Sage Journals: Discover world-class research

Abstract

As the prevalence of obesity continues to rise globally, the research on adipocytes has attracted more and more attention. In the presence of nutrient overload, adipocytes are exposed to pressures such as hypoxia, inflammation, mechanical stress, metabolite, and oxidative stress that can lead to organelle dysfunction. Endoplasmic reticulum (ER) is a vital organelle for sensing cellular pressure, and its homeostasis is essential for maintaining adipocyte function. Under conditions of excess nutrition, ER stress (ERS) will be triggered by the gathering of abnormally folded proteins in the ER lumen, resulting in the activation of a signaling response known as the unfolded protein responses (UPRs), which is a response system to relieve ERS and restore ER homeostasis. However, if the UPRs fail to rescue ER homeostasis, ERS will activate pathways to damage cells. Studies have shown a role for disturbed activation of adipocyte ERS in the pathophysiology of obesity and its complications. Prolonged or excessive ERS in adipocytes can aggravate lipolysis, insulin resistance, and apoptosis and affect the bioactive molecule production. In addition, ERS also impacts the expression of some important genes. In view of the fact that ERS influences adipocyte function through various mechanisms, targeting ERS may be a viable strategy to treat obesity. This article summarizes the effects of ERS on adipocytes during obesity.

Keywords

adipocyte endoplasmic reticulum stress inflammation insulin resistance lipolysis obesity

Introduction

Obesity is one of the most prevalent health issues in modern society, which places a heavy burden on society.¹ In 2022, the World Health Organization (WHO) announced epidemiological data showing that obesity is widespread in different age groups worldwide, including 39 million children, 340 million adolescents, and 650 million adults, totaling more than 1 billion obese individuals. WHO estimates that approximately 167 million people will suffer from overweight or obese by 2025.² Both being overweight and obese have serious adverse effects on the occurrence and development of various diseases in different organs, such as type 2 diabetes mellitus (T2DM), cardiovascular and cerebrovascular diseases, non-alcoholic fatty liver disease (NAFLD), musculoskeletal diseases, chronic kidney disease (CKD), inflammatory bowel diseases, Alzheimer’s disease, cancers, sleep apnea, as well as mental health problems.^3–5 Therefore, obesity poses a huge threat to human health.

The main feature of obesity is the expansion of white adipose tissue (WAT) accompanied by dysfunction, which is caused by a long-term imbalance between energy intake and expenditure. WAT is a major storage for excess energy and an endocrine organ, containing subcutaneous fat and visceral fat.⁶ Perivascular adipose tissue (PVAT) is a special type of adipose tissue surrounding blood vessels that not only serves as a mechanical support for the vascular system but also plays a crucial role in the homeostasis of the vascular system. PVAT exhibits WAT, brown adipose tissue (BAT), and mixed phenotypes depending on their anatomical location. In abdominal PVAT, WAT is more abundant, while thoracic PVAT contains more BAT. These regional differences in PVAT are consistent with the clinical phenomenon that the abdominal aorta is more prone to atherosclerosis than the thoracic aorta. Obesity leads to elevated oxidative stress, and inflammatory and hypoxic states, which result in PVAT dysfunction.^7,8 Abdominal obesity formed by visceral fat dilation is a significant risk factor for metabolic syndrome and the pathological basis for the body in a state of chronic low-grade inflammation and insulin resistance (IR).^9,10 WAT is made up of generous adipocytes and extracellular matrix component (EMC), as well as a few other cell types. Adipocyte is the main component of WAT and is absolutely dominant in size.¹¹ Therefore, impaired adipocyte function is the most direct, initial, and major manifestation of WAT dysfunction.

The endoplasmic reticulum (ER) is an important organelle that has the function of synthesizing, folding, and transporting proteins, as well as being responsible for lipid synthesis and calcium homeostasis.^12,13 As a pressure sensor, the accumulation of abnormally folded proteins in the ER lumen leads to the imbalance of ER homeostasis. In the excess energy states such as obesity and T2DM, where adipocytes are exposed to multiple stresses such as hypoxia, inflammation, mechanical stress, metabolite, and oxidative stress, complex signaling networks called the unfolded protein responses (UPRs) in adipocytes are activated, including transcriptional induction of ER chaperones and translation attenuation, thus triggering a series of ER stress (ERS) responses.^14–16 The UPRs signaling pathways consist of three typical branches: inositol-requiring enzyme 1 and X-box binding protein 1 (IRE1-XBP1), protein kinase R-like endoplasmic reticulum kinase and eukaryotic initiation factor 2α (PERK-eIF2α), and activating transcription factor 6 (ATF6).^17–19 Although ERS is conducive to eliminate the accretion of misfolded/unfolded proteins, prolonged or excessive ERS promotes the development of programmed cell death and interferes with normal cellular function. Activation of ERS is strongly associated with many metabolic diseases, such as obesity and NAFLD, making ERS a promising therapeutic target for these diseases.^20,21 ERS is a momentous factor contributing to the dysfunction of hypertrophic adipocytes, which causes abnormalities in WAT.²² Currently, increasing evidence supporting a causal link between ERS and adipocyte dysfunction in obesity has been reported. However, there is a lack of comprehensive review about the impact of ERS on adipocytes during obesity. Hence, there is a need to review the existing research to draw more attention and provide thoughts for exploration.

ERS and lipolysis

Pro-inflammatory cytokines and excessive metabolites such as free fatty acid (FFA) derived from WAT enter the bloodstream and flow to other organs, bringing about metabolic damage to tissues and eventually progressing to various complications, such as NAFLD, cardiovascular diseases, and T2DM.^23–25 In mammals, fatty acids are stored in adipocytes in the form of triacylglycerol (TG), which constructs the main energy reserve. The hydrolysis of TG in adipocytes, known as lipolysis, generates glycerol and FFA. Lipolysis is regulated by multiple signaling pathways and is a complex process in adipocytes in which TG is catabolized to glycerol and FFA catalyzed by lipolytic enzymes.^26–28 Due to the lack of glycerol kinase in regular adipocytes, glycerol is rarely reused to resynthesis TG; instead, it is released into the bloodstream along with FFA to provide energy for different tissues. Adipocyte lipolysis is a crucial procedure for controlling the plasma FFA concentration and modulating metabolic homeostasis via the Randle glucose-fatty acid cycle.²⁹ The abnormalities in lipolysis pathways lead to the increase of circulating FFA, which can contribute to lipotoxicity and IR in obesity. ERS can regulate adipocyte lipolysis. cAMP-dependent protein kinase A (PKA) and extracellular signal-regulated kinase-1/2 (ERK1/2) are major signals adjusting lipolysis.^30–33 In the PKA-stimulated downstream lipolytic cascade, the key to complete activation of hormone-sensitive lipase (HSL) is the phosphorylation of HSL and lipid droplet-associated protein perilipin A, and then the transfer of HSL from the cytoplasm to the surface of lipid droplet.³⁴ Adipose triglyceride lipase (ATGL) is another vital lipolytic enzyme that may be indirectly activated in PKA-mediated lipolysis.³⁵ Lipolysis-derived FFA may amplify the WAT lipolysis, inflammation, and IR by activating toll-like receptor 4 in immune and non-immune cells to release more pro-inflammatory cytokines.³⁶ The research on adipocyte lipolysis discussed below is not limited to obesity, to provide broader research perspectives.

