Deciphering a GABAergic Neural Circuit in Critical Control of Leptin-Mediated Feeding, Body Weight, and Glucose Homeostasis

Abstract

Leptin plays a major role in control of glucose metabolism and feeding behavior by acting upon the LepR neurons that widely distribute through the brain. Although several LepR-expressing neuronal groups were identified in distinct nuclei, a dominant neural circuit that mediates the physiological roles of leptin remains elusive, largely due to the inadequate phenotypes as a result of developmental and neural compensations. In this report, a novel, non-sense suppression-based, inducible genetic system is implemented to rapidly delete a specific group of LepR signaling from adult mice within 4 days. Acute deletion of LepR from AgRP neurons show a drastic increase of food intake, massive weight gain, and severe glucose intolerance, developing in a rate with tight manifestation of the global leptin deficiency. Furthermore, a neural circuit comprising of LepR-expressing AgRP neurons and downstream GABAergic neurons in the DMH is mapped by genetic and functional tracing approaches. Optogenetic manipulation of AgRPLepR-DMHGABA neural circuit or the post-synaptic DMHMC4R neurons strongly altered food intake and glucose tolerance in a bidirectional controlled manner. Among all GABAA subunits examined, Gabra3 (encoding GABAA α3 subunits) displayed the most robust changes in response to genetic inactivation of LepRAgRP signaling. Using CRISPR/Cas9 gene editing technique, loss of Gabra3 in DMHMC4R neurons reduced food intake and enhanced glucose intolerance. Surprisingly, chronic infusion of bicuculline into the DMH fully reversed the obesity and glucose intolerance as a result of acute deletion of LepRAgRP signaling. Furthermore, genetic ablation of GABADMH neurons blunted leptin-mediated control of glucose metabolism and food intake. In conclusion, we unveil a novel AgRPLepR-DMHGABA neural circuit and associated GABAA receptor signaling system in fundamental control of leptin-associated obesity and diabetes. Disclosure Q. Wu: None. Y. Han: None.