike peptide I (GLP-I), glucagon, and glicentin in the rat brain: an immunocytochemical study. J Comp Neurol. 1988;271:519-532.

229.

Barrera

Sandoval

D’Alessio

Seeley

RJ.

GLP-1 and energy balance: an integrated model of short-term and long-term control. Nat Rev Endocrinol. 2011;7:507-516.

230.

Turton

O’Shea

Gunn

, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996;379:69-72.

231.

Scrocchi

Brown

MaClusky

, et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med. 1996;2:1254-1258.

232.

Hansotia

Maida

Flock

, et al. Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J Clin Invest. 2007;117:143-152.

233.

Tang-Christensen

Vrang

Larsen

PJ.

Glucagon-like peptide containing pathways in the regulation of feeding behaviour. Int J Obes Relat Metab Disord. 2001;25(suppl 5):S42-S47.

234.

McMahon

Wellman

PJ.

PVN infusion of GLP-1-(7-36) amide suppresses feeding but does not induce aversion or alter locomotion in rats. Am J Physiol. 1998;274:R23-R29.

235.

Sandoval

Bagnol

Woods

D’Alessio

Seeley

RJ.

Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes. 2008;57:2046-2054.

236.

Ranganath

Beety

Morgan

Wright

Howland

Marks

Attenuated GLP-1 secretion in obesity: cause or consequence?

Gut. 1996;38:916-919.

237.

Meeran

O’Shea

Edwards

, et al. Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat. Endocrinology. 1999;140:244-250.

238.

Schjoldager

Mortensen

Myhre

Christiansen

Holst

JJ.

Oxyntomodulin from distal gut. Role in regulation of gastric and pancreatic functions. Dig Dis Sci. 1989;34:1411-1419.

239.

Wynne

Park

Small

, et al. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes. 2005;54:2390-2395.

240.

Wynne

Park

Small

, et al. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int J Obes (Lond). 2006;30:1729-1736.

241.

Dakin

Gunn

Small

, et al. Oxyntomodulin inhibits food intake in the rat. Endocrinology. 2001;142:4244-4250.

242.

Dakin

Small

Batterham

, et al. Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology. 2004;145:2687-2695.

243.

Cowan

Burch

Green

Grieve

DJ.

Obestatin as a key regulator of metabolism and cardiovascular function with emerging therapeutic potential for diabetes. Br J Pharmacol. 2016;173:2165-2181.

244.

Shimizu

Oh-I

Hashimoto

, et al. Peripheral administration of nesfatin-1 reduces food intake in mice: the leptin-independent mechanism. Endocrinology. 2009;150:662-671.

245.

Shimizu

Ohsaki

Oh-I

Okada

Mori

A new anorexigenic protein, nesfatin-1. Peptides. 2009;30:995-998.

246.

Iwasaki

Nakabayashi

Kakei

Shimizu

Mori

Yada

Nesfatin-1 evokes Ca²⁺ signaling in isolated vagal afferent neurons via Ca2+ influx through N-type channels. Biochem Biophys Res Commun. 2009;390:958-962.

247.

Crawley

Beinfeld

MC.

Rapid development of tolerance to the behavioural actions of cholecystokinin. Nature. 1983;302:703-706.

248.

Heymsfield

Greenberg

Fujioka

, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999;282:1568-1575.

249.

Erondu

Wadden

Gantz

, et al. Effect of NPY5R antagonist MK-0557 on weight regain after very-low-calorie diet-induced weight loss. Obesity (Silver Spring). 2007;15:895-905.

250.

Tan

Behary

Tharakan

, et al. The effect of a subcutaneous infusion of GLP-1, OXM and PYY on energy intake and expenditure in obese volunteers [published online April 4, 2017]. J Clin Endocrinol Metab. doi:10.1210/jc.2017-00469.

251.

Perry

Wang

Appetite regulation and weight control: the role of gut hormones. Nutr Diabetes. 2012;2:e26.

252.

Williams

Elmquist

JK.

From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat Neurosci. 2012;15:1350-1355.

253.

Vinik

Maser

Mitchell

Freeman

Diabetic autonomic neuropathy. Diabetes Care. 2003;26:1553-1579.

254.