During obesity, the inflammatory response of adipocytes is dependent or independent of ERS. Inflammation, ERS, and lipolysis in adipocytes can form malignant interactions. The inflammatory response is the downstream of ERS. Inflammatory cytokines can exacerbate ERS and promote adipocyte lipolysis, releasing excessive FFA, which in turn enhances adipocyte inflammatory response and ERS, starting a vicious cycle.^37,38 Tumor necrosis factor α (TNF-α) has been reported to promote lipolysis in differentiated human adipocytes through activation of ERK signal and elevation of intracellular cAMP, as activated cAMP-dependent PKA leads to hyperphosphorylation of perilipin.³⁹ Foley et al. showed that inhibiting IRE1 kinase activity was sufficient to block adipocyte-autonomous lipolysis from multiple inflammatory ligands. They suggested that IRE1 kinase activity, rather than RNase activity, regulated inflammation-induced adipocyte lipolysis, that is, independent of typical UPR signal.⁴⁰ Xia et al. found that the chemical chaperone tauroursodeoxycholic acid (TUDCA) inhibited TNF-α-stimulated ERS and lipolysis in 3T3-L1 adipocytes. Its potential mechanism might be related to the inhibition of the IRE-c-Jun N-terminal kinase (JNK) signaling pathway, which influenced the expression of perilipin A.⁴¹ Wang et al. reported that administration of curcumin or TUDCA inhibited ERS-related lipolysis induced by the high-fat diet feeding, at least in part via suppression of cAMP/PKA/HSL signal.⁴² The ERS inducer tunicamycin has been reported to induce lipolysis in cultured human adipocytes.⁴³ Deng et al. explored the effect of ERS inducers on lipolysis in rat adipocytes, demonstrating that ERS elicits lipolysis by activating cAMP/PKA and ERK1/2 signals in adipocytes.⁴⁴ In addition to mammals, ERS was found to promote cAMP/PKA signal-mediated lipolysis and apoptosis of adipocytes in grass carp. ⁴⁵ Amiodarone is an antiarrhythmic drug with hepatotoxicity. Hubel et al. established a mouse model of repetitive amiodarone administration. Amiodarone-caused liver injury was at least partly due to induced ERS-dependent lipolysis in epididymis WAT (eWAT), which increased circulating FFA level, resulting in increased hepatotoxic FFA accumulation. Besides, amiodarone up-regulated the phosphorylation of JNK and the expression of its downstream target TNF-α in eWAT.⁴⁶ 4-phenyl butyric acid (PBA) is a chemical chaperone known to reduce ERS in vitro and in vivo. Xiong et al. established a rat model of high-altitude hypoxia using a hypobaric chamber and found that hypoxia exposure displayed significant ERS and lipolysis in WAT. Treatment with PBA effectively reduced hypoxia-induced lipolysis via cAMP-PKA-HSL/perilipin pathway.⁴⁷ The accumulation of asymmetrical dimethylarginine (ADMA) is common in advanced CDK. Zhou et al. reported that ADMA induced lipolysis in 3T3-L1 adipocytes by reducing perilipin-A expression, rather than affecting the expression or activity of lipases. ADMA also promoted the expression of inflammatory cytokines such as TNF-α, interleukin (IL)-6, and monocyte chemotactic protein-1 (MCP-1) via activating nuclear factor-κB (NF-κB). Blocking ADMA-caused inflammatory responses with NF-κB inhibitor also partially inhibited the lipolysis. Treatment with ERS inhibitor completely eliminated ADMA-triggered lipolysis and inflammatory responses in cultured adipocytes.⁴⁸ Zhu et al. found that in a rat model of CKD constructed via a five-sixths nephrectomy, visceral WAT underwent enhanced lipolysis and ERS, while PBA markedly alleviated lipolysis, mainly by blocking the activation of ATGL.⁴⁹

The ER is rich in chaperones and oxidoreductases that control proper protein folding and ER-related degradation of abnormally folded proteins. The lipotoxic of FFA and overproduction of reactive oxygen species (ROS) disrupt the redox state of the ER, increasing the frequency of abnormally folded proteins.⁵⁰ The major pathways of oxidative protein folding consist of ER oxidoreductase 1 (Ero1) and the protein disulfide isomerase (PDI) family. Normally, Ero1 re-oxidizes and re-activates PDI to promote the formation of disulfide bonds, thus improving protein folding. However, this process consumes O₂ and produces H₂O₂, and over-activation of the Ero1-PDI system can lead to ER peroxidation, which in turn exacerbates ERS.^51–53 Homocysteine is a noxious sulfur-containing amino acid produced in the process of methionine metabolism.⁵⁴ Yan et al. established a hyperhomocysteinemia (HHcy) mouse model fed with a high-methionine diet and demonstrated that homocysteine activated lipolysis in WAT through activating HIF1α/ERO1α-dependent ER overoxidation and ERS, which released excess FFA and the FFA was eventually absorbed by hepatocytes, leading to hepatic steatosis.⁵⁵ The above ERS-related lipolysis models of adipocytes or adipose tissue are listed in Table 1.

Table 1.

Human, mouse or cell models of ERS-related lipolysis.

Model type	Inducer of ERS	The signal molecules involved in lipolysis
3T3-L1 adipocyte⁴¹	TNF-α	IRE-JNK signal-mediated decline in perilipin-A expression
Mouse model⁴²	A high-fat diet	cAMP/PKA-mediated phosphorylation of HSL
Human adipocyte⁴³	Tunicamycin	Not mentioned
Rat adipocyte⁴⁴	Thapsigargin; tunicamycin; brefeldin A	cAMP/PKA and ERK1/2 signals accompanied by phosphorylation of perilipin and HSL and activation of cellular lipases
Mouse model⁴⁶	Amiodarone	Increased the level of p-HSL
Rat model⁴⁷	Using hypobaric chamber to establish high-altitude hypoxia	cAMP/PKA signal-mediated phosphorylation of perilipin and HSL
3T3-L1 adipocyte⁴⁸	Asymmetrical dimethylarginine	Decreased perilipin-A expression; No alteration of lipase expression or activity
Rat model⁴⁹	A five-sixths nephrectomy to establish chronic kidney disease	Activation of ATGL
Mouse model⁵⁵	A high-methionine diet	Increased the level of ATGL and p-HSL

ERS, Endoplasmic reticulum stress.

ERS and IR

ERS has been considered an important mechanism of obesity-related IR.^56,57 In general, insulin activates cellular procedures by binding to the insulin receptor on the cytomembrane, mediating the activation of insulin receptor tyrosine kinases and subsequent tyrosine phosphorylation of downstream signal molecules such as insulin receptor substrate (IRS) proteins, which then activate the phosphatidylinositol 3-kinase (PI3K) signal pathway, ultimately contributing to insulin signal transduction. ^58,59 Li et al. found that ERS inducer tunicamycin caused the autophagy defect and impaired insulin sensitivity in adipocytes, partly due to the upregulation of IRE1-JNK pathway, which is a direct repressor of cytoplasmic insulin signaling, as the activated JNK pathway can phosphorylate IRS-1 at Ser307. Moreover, the autophagy defect further aggravated ERS and IR.⁶⁰ Zhou et al. reported that ERS downregulated insulin receptors in adipocytes via autophagy-dependent ER-related degradation, but had little effect on insulin receptor tyrosine phosphorylation, thereby inhibiting the downstream signal of the insulin receptor. They found that pretreatment with ER chemical chaperone rescued tunicamycin-induced ERS, insulin receptor reduction, and IR in adipocytes. Although the autophagy inhibitor 3-methyladenine significantly alleviated the decreased insulin receptor induced by ERS, it could not save the downstream signal of insulin receptor in adipocytes, which is consistent with the fact that ERS also affects insulin signaling through other mechanisms.⁶¹

