GABA: A Cotransmitter Linking Leptin to Obesity Prevention

Extract

The recent surge of obesity, type II diabetes, and other obesity-related diseases has focused attention on brain mechanisms underlying the regulation of body weight. Leptin is a key factor linking body fat to brain mechanisms controlling food intake and energy expenditure. This hormone is released from adipocytes to circulate at levels that are approximately proportional to the levels of body fat (1). High levels of leptin act on brain feeding control mechanisms as a negative feedback signal to produce satiety, an action produced when leptin binds to isoform B leptin receptors in specific brain regions (2). Consequently, subjects overeat and become massively obese if either endogenous leptin or its receptors are absent or ineffective.

A question that has generated much interest and research is: What classes of neurons and neurotransmitters mediate leptin's antiobesity actions? Significant insight into this question is provided by Xu et al. (3) in this issue. Their work suggests that a portion of leptin's antiobesity effects are mediated by synaptic release of γ amino butyric acid (GABA) from the specific subset of hypothalamic GABAergic neurons that also express leptin receptors. To explore this question, they generated mice in which the vesicular GABA transporter (Vgat) gene was specifically deleted within leptin receptor-expressing neurons (i.e. LepR-Ires-Cre:Vgat^flox/flox mice). The cellular impact of this manipulation is that the GABAergic neurons with leptin receptors lose their ability to secrete GABA. However, they retain the ability to secrete their cotransmitters and respond to leptin. Given this manipulation, Xu et al. evaluated the impact of abolishing GABA release specifically from the subset of GABAergic neurons that also express leptin receptors. Controls for effectiveness and specificity of the gene deletions included evidence that deletion of Vgat in leptin receptor neurons: dramatically reduced Vgat mRNA expression in the arcuate nucleus, dorsomedial hypothalamus, and lateral hypothalamus (LH), the only brain regions with GABAergic neurons that express leptin receptors (4); produced little apparent change in Vgat expression in other brain regions (e.g. cortex); reduced vesicular GABA transporter immunoreactivity but left intact the leptin receptor p-STAT3 response to leptin application. The key behavioral findings were that the experimental mice exhibited mild but significant overeating, obesity, and had reduced energy expenditure as suggested by the mild reduction in O₂ consumption during the night phase of the light-dark cycle. The satiating effect of peripherally injected leptin was also blunted. Collectively, these findings suggest that a small but significant portion of leptin's antiobesity actions are mediated by GABA released from hypothalamic leptin receptor-bearing neurons originating from the LH, dorsomedial hypothalamus, and especially the arcuate nucleus of the hypothalamus. Independent support for GABA involvement in hypothalamic mechanisms of body weight control comes from pharmacological data showing that the repeated activation of GABA_A receptors in the LH suppresses eating and produces weight loss, whereas acute application of GABA receptor antagonists actually elicits eating (5, 6).