Kentish

Philp

, et al. Diet-induced adaptation of vagal afferent function. J Physiol (Lond). 2012;590:209-221.

255.

Naznin

Toshinai

Waise

TMZ

, et al. Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation. J Endocrinol. 2015;226:81-92.

256.

Waise

TMZ

Toshinai

Naznin

, et al. One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice. Biochem Biophys Res Commun. 2015;464:1157-1162.

257.

Jordan

Könner

Brüning

JC.

Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis. Cell Mol Life Sci. 2010;67:3255-3273.

258.

Belgardt

Brüning

JC.

CNS leptin and insulin action in the control of energy homeostasis. Ann N Y Acad Sci. 2010;1212:97-113.

259.

Altman

Rutledge

JC.

The vascular contribution to Alzheimer’s disease. Clin Sci. 2010;119:407-421.

260.

Anthony

Reed

Dunn

, et al. Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance: the cerebral basis for impaired control of food intake in metabolic syndrome? Diabetes. 2006;55:2986-2892.

261.

Näslund

Grybäck

Backman

, et al. Distal small bowel hormones: correlation with fasting antroduodenal motility and gastric emptying. Dig Dis Sci. 1998;43:945-952.

262.

Enriori

Evans

Sinnayah

, et al. Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metab. 2007;5:181-194.

263.

Münzberg

Flier

Bjørbaek

Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology. 2004;145:4880-4889.

264.

Münzberg

Björnholm

Bates

Myers

MG.

Leptin receptor action and mechanisms of leptin resistance. Cell Mol Life Sci. 2005;62:642-652.

265.

Lin

Thomas

Storlien

Huang

XF.

Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice. Int J Obes Relat Metab Disord. 2000;24:639-646.

266.

Thaler

Schur

, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest. 2012;122:153-162.

267.

Huang

Han

Storlien

LH.

The level of NPY receptor mRNA expression in diet-induced obese and resistant mice. Brain Res Mol Brain Res. 2003;115:21-28.

268.

Huang

Xin

McLennan

Storlien

Role of fat amount and type in ameliorating diet-induced obesity: insights at the level of hypothalamic arcuate nucleus leptin receptor, neuropeptide Y and pro-opiomelanocortin mRNA expression. Diabetes Obes Metab. 2004;6:35-44.

269.

Carvajal

Wadden

Tsai

Peck

Moran

CH.

Managing obesity in primary care practice: a narrative review. Ann N Y Acad Sci. 2013;1281:191-206.

270.

Bray

Frühbeck

Ryan

Wilding

JPH

. Management of obesity. Lancet. 2016;387:1947-1956.

271.

Farooqi

Wangensteen

Collins

, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356:237-247.

272.

Farooqi

O’Rahilly

Monogenic obesity in humans. Annu Rev Med. 2005;56:443-458.

273.

Santoro

Mattace Raso

Meli

Drug targeting of leptin resistance. Life Sci. 2015;140:64-74.

274.

Bhavsar

Watkins

Young

Synergy between amylin and cholecystokinin for inhibition of food intake in mice. Physiol Behav. 1998;64:557-561.

275.

Roth

Roland

Cole

, et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci USA. 2008;105:7257-7262.

276.

Trevaskis

Coffey

Cole

, et al. Amylin-mediated restoration of leptin responsiveness in diet-induced obesity: magnitude and mechanisms. Endocrinology. 2008;149:5679-5687.

277.

Williams

Baskin

Schwartz

MW.

Leptin regulation of the anorexic response to glucagon-like peptide-1 receptor stimulation. Diabetes. 2006;55:3387-3393.

278.

Roujeau

Jockers

Dam

New pharmacological perspectives for the leptin receptor in the treatment of obesity. Front Endocrinol (Lausanne). 2014;5:167.

279.

Kaszubska

Falls

Schaefer

, et al. Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line. Mol Cell Endocrinol. 2002;195:109-118.

280.

Reed

Unger

Olofsson

Piper

Myers

AW.

Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis. Diabetes. 2010;59:894-906.

281.

Ravussin

Smith

Mitchell

, et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring). 2009;17:1736-1743.

282.

Müller

Sullivan

Habegger

, et al. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. J Pept Sci. 2012;18:383-393.

283.

Khera

Murad

Chandar

, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA. 2016;315:2424-2434.

284.

Smith

Weissman

Anderson

, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363:245-256.

285.

Yumuk

Tsigos

Fried

, et al. European guidelines for obesity management in adults. Obes Facts. 2015;8:402-424.

286.

Holst

JJ.

Incretin hormones and the satiation signal. Int J Obes (Lond). 2013;37:1161-1168.

287.

Troke

Tan

Bloom

SR.

The future role of gut hormones in the treatment of obesity. Ther Adv Chronic Dis. 2014;5:4-14.

288.

Marso

Bain

Consoli

, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844.

289.

Marso

Daniels

Brown-Frandsen

, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-322.

290.

Colbert

Jangi

Training physicians to manage obesity: back to the drawing board. N Engl J Med. 2013;369:1389-1391.

291.

Lawson

Marengi

DeSanti

Holmes

Schoenfeld

Tolley

CJ.

Oxytocin reduces caloric intake in men. Obesity (Silver Spring). 2015;23:950-956.

292.

Iwasaki

Maejima

Suyama

, et al. Peripheral oxytocin activates vagal afferent neurons to suppress feeding in normal and leptin-resistant mice: a route for ameliorating hyperphagia and obesity. Am J Physiol Regul Integr Comp Physiol. 2015;308:R360-R369.

293.

Borowsky

Durkin

Ogozalek

, et al. Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat Med. 2002;8:825-830.

294.

Ito

Ishihara

Gomori

, et al. Melanin-concentrating hormone 1-receptor antagonist suppresses body weight gain correlated with high receptor occupancy levels in diet-induced obesity mice. Eur J Pharmacol. 2009;624:77-83.

295.

Maglione

, et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med. 2005;142:532-546.

296.

Maayan

Vakhrusheva

Correll

CU.

Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis. Neuropsychopharmacology. 2010;35:1520-1530.

297.

Gadde

Franciscy

Wagner

Krishnan

KRR

. Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA. 2003;289:1820-1825.

298.

Singh-Franco

Perez

Harrington

The effect of pramlintide acetate on glycemic control and weight in patients with type 2 diabetes mellitus and in obese patients without diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2011;13:169-180.

299.

Chen

Muniyappa

Abel

, et al. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab. 2015;100:1639-1645.

300.

Martinussen

Bojsen-Moller

Svane

Dejgaard

Madsbad

Emerging drugs for the treatment of obesity. Expert Opin Emerg Drugs. 2017;22:87-99.

301.

Balthasar

Dalgaard

Lee

, et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell. 2005;123:493-505.

302.

Astrup

Madsbad

Breum

Jensen

Kroustrup

Larsen

TM.

Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1906-1913.

303.

Gilbert

Gasteyger

Raben

Meier

Astrup

Sjödin

The effect of tesofensine on appetite sensations. Obesity (Silver Spring). 2012;20:553-561.

304.

Zinman

Wanner

Lachin

, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.

305.

Joharapurkar

Dhanesha

Jain

MR.

Inhibition of the methionine aminopeptidase 2 enzyme for the treatment of obesity. Diabetes Metab Syndr Obes. 2014;7:73-84.

306.

Watts

Manchem

, et al. Peripheral reduction of FGFR4 with antisense oligonucleotides increases metabolic rate and lowers adiposity in diet-induced obese mice. PLoS One. 2013;8:e66923.

307.

Timmers

Konings

Bilet

, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011;14:612-622.

308.

Omori

Kouyama

Yukimasa

, et al. Hit to lead SAR study on benzoxazole derivatives for an NPY Y5 antagonist. Bioorg Med Chem Lett. 2012;22:2020-2023.

309.

Tschöp

Finan

Clemmensen

, et al. Unimolecular polypharmacy for treatment of diabetes and obesity. Cell Metab. 2016;24:51-62.

Appetite Regulation: Hormones,Peptides,and Neurotransmitters and Their Role in Obesity

Abstract

Keywords

Role of the Brain

Peripheral Signals

Leptin

Insulin

Gut Hormones

CCK

Ghrelin

PYY

GLP-1

Oxyntomodulin

Obestatin

Nesfatin

Altered Pathways in Obesity

Obesity Therapeutics

Summary

Footnotes

Declaration of Conflicting Interests

Funding

References