GLUT4 is an insulin-responsive glucose transporter. When insulin binds to its receptor, it starts a series of events that cause GLUT4 to transfer from the intracellular chamber and insert into the plasma membrane.^62,63 In adipocytes, the attenuated insulin sensitivity in obesity and T2DM is due to the insulin-stimulated GLUT4 translocation defect and decreased expression.^64,65 It has been found that activation of ERS in adipocytes repressed GLUT4 expression at the gene transcriptional level, possibly by increasing the expression of CAAT/enhancer binding protein homologous protein-10 (CHOP10).⁶⁶ The CHOP10 protein has marked homology with other CAAT/enhancer binding proteins (C/EBPs), and it can interact dominantly and negatively with other C/EBPs to inhibit the transcription of their targets.⁶⁷ CHOP10 is a suppressor of C/EBPα activity and expression, while C/EBPα is an activator of GLUT4 expression.^68,69 This suggests that adipocyte ERS activation inhibits GLUT4 expression as an additional mechanism benefiting IR in obesity. ERp44 is a member of the PDI family that preferentially assists in the intracellular localization of ER enzymes lacking the ER retention motif and recognizes folded proteins in the secretion pathway.^70,71 Ubc9 is the only E2 conjugating enzyme in the post-translational modified SUMO system. Xie et al. found that overnutrition increased the Ubc9 level in adipocytes and underwent SUMOylation conversion. Adipocyte-specific Ubc9 deletion protected mice from high-fat diet-induced obesity and IR by alleviating ERS in WAT.⁷² Mechanistically, ERp44 showed the highest change in SUMOylation level of ER-related substrates after palmitic acid stimulated adipocytes. Loss of Ubc9 led to the deficiency of SUMOylation in ERp44, enhancing its degradation and inhibiting its covalent binding to Ero1α, an oxidase present in the ER but lacking ER retention motif, thereby relieving lipotoxic-induced ERS by boosting the secretion of Ero1α.^73,74 Intestinal hormone glucagon-like peptide 1 (GLP-1) is effective in improving blood glucose in T2DM.⁷⁵ GLP-1 has been reported to reduce the expression of ATF4 and CHOP by curbing the mTOR signaling pathway, thereby ameliorating ERS-induced impairment of insulin signaling in adipocytes.⁷⁶ Progranulin is an important growth factor that promotes IR. Guo et al reported that progranulin enhanced adipocyte autophagy-mediated insulin sensitivity reduction in adipocytes, at least partially via activating oxidative stress and ERS.⁷⁷

ERS and adipokines

Except for storing excess energy, WAT is also an active endocrine tissue that secretes bioactive molecules, including unique adipokines and conventional cytokines. Secretory profile of hypertrophic adipocytes is shifted toward the pro-inflammatory spectrum.^78,79 ERS participates in adjusting the expression of multiple bioactive molecules in adipocytes (Table 2). Resistin is an adipokine that damages glucose metabolism.⁸⁰ In rodents, resistin is almost entirely derived from adipocytes. In obese mice, the circulating resistin level is increased, but its gene expression in WAT is paradoxically decreased.^81,82 Martina et al. found that ERS decreases the gene transcription of resistance in adipocytes, concerning at least three transcription factors. The action of ERS on resistin transcript level in adipocytes appears to be a joint result of reducing the expression of activated transcription factors, including C/EBPα and peroxisome proliferator-activated receptor (PPARγ), and increasing the expression of inhibitory factors such as CHOP10.⁸³ Adpsin is an adipokine that can maintain insulin secretion function of β-cells to improve glucose tolerance.⁸⁴ The lightened transcription of Adipsin in adipocytes of obese mice has relevance to ERS-mediated downregulation of PPARγ.⁸⁵ Takashi et al reported that adipolin is an anti-inflammatory and insulin-sensitive adipokine, which is reduced in WAT and plasma of obese rodent models. Palmitic acid and ERS inducers significantly inhibit adipolin transcription in adipocytes.⁸⁶ Adiponectin is a protective adipocytokine with the effects of anti-inflammation, anti-apoptosis, and promoting insulin sensitivity. The expression and secretion of adiponectin are dropped in adipocytes in obesity.⁸⁷ ERS is relevant to modulating adiponectin expression.⁸⁸ WAT is in a hypoxic state during obesity, which activates the PERK and IRE1 signal pathways in adipocytes, thus suppressing adiponectin expression by activating ERS.⁸⁹ The hypoxia-caused decline of adiponectin is also mediated by CHOP, which attenuates the transcriptional activity of adiponectin promoter. The RNA interference of CHOP partially rescued the inhibition of adiponectin transcription induced by hypoxia in adipocytes.⁹⁰ In addition, ERS can diminish adiponectin levels through advancing autophagy-dependent degradation of adiponectin.⁹¹ As the chaperone protein, PDI family heavily exists in the ER and is markedly induced by the UPRs.⁹² PDIA4 pertains to the PDI family. The lessening of adiponectin expression in adipocytes stimulated by palmitate was concerned with the upregulation of PDIA4. Pharmacological and genetic disturbance of PDIA4 could rescue the adiponectin expression in hypertrophic adipocytes.⁹³

Table 2.

Effect of ERS on the expression of bioactive molecules.

Gene name	Role in obesity	Expression regulated by ERS
Resistin	Adverse	Downregulation
Adpsin	Protective	Downregulation
Adipolin	Protective	Downregulation
Adiponectin	Protective	Downregulation
TNF-α/MCP-1/IL-6/IL-1β	Adverse	Upregulation

ERS, Endoplasmic reticulum stress.

Apart from adipokines, ERS alters the production of pro-inflammatory cytokines in adipocytes during obesity.⁷⁹ ER chemical chaperones can effectively abolish adipocyte ERS and downstream inflammatory response triggered by multiple stimuli. ERS inducer thapsigargin stimulates adipocytes to produce monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and TNF-α.⁹⁴ ERS inducer tunicamycin also provokes adipocytes to generate TNF-α and IL-6, which are blocked by ER chemical chaperones.⁹⁵ ERS in adipocytes can also be activated by FFA. The pivotal downstream target of FFA-caused ERS is IκB kinase β (IKKβ), a major mediator in regulating inflammation and IR. Both ER chemical chaperone and PERK deletion can weaken the activation of IKKβ in adipocytes to interrupt FFA-induced expression of TNF-α and IL-6, and improve insulin signal.³⁷ Oxidized low-density lipoprotein promotes the expression of TNF-α and MCP-1 by activating adipocyte ERS.⁹⁶ Homocysteine can promote MCP-1 and TNF-α expression in part through activating ERS in adipocytes, thus impairing insulin signaling.⁹⁷ In hypertrophic adipocytes, autophagy is inhibited, which can activate ERS-mediated inflammation, resulting in increased expression of MCP-1, IL-6, and IL-1β.⁹⁸ Homeobox a5 (Hoxa5) is a noteworthy transcription factor abundantly expressed in WAT.⁹⁹ Cao et al. reported that a high-fat diet decreased the Hoxa5 expression in WAT. Hoxa5 acted to attenuate adipocyte ERS and inflammatory responses by blocking the PERK-eIF2α signaling pathway.¹⁰⁰ During obesity, the abnormal accumulation of EMC in WAT is involved in WAT inflammation and fibrosis, in which collagen XV is very abundant.¹⁰¹ Focal adhesion kinase (FAK) is the main downstream moderator of integrin β1, which is phosphorylated and activated upon binding of integrin β1 to EMC proteins.^102,103 It has been shown that the FAK-PI3K-Ca2+ signal pathway was enabled by connecting with α3β1 integrin.¹⁰⁴ Li et al. have demonstrated that collagen XV caused intracellular Ca²⁺ imbalance by activating the integrin β1/FAK axis, which triggered ERS mainly the IRE1α-XBP1 pathway, thus promoting the production of inflammatory cytokines.¹⁰⁵

ERS and apoptosis

ERS is associated with adipocyte apoptosis. Huang et al. reported that docosahexaenoic acid (DHA) induced apoptosis of grass carp adipocytes through ERS, and B-cell lymphoma-2-related ovarian killer (BOK) may be an important link between ERS and apoptosis. BOK is considered to be a pro-apoptotic member of the BCL-2 family, handling the mitochondrial apoptosis pathway. DHA significantly increased the transcript of BOK, which was blocked by the ERS inhibitor.¹⁰⁶ Beclin-1 is a basic composition of the class III PI3K complex, which is necessary for autophagosome formation and vesicle transport. Ablation of Beclin-1 in adipocytes has made them more sensitive to the ERS-stimulated apoptotic signal. The inhibition of ERS by Beclin-1 is a crucial player in maintaining adipocyte survival and WAT homeostasis in obesity.¹⁰⁷ ERS triggered adipocyte apoptosis by increasing intracellular FFA and Ca²⁺ levels. Adiponectin was able to attenuate ERS-induced adipocyte apoptosis by activating the AMPK signaling pathway via binding to adiponectin receptors and inhibiting ATF2 transcription through upregulation of PPARα.¹⁰⁸

ERS and mitochondrial dysfunction

There is a cross-talk between the ER and mitochondria, which are closely linked both physically and functionally.¹⁰⁹ Laura Jacksch et al. treated human differentiated adipocytes from Chub-S7 cell line and primary abdominal subcutaneous adipocytes from lean and obese individuals with tunicamycin to induce ERS and evaluate mitochondrial function. Chronic ERS caused by obesity leads to increased oxidative stress, and decreased antioxidant protection, as well as inefficient mitochondrial oxidative capacity, diminished membrane potential, and increased mitochondrial fragmentation in human adipocytes. These human data indicate that adipocyte mitochondrial inefficiency is driven by ERS and aggravated during obesity. Adipocyte ERS induced by overnutrition can lead to mitochondrial dysfunction.¹¹⁰ Nisha et al. found that treatment of 3T3-L1 adipocytes with tunicamycin significantly increased intracellular ROS and reduced mitochondrial biosynthesis.¹¹¹ Manuel et al. found that the active-site cysteines of PDI were succinated during glucotoxicity-caused mitochondrial stress, diminishing PDI oxidoreductase activity and induced protein folding disorder, which led to increased ERS in adipocytes under the high glucose condition and in the epididymal WAT of db/db mice. After targeting mitochondrial stress in adipocytes under high glucose conditions with the chemical uncoupler niclosamide, PAI protein succination, and ERS were reduced. Succination of PDI can link mitochondrial stress and ERS in adipocytes during diabetes.¹¹²

ERS and other functions

ERS adjusts the expression of some important genes in adipocytes. PPARα is a ligand-dependent transcription factor that regulates genes associated with lipid metabolism, and PPARα expression is reduced in WAT of obese mice.¹¹³ Studies have shown that activation of the PPARα signal in adipocytes may ameliorate obesity.^114,115 Jungin et al. investigated the regulatory mechanism of PPARα gene transcription in adipocytes under inflammatory conditions. They found that nitric oxide (NO) secreted by activated macrophages downregulated PPARα expression in adipocytes, at least partially by inducing ERS. NO-mediated ERS in adipocytes decreased the occupation of transcription factor Sp1 at the binding site in the proximal promoter region of PPARα, then inhibiting the transcription of PPARα.¹¹⁶ As a key protein for adipocytes to integrate inflammation and metabolism, the six transmembrane proteins of prostate 2 (STAMP2) play an important role in maintaining metabolic homeostasis. Mice with STAMP2 gene deletion in visceral fat developed spontaneous metabolic disease even on a normal diet.¹¹⁷ ERS inducers could markedly decrease STAMP2 expression in adipocytes. In mechanism, C/EBPα directly bound to and activated the STAMP2 promoter, while ERS reduced Stamp2 transcription by lessening the expression of C/EBPα.¹¹⁸ Nuclear transcription factor-Y A (NF-YA) is an evolutionarily conserved transcription factor that can regulate the expression of adipocyte-specific genes. It has been reported that ERS inhibited NF-YA expression in adipocytes at the transcriptional level, which may be related to the decrease of PPARγ. Activation of PPARγ could alleviate the inhibition of NF-YA expression by ERS.¹¹⁹ The transcriptional regulator TRIP-Br2 is specifically up-regulated in obese visceral fat. TRIP-Br2 deficiency can protect mice from obesity and related complications.¹²⁰ Qiang et al. found that the TRIP-Br2 expression in obese visceral adipocytes was regulated by inflammatory cytokines and FFA-activated ERS. ERS promoted TRIP-Br2 expression by up-regulating the transcription factor GATA3. In turn, the increase of TRIP-Br2 further facilitated ERS-induced inflammatory response.¹²¹ Fatty acid–binding protein 4 (FABP4) is highly expressed in adipocytes and primarily controls lipid metabolism pathways. As a lipid chaperone, FABP4 is secreted along with lipolysis in adipocytes. Raised circulating FABP4 level is pertinent to obesity.^122,123 The relationship between Chlamydia pneumoniae infection and metabolic syndrome has been demonstrated.^124,125 Nirwana et al. investigated that Chlamydia pneumoniae infection caused ERS in adipocytes, which promoted lipolysis-related FABP4 secretion by eliciting elevated mitochondrial ROS and cytosolic Ca2+. Chlamydia pneumoniae-induced lipolysis and FABP4 secretion were inhibited by utilizing the ER chemical chaperone, CHOP gene silencing, and mitochondrial ROS scavenger. Moreover, ERS inducers also promoted FABP4 secretion in adipocytes.¹²⁶

ERS in adipocytes as a potential target for obesity management

Inhibiting ERS could be a therapeutic intervention against the morphological and functional alterations of overall adipose tissue depots in obesity. The ERS inhibitor TUDCA, as a bile acid conjugated to taurine with chemical chaperone activity, has emerged as a therapeutic strategy to minimize obesity-related adipose tissue dysfunction and metabolic disorders. TUDCA has been approved by the US administration for clinical application of cholelithiasis and cholestatic liver disease. Thus, TUDCA treatment may also be a feasible therapeutic agent for obesity management.¹²⁷ Due to the limited amount of human subcutaneous adipose tissue (SAT) biopsies, peripheral blood mononuclear cells (PBMCs) can be used as surrogate cells for studying metabolic syndrome, diabetes, and obesity. Abdelkrim Khadi et al. collected SAT and PBMCs from nondiabetes human lean and obese subjects at baseline and after physical exercise. Obese individuals had higher levels of ERS markers in SAT and PBMCs compared to lean individuals and could be improved by physical exercise. This suggests that regular moderate physical exercise could be an effective non-pharmacological approach to alleviate ERS and maintain metabolic homeostasis.¹²⁸ Sandra et al. reported that after receiving calorie restriction, obese individuals lost weight, raised insulin sensitivity, and reduced serum inflammation levels, as well as decreased ERS in PBMCs.¹²⁹ Gregor et al. collected SAT samples from obese subjects before and 1 year after gastric bypass surgery and found that after the surgery, the subjects experienced weight loss and improved insulin sensitivity. The ERS markers of SAT significantly decreased with weight loss, indicating that weight loss is also a considerable method of mitigating ERS in adipose tissue of obese subjects.¹³⁰ In general, Pharmacological regulators of ERS or weight loss including physical exercise, dietary interventions, and surgery may be promising clinical options for relieving ERS in adipose tissue and obesity management.

