Unraveling Novel Leptin-Dependent Signaling Pathways in the Basomedial Hypothalamus.

Abstract

Leptin is secreted by the adipose tissue in proportion to fat stores and acts on the hypothalamus to inhibit appetite and promote energy expenditure. Leptin also regulates glucose homeostasis independently of feeding, and has a permissive action on reproduction. Activation of the leptin receptor (LepRb) initiates a cascade of signaling events, including the phosphorylation of residues on the intracellular domain of LepRb: Tyr985, Tyr1077 and Tyr1138. The ongoing analysis of LepRb signaling mutants in vivo has revealed a crucial role for Tyr1138 in energy homeostasis, while Tyr985 appears to be important for the attenuation of LepRb signaling. However, a number of the molecular mechanisms by which LepRb controls other physiological events, including neuronal firing, reproduction and glucose homeostasis, remain poorly defined. Also unclear are the mechanisms that control leptin regulation of a variety of signals including mTORC1. In this study, we examined the regulation of the mTORC1 pathway in the basomedial hypothalamus, and investigated the specific role of LepRb-Tyr1077 in leptin action in vivo. We found that leptin does not modulate hypothalamic mTORC1 in a uniform manner, but rather controls mTORC1 in opposite directions, in different cell types and brain regions. Indeed, neuronal activation is the main regulator of mTORC1 activity in the hypothalamus in response to metabolic perturbations. We also examined the phenotype of mice mutant for LepRb-Tyr1077 on a normal chow and a high fat diