New Clues and New Questions regarding Leptin and Brain Metabolism

The hormone leptin, which circulates in proportion to body fat, has a role in glucose homeostasis and food intake regulation thought to be mediated centrally through activation of specific hypothalamic nuclei (Koch et al, 2011; Scherer and Buettner, 2011). Recent data show that leptin improves glucose homeostasis by increasing hypothalamic insulin sensitivity (Koch et al, 2011). There is a crucial need to understand the mechanisms and targets of leptin's actions since this hormone acts via neuronal receptors to decrease food intake and increase energy expenditure (Williams and Schwartz, 2011). Insights into these mechanisms may provide new targets for controlling obesity.

In the arcuate nucleus, leptin stimulates the anorexiogenic proopiomelanocortin/cocaine and amphetamine regulated transcript neurons, and inhibits the orexiogenic (increasing food intake) compounds neuropeptide Y/agouti-related protein (Williams and Schwartz, 2011). Less is known about how leptin affects other pathways including the GABAergic, glutamatergic, and dopaminergic systems (Scherer and Buettner, 2011; Vong et al, 2011).

Understanding the dynamics and players involved in hypothalamic metabolism in obesity has been an elusive goal despite many decades of research, and is an intense area of current research (Koch et al, 2011; Scott et al, 2011; Vong et al, 2011; Williams and Schwartz, 2011). In the featured manuscript on neuroglial metabolic compartmentation underlying leptin deficiency in the obese ob/ob mice, Delgado et al (2011) used a multifaceted approach to study activity and metabolism in hypothalamic nuclei of control and ob/ob mice. They used three different techniques to obtain new insights into alterations in metabolism and neuronal–glial interactions in the ob/ob mouse brain.

Manganese Enhanced Magnetic Resonance Imaging is a technique that involves obtaining T1-weighted Magnetic Resonance Imaging scans during the uptake of infused manganese (MnCl₂) in brain, and T2-weighted Magnetic Resonance Imaging to determine total cerebral volume. This technique is powerful due to unique properties of the manganese which acts as an indicator of Ca⁺² influx into activated neurons, and by its paramagnetic properties is also a contrast agent to identify activated brain regions (Kuo et al, 2006; Silva et al, 2004).

¹³C-NMR is a powerful technique for determining metabolism and neuronal–glial interactions in brain (Cruz and Cerdan, 1999). Delgado et al used neuronal- or glial-specific precursors and used ¹H and ¹³C High Resolution-Magic Angle Spinning Spectroscopy to obtain high quality spectra of metabolites in small biopsies of hypothalamus from microwave fixed brain. Gene expression studies gave more information about differences in the hypothalamus of ob/ob mice.

The overall picture that emerges from this combined approach is enlightening. There was increased activation (by Manganese Enhanced Magnetic Resonance Imaging) in both the ventromedial and arcuate nucleus of the ob/ob mouse combined with a significant increase in glutamate metabolism and glutamate–glutamine cycling in the neuropeptide Y/agouti-related protein neurons, which are normally inhibited by leptin. Ob/ob mice had decreased glutamate metabolism in proopiomelanocortin/cocaine and amphetamine regulated transcript neurons normally activated by leptin. Overall, these studies suggest that glutamate signaling may have an important, but previously unrecognized, role in leptin-mediated neuronal pathways in hypothalamus. This exciting finding speaks to the need to determine more about the roles of amino acid neurotransmitters in hypothalamic nuclei. It is curious that no difference was found in GABA metabolism given that a recent report (Vong et al, 2011) showed that most of the antiobesity effects of leptin are mediated by GABAergic, not glutamatergic neurons.