Current limitations of knowledge and future directions

Since ERS in adipose tissue is primarily afflicted by obesity, the development of novel treatments for obesity may provide new insights into mitigating ERS. Although pharmacological inhibitors of ERS have therapeutic potential as new targets for metabolic diseases, obesity is adjusted by multiple factors and variables, making it a highly complicated disease for which a single therapeutic approach is usually less effective. The current lifestyle management strategies such as caloric restriction and physical activity are often inadequate. In addition to lifestyle changes, treatments for obesity generally include pharmacotherapy and bariatric surgery.¹³¹ Pharmacotherapeutics contain anti-inflammatory drugs, antioxidant agents, lipid-lowering medications, and anti-obesity medications. Moreover, alternative strategies for confronting obesity are being explored, including regulation of the gut microbiome, anti-obesity vaccines, and gene therapy. With the continuous research and understanding of the pathophysiological mechanism of obesity, personalized and multimodal obesity treatment will be the future direction.¹³²

Conclusion

On a global scale, the gradual increase in the prevalence of obesity over the past several decades is regarded as a serious threat to public health. The rising obesity epidemic and its related complications have made adipocytes an important topic of scientific research and a target for therapeutic intervention. The ER controls the correct folding of peptides and proteins through a variety of chaperones and enzymes on its membrane. When the overloaded protein folding exceeds the processing capacity, the ER folding process will be disordered, leading to the accumulation of misfolded/unfolded proteins in the ER lumen and ultimately triggering ERS. With the progression of obesity, excessive or sustained ERS disrupts adipocyte functions, including lipolysis, IR, apoptosis, bioactive molecule production, mitochondrial dysfunction, and impacting the expression of some important genes, thereby affecting WAT (Figure 1). Growing evidence implies that severe ERS in adipocytes plays a crucial role in the pathogenesis of obesity-related metabolic diseases, and alleviating ERS in adipocytes may be a potential target for obesity management.

Figure 1.

The effects of ERS on the hypertrophic adipocyte.

Footnotes

Acknowledgements

We would like to thank the BioRender website () for its templates.

Declarations

ORCID iD

Yu-Yu Yao

References

Chew

NWS

Tan

DJH

, et al. The global burden of metabolic disease: Data from 2000 to 2019. Cell Metab 2023; 35(3): 414–428 e3.

World Obesity Day 2022 – Accelerating action to stop obesity. https://www.who.int/news/item/04-03-2022-world-obesity-day-2022-accelerating-action-to-stop-obesity (accessed 24 July 2024).

Stanek

Grygiel-Gorniak

Brozyna-Tkaczyk

, et al. The influence of dietary interventions on arterial stiffness in overweight and obese subjects. Nutrients 2023; 15(6): 1440.

Adolph

Meyer

Jukic

, et al. Heavy arch: from inflammatory bowel diseases to metabolic disorders. Gut 2024; 73(8): 1376–1387.

Weijie

Meng

Chunxiao

, et al. Obesity-induced chronic low-grade inflammation in adipose tissue: a pathway to Alzheimer’s disease. Ageing Res Rev 2024; 99: 102402.

Sakers

De Siqueira

Seale

, et al. Adipose-tissue plasticity in health and disease. Cell 2022; 185(3): 419–446.

Stanek

Brozyna-Tkaczyk

Myslinski

The role of obesity-induced perivascular adipose tissue (PVAT) dysfunction in vascular homeostasis. Nutrients 2021; 13(11): 3843.

Agabiti-Rosei

Paini

De Ciuceis

, et al. Modulation of vascular reactivity by perivascular adipose tissue (PVAT). Curr Hypertens Rep 2018; 20(5): 44.

Susca

Leone

Prete

, et al. Adipose failure through adipocyte overload and autoimmunity. Autoimmun Rev 2023; 23(3): 103502.

10.

Perdomo

Aviles-Olmos

Dicker

, et al. Towards an adiposity-related disease framework for the diagnosis and management of obesities. Rev Endocr Metab Disord 2023; 24(5): 795–807.

11.

Bradley

Deng

Shantaram

, et al. Orchestration of the adipose tissue immune landscape by adipocytes. Annu Rev Physiol 2024; 86: 199–223.

12.

Farese

Jr. Walther

TC.

Glycerolipid synthesis and lipid droplet formation in the endoplasmic reticulum. Cold Spring Harb Perspect Biol 2023; 15(5): a041246.

13.

Arruda

Parlakgul

Endoplasmic reticulum architecture and inter-organelle communication in metabolic health and disease. Cold Spring Harb Perspect Biol 2023; 15(2): a041261.

14.

AlZaim

de Rooij

Sheikh

, et al. The evolving functions of the vasculature in regulating adipose tissue biology in health and obesity. Nat Rev Endocrinol 2023; 19(12): 691–707.

15.

Kim

Lee

, et al. Endoplasmic reticulum stress and its impact on adipogenesis: molecular mechanisms implicated. Nutrients 2023; 15(24): 5082.

16.

Han

Tian

Wang

, et al. LncRNA SNHG14/miR-497a-5p/BACE1 axis modulates obesity-induced adipocyte inflammation and endoplasmic reticulum stress. J Biochem Mol Toxicol 2023; 37(6): e23343.

17.

Ajoolabady

Lebeaupin

, et al. ER stress and inflammation crosstalk in obesity. Med Res Rev 2023; 43(1): 5–30.

18.

Ajoolabady

Liu

Klionsky

, et al. ER stress in obesity pathogenesis and management. Trends Pharmacol Sci 2022; 43(2): 97–109.

19.

Menikdiwela

Torres Guimaraes

Ramalingam

, et al. Mechanisms linking endoplasmic reticulum (ER) stress and microRNAs to adipose tissue dysfunction in obesity. Crit Rev Biochem Mol Biol 2021; 56(5): 455–481.

20.

Lemmer

Willemsen

Hilal

, et al. A guide to understanding endoplasmic reticulum stress in metabolic disorders. Mol Metab 2021; 47: 101169.

21.

Celik

Lee

SYT

Yap

, et al. Endoplasmic reticulum stress and lipids in health and diseases. Prog Lipid Res 2023; 89: 101198.

22.

Cinti

Obese adipocytes have altered redox homeostasis with metabolic consequences. Antioxidants (Basel) 2023; 12(7): 1449.

23.

Gunasekar

Heebink

Carpenter

, et al. Adipose-targeted SWELL1 deletion exacerbates obesity- and age-related nonalcoholic fatty liver disease. JCI Insight 2023; 8(5): e154940.

24.

Polkinghorne

West

Antoniades

Adipose tissue in cardiovascular disease: From basic science to clinical translation. Annu Rev Physiol 2024; 86: 175–198.

25.

Ullah

Ud Din

Ding

, et al. A narrative review: CXC chemokines influence immune surveillance in obesity and obesity-related diseases: type 2 diabetes and nonalcoholic fatty liver disease. Rev Endocr Metab Disord 2023; 24(4): 611–631.

26.

Grabner

Xie

Schweiger

, et al. Lipolysis: cellular mechanisms for lipid mobilization from fat stores. Nat Metab 2021; 3(11): 1445–165.

27.

Preston

Scalia

Autieri

MV.

Adipocyte phenotype flexibility and lipid dysregulation. Cells 2022; 11(5): 882.

28.

Wang

Nguyen

Xue

, et al. ApoL6 associates with lipid droplets and disrupts Perilipin1-HSL interaction to inhibit lipolysis. Nat Commun 2024; 15(1): 186.

29.

Camastra

Ferrannini

Role of anatomical location, cellular phenotype and perfusion of adipose tissue in intermediary metabolism: a narrative review. Rev Endocr Metab Disord 2022; 23(1): 43-50.

30.

Song

Hogstrand

Wei

, et al. Endoplasmic reticulum (ER) stress and cAMP/PKA pathway mediated Zn-induced hepatic lipolysis. Environ Pollut 2017; 228: 256–264.

31.

Hong

Song

Zushin

, et al. Phosphorylation of Beta-3 adrenergic receptor at serine 247 by ERK MAP kinase drives lipolysis in obese adipocytes. Mol Metab 2018; 12: 25–38.

32.

van Krieken

Roos

Fischer-Posovszky

, et al. Oncostatin M promotes lipolysis in white adipocytes. Adipocyte 2022; 11(1): 315–324.

33.

Zechner

Kienesberger

Haemmerle

, et al. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores. J Lipid Res 2009; 50(1): 3–21.

34.

Abe

Sato

Murotomi

Sudachitin and nobiletin stimulate lipolysis via activation of the cAMP/PKA/HSL pathway in 3T3-L1 adipocytes. Foods 2023; 12(10): 1947.

35.

Sun

Bian

, et al. PKA/ATGL signaling pathway is involved in ER stress-mediated lipolysis in adipocytes of grass carp (Ctenopharyngodon idella). Fish Physiol Biochem 2022; 48(3): 683–691.

36.

Gentile

Magnacca

de Matteis

, et al. Ablation of uncoupling protein 3 affects interrelated factors leading to lipolysis and insulin resistance in visceral white adipose tissue. FASEB J 2022; 36(5): e22325.

37.

Jiao

Feng

, et al. FFA-induced adipocyte inflammation and insulin resistance: involvement of ER stress and IKKbeta pathways. Obesity (Silver Spring) 2011; 19(3): 483–491.

38.

Feingold

Doerrler

Dinarello

, et al. Stimulation of lipolysis in cultured fat cells by tumor necrosis factor, interleukin-1, and the interferons is blocked by inhibition of prostaglandin synthesis. Endocrinology 1992; 130(1): 10–16.

39.

Zhang

Halbleib

Ahmad

, et al. Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes 2002; 51(10): 2929–2935.

40.

Foley

Chen

Barra

, et al. Inflammation promotes adipocyte lipolysis via IRE1 kinase. J Biol Chem 2021; 296: 100440.

41.

Xia

Zhou

Wang

, et al. Tauroursodeoxycholic acid inhibits TNF-alpha-induced lipolysis in 3T3-L1 adipocytes via the IRE-JNK-perilipin-A signaling pathway. Mol Med Rep 2017; 15(4): 1753–1758.

42.

Wang

Zhang

Huang

, et al. Curcumin inhibits lipolysis via suppression of ER stress in adipose tissue and prevents hepatic insulin resistance. J Lipid Res 2016; 57(7): 1243–1255.

43.

Bogdanovic

Kraus

Patsouris

, et al. Endoplasmic reticulum stress in adipose tissue augments lipolysis. J Cell Mol Med 2015; 19(1): 82–91.

44.

Deng

Liu

Zou

, et al. Lipolysis response to endoplasmic reticulum stress in adipose cells. J Biol Chem 2012; 287(9): 6240–6249.

45.

Huang

Bian

, et al. DHA induces adipocyte lipolysis through endoplasmic reticulum stress and the cAMP/PKA signaling pathway in grass carp (Ctenopharyngodon idella). Anim Nutr 2023; 13: 185–196.

46.

Hubel

Fishman

Holopainen

, et al. Repetitive amiodarone administration causes liver damage via adipose tissue ER stress-dependent lipolysis, leading to hepatotoxic free fatty acid accumulation. Am J Physiol Gastrointest Liver Physiol 2021; 321(3): G298–G307.

47.

Xiong

Wang

Xiong

, et al. 4-PBA inhibits hypoxia-induced lipolysis in rat adipose tissue and lipid accumulation in the liver through regulating ER stress. Food Sci Nutr 2023; 11(3): 1223–1231.

48.

Zhou

Hou

, et al. Asymmetrical dimethylarginine triggers lipolysis and inflammatory response via induction of endoplasmic reticulum stress in cultured adipocytes. Am J Physiol Endocrinol Metab 2009; 296(4): E869–E878.

49.

Zhu

Chen

, et al. The effect of inhibition of endoplasmic reticulum stress on lipolysis in white adipose tissue in a rat model of chronic kidney disease. Acta Pharmacol Sin 2014; 35(3): 356–362.

50.

Choi

, et al. Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes. Exp Mol Med 2017; 49(2): e291.

51.

Shergalis

Bankhead

3rd , et al. Role of the ERO1-PDI interaction in oxidative protein folding and disease. Pharmacol Ther 2020; 210: 107525.

52.

Wang

CC.

Oxidative protein folding fidelity and redoxtasis in the endoplasmic reticulum. Trends Biochem Sci 2023; 48(1): 40–52.

53.

Jha

Kumari

Manickam

, et al. ERO1-PDI Redox signaling in health and disease. Antioxid Redox Signal 2021; 35(13): 1093–115.

54.

Koklesova

Mazurakova

Samec

, et al. Homocysteine metabolism as the target for predictive medical approach, disease prevention, prognosis, and treatments tailored to the person. EPMA J 2021; 12(4): 477–505.

55.

Yan

Wang

, et al. Homocysteine promotes hepatic steatosis by activating the adipocyte lipolysis in a HIF1alpha-ERO1alpha-dependent oxidative stress manner. Redox Biol 2020; 37: 101742.

56.

Fernandes-da-Silva

Miranda

Santana-Oliveira

, et al. Endoplasmic reticulum stress as the basis of obesity and metabolic diseases: focus on adipose tissue, liver, and pancreas. Eur J Nutr 2021; 60(6): 2949–2960.

57.

Villalobos-Labra

Subiabre

Toledo

, et al. Endoplasmic reticulum stress and development of insulin resistance in adipose, skeletal, liver, and foetoplacental tissue in diabesity. Mol Aspects Med 2019; 66: 49–61.

58.

Kubota

Kadowaki

Imbalanced insulin actions in obesity and Type 2 diabetes: Key mouse models of insulin signaling pathway. Cell Metab 2017; 25(4): 797–810.

59.

Boura-Halfon

Zick

Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab 2009; 296(4): E581–E591.

60.

Zhou

, et al. The reciprocal interaction between autophagic dysfunction and ER stress in adipose insulin resistance. Cell Cycle 2014; 13(4): 565–579.

61.

Zhou

Zhang

Fang

, et al. Autophagy-mediated insulin receptor down-regulation contributes to endoplasmic reticulum stress-induced insulin resistance. Mol Pharmacol 2009; 76(3): 596–603.

62.

Calejman

Doxsey

Fazakerley

, et al. Integrating adipocyte insulin signaling and metabolism in the multi-omics era. Trends Biochem Sci 2022; 47(6): 531–546.

63.

Cheatham

GLUT4 and company: SNAREing roles in insulin-regulated glucose uptake. Trends Endocrinol Metab 2000; 11(9): 356–361.

64.

Watson

Kanzaki

Pessin

JE.

Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes. Endocr Rev 2004; 25(2): 177–204.

65.

Kraus

Yang

Kong

, et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature 2014; 508(7495): 258–262.

66.

Miller

Diaczok

Cooke

DW.

Repression of GLUT4 expression by the endoplasmic reticulum stress response in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2007; 362(1): 188–92.

67.

Ron

Habener

JF.

CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev 1992; 6(3): 439–453.

68.

Tang

Lane

MD.

Role of C/EBP homologous protein (CHOP-10) in the programmed activation of CCAAT/enhancer-binding protein-beta during adipogenesis. Proc Natl Acad Sci USA 2000; 97(23): 12446–12450.

69.

Cha

Oak

Kang

, et al. Phosphorylation of CCAAT/enhancer-binding protein alpha regulates GLUT4 expression and glucose transport in adipocytes. J Biol Chem 2008; 283(26): 18002–18011.

70.

Amagai

Yamada

Kowada

, et al. Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface. Nat Commun 2023; 14(1): 2683.

71.

Tempio

Orsi

Sicari

, et al. A virtuous cycle operated by ERp44 and ERGIC-53 guarantees proteostasis in the early secretory compartment. iScience 2021; 24(3): 102244.

72.

Xie

Wang

Liu

, et al. SUMOylation of ERp44 enhances Ero1alpha ER retention contributing to the pathogenesis of obesity and insulin resistance. Metabolism 2023; 139: 155351.

73.

Watanabe

Harayama

Kanemura

, et al. Structural basis of pH-dependent client binding by ERp44, a key regulator of protein secretion at the ER-Golgi interface. Proc Natl Acad Sci USA 2017; 114(16): E3224–E3232.

74.

Zhang

Zhu

Wang

, et al. Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1alpha. EMBO J 2018; 37(14): e98699.

75.

Nauck

Muller

TD.

Incretin hormones and type 2 diabetes. Diabetologia 2023; 66(10): 1780–1795.

76.

Jiang

Wang

, et al. GLP-1 Improves adipocyte insulin sensitivity following induction of endoplasmic reticulum stress. Front Pharmacol 2018; 9: 1168.

77.

Guo

, et al. Retraction note: progranulin causes adipose insulin resistance via increased autophagy resulting from activated oxidative stress and endoplasmic reticulum stress. Lipids Health Dis 2022; 21(1): 136.

78.

Blaszczak

Jalilvand

Hsueh

WA.

Adipocytes, innate immunity and obesity: a mini-review. Front Immunol 2021; 12: 650768.

79.

Maurizi

Della Guardia

Maurizi

, et al. Adipocytes properties and crosstalk with immune system in obesity-related inflammation. J Cell Physiol 2018; 233(1): 88–97.

80.

Kim

, et al. The roles and associated mechanisms of adipokines in development of metabolic syndrome. Molecules 2022; 27(2): 334.

81.

Oliveira

LDC

Morais

de Oliveira

, et al. Intermittent fasting combined with exercise training reduces body mass and alleviates hypothalamic disorders induced by high-fat diet intake. J Nutr Biochem 2023; 119: 109372.

82.

Way

Gorgun

Tong

, et al. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 2001; 276(28): 25651–2563.

83.

Lefterova

Mullican

Tomaru

, et al. Endoplasmic reticulum stress regulates adipocyte resistin expression. Diabetes 2009; 58(8): 1879–1886.

84.

Gomez-Banoy

Guseh

, et al. Adipsin preserves beta cells in diabetic mice and associates with protection from type 2 diabetes in humans. Nat Med 2019; 25(11): 1739–1747.

85.

Ryu

Jeon

Leem

, et al. Regulation of adipsin expression by endoplasmic reticulum stress in adipocytes. Biomolecules 2020; 10(2): 314.

86.

Enomoto

Ohashi

Shibata

, et al. Adipolin/C1qdc2/CTRP12 protein functions as an adipokine that improves glucose metabolism. J Biol Chem 2011 ;286(40): 34552–34558.

87.

da Silva Rosa

Liu

Sweeney

Adiponectin synthesis, secretion and extravasation from circulation to interstitial space. Physiology (Bethesda) 2021; 36(3): 134–149.

88.

Torre-Villalvazo

Bunt

Aleman

, et al. Adiponectin synthesis and secretion by subcutaneous adipose tissue is impaired during obesity by endoplasmic reticulum stress. J Cell Biochem 2018; 119(7): 5970–5984.

89.

Guo

Jin

, et al. Hypoxia in 3T3-L1 adipocytes suppresses adiponectin expression via the PERK and IRE1 unfolded protein response. Biochem Biophys Res Commun 2017; 493(1): 346–351.

90.

Hosogai

Fukuhara

Oshima

, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 2007; 56(4): 901–911.

91.

Zhou

Liu

Autophagy: roles in obesity-induced ER stress and adiponectin downregulation in adipocytes. Autophagy 2010; 6(8): 1196–1197.

92.

Perri

Thomas

Parakh

, et al. The unfolded protein response and the role of protein disulfide isomerase in neurodegeneration. Front Cell Dev Biol 2015; 3: 80.

93.

Chien

Chen

, et al. PDIA4, a novel ER stress chaperone, modulates adiponectin expression and inflammation in adipose tissue. Biofactors 2022; 48(5): 1060–1075.

94.

Park

CY.

1,25-dihydroxyvitamin D(3) affects thapsigargin-induced endoplasmic reticulum stress in 3T3-L1 adipocytes. Nutr Res Pract 2024; 18(1): 1–18.

95.

Kawasaki

Asada

Saito

, et al. Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Sci Rep 2012; 2: 799.

96.

Chen

Zhao

SP.

Simvastatin inhibits ox-LDL-induced inflammatory adipokines secretion via amelioration of ER stress in 3T3-L1 adipocyte. Biochem Biophys Res Commun 2013; 432(2): 365–369.

97.

Zhang

Jiang

, et al. Hyperhomocysteinemia promotes insulin resistance by inducing endoplasmic reticulum stress in adipose tissue. J Biol Chem 2013; 288(14): 9583–9592.

98.

Yoshizaki

Kusunoki

Kondo

, et al. Autophagy regulates inflammation in adipocytes. Biochem Biophys Res Commun 2012; 417(1): 352–357.

99.

Parrillo

Spinelli

Longo

, et al. The transcription factor HOXA5: novel insights into metabolic diseases and adipose tissue dysfunction. Cells 2023; 12(16): 2090.

100.

Cao

Zhang

Feng

, et al. Hoxa5 alleviates obesity-induced chronic inflammation by reducing ER stress and promoting M2 macrophage polarization in mouse adipose tissue. J Cell Mol Med 2019; 23(10): 7029–7042.

101.

Xia

Shen

Cai

, et al. ColXV aggravates adipocyte apoptosis by facilitating abnormal extracellular matrix remodeling in mice. Int J Mol Sci 2020; 21(3): 959.

102.

Pietila

Gonzalez-Molina

Moyano-Galceran

, et al. Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance. Nat Commun 2021; 12(1): 3904.

103.

Berrazouane

Boisvert

Salti

, et al. Beta1 integrin blockade overcomes doxorubicin resistance in human T-cell acute lymphoblastic leukemia. Cell Death Dis 2019; 10(5): 357.

104.

Tang

Zhao

, et al. Overexpression of HAb18G/CD147 promotes invasion and metastasis via alpha3beta1 integrin mediated FAK-paxillin and FAK-PI3K-Ca2+ pathways. Cell Mol Life Sci 2008; 65(18): 2933–2942.

105.

Liu

, et al. Collagen XV promotes ER stress-induced inflammation through activating integrin beta1/FAK signaling pathway and M1 macrophage polarization in adipose tissue. Int J Mol Sci 2021; 22(18): 9997.

106.

Huang

Bian

, et al. The endoplasmic reticulum stress and B cell lymphoma-2 related ovarian killer participate in docosahexaenoic acid-induced adipocyte apoptosis in grass carp (Ctenopharyngodon idellus). J Anim Sci 2023; 101: skad101.

107.

Jin

Song

, et al. Depletion of adipocyte Becn1 leads to lipodystrophy and metabolic dysregulation. Diabetes 2021; 70(1): 182–195.

108.

Liu

Gan

, et al. Adiponectin reduces ER stress-induced apoptosis through PPARalpha transcriptional regulation of ATF2 in mouse adipose. Cell Death Dis 2016; 7(11): e2487.

109.

Elwakiel

Mathew

Isermann

The role of endoplasmic reticulum-mitochondria-associated membranes in diabetic kidney disease. Cardiovasc Res 2024; 119(18): 2875–2883.

110.

Jackisch

Murphy

Kumar

, et al. Tunicamycin-induced endoplasmic reticulum stress mediates mitochondrial dysfunction in human adipocytes. J Clin Endocrinol Metab 2020; 105(9): dgaa258.

111.

Nisha

Anusree

Priyanka

, et al. Apigenin and quercetin ameliorate mitochondrial alterations by tunicamycin-induced ER stress in 3T3-L1 adipocytes. Appl Biochem Biotechnol 2014; 174(4): 1365–1375.

112.

Manuel

Walla

Faccenda

, et al. Succination of protein disulfide isomerase links mitochondrial stress and endoplasmic reticulum stress in the adipocyte during diabetes. Antioxid Redox Signal 2017; 27(16): 1281–1296.

113.

Goto

Lee

Teraminami

, et al. Activation of peroxisome proliferator-activated receptor-alpha stimulates both differentiation and fatty acid oxidation in adipocytes. J Lipid Res 2011; 52(5): 873–884.

114.

Yao

Yang

Huang

, et al. Phytochemical wedelolactone reverses obesity by prompting adipose browning through SIRT1/AMPK/ PPARalpha pathway via targeting nicotinamide N-methyltransferase. Phytomedicine 2022; 94: 153843.

115.

Hinds

Jr. Kipp

, et al. Adipose-specific PPARalpha knockout mice have increased lipogenesis by PASK-SREBP1 signaling and a polarity shift to inflammatory macrophages in white adipose tissue. Cells 2021; 11(1): 4.

116.

Kwon

Aoki

Takahashi

, et al. Inflammation-induced nitric oxide suppresses PPARalpha expression and function via downregulation of Sp1 transcriptional activity in adipocytes. Biochim Biophys Acta Gene Regul Mech 2023; 1866(4): 194987.

117.

Wellen

Fucho

Gregor

, et al. Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis. Cell 2007; 129(3): 537–548.

118.

Sikkeland

Lindstad

Nenseth

, et al. Inflammation and ER stress differentially regulate STAMP2 expression and localization in adipocytes. Metabolism 2019; 93: 75–85.

119.

Liu

Zhang

, et al. Obesity-induced endoplasmic reticulum stress suppresses nuclear factor-Y expression. Mol Cell Biochem 2017; 426(1–2): 47–54.

120.

Liew

Boucher

Cheong

, et al. Ablation of TRIP-Br2, a regulator of fat lipolysis, thermogenesis and oxidative metabolism, prevents diet-induced obesity and insulin resistance. Nat Med 2013; 19(2): 217–26.

121.

Qiang

Kong

Fang

, et al. The obesity-induced transcriptional regulator TRIP-Br2 mediates visceral fat endoplasmic reticulum stress-induced inflammation. Nat Commun 2016; 7: 11378.

122.

Prentice

Saksi

Hotamisligil

GS.

Adipokine FABP4 integrates energy stores and counterregulatory metabolic responses. J Lipid Res 2019; 60(4): 734–740.

123.

Gargari

Mukhopadhyay

Saboo

, et al. Fabkin and glucose homeostasis. Diabetes Metab Syndr 2022; 16(8): 102565.

124.

Rodriguez

Plascencia-Villa

Witt

, et al. Chlamydia pneumoniae promotes dysfunction of pancreatic beta cells. Cell Immunol 2015; 295(2): 83–91.

125.

Wang

Gao

Kaltenboeck

Acute Chlamydia pneumoniae reinfection accelerates the development of insulin resistance and diabetes in obese C57BL/6 mice. J Infect Dis 2009; 200(2): 279–287.

126.

Walenna

Kurihara

Chou

, et al. Chlamydia pneumoniae infection-induced endoplasmic reticulum stress causes fatty acid-binding protein 4 secretion in murine adipocytes. J Biol Chem 2020; 295(9): 2713–2723.

127.

Freitas

da Silva

Jr. de Oliveira

, et al. Insights by which TUDCA is a potential therapy against adiposity. Front Endocrinol (Lausanne) 2023; 14: 1090039.

128.

Khadir

Kavalakatt

Abubaker

, et al. Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone. Metabolism 2016; 65(9): 1409–1420.

129.

Lopez-Domenech

Abad-Jimenez

Iannantuoni

, et al. Moderate weight loss attenuates chronic endoplasmic reticulum stress and mitochondrial dysfunction in human obesity. Mol Metab 2019; 19: 24–33.

130.

Gregor

Yang

Fabbrini

, et al. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 2009; 58(3): 693–700.

131.

Wharton

Lau

DCW

Vallis

, et al. Obesity in adults: a clinical practice guideline. CMAJ 2020; 192(31): E875–E91.

132.

Yang

Chen

Zhang

, et al. Therapeutic targeting of white adipose tissue metabolic dysfunction in obesity: mechanisms and opportunities. MedComm (2020) 2024; 5(6): e560.

Excessive or sustained endoplasmic reticulum stress: one of the culprits of adipocyte dysfunction in obesity

Abstract

Keywords

Introduction

ERS and lipolysis

ERS and IR

ERS and adipokines

ERS and apoptosis

ERS and mitochondrial dysfunction

ERS and other functions

ERS in adipocytes as a potential target for obesity management

Current limitations of knowledge and future directions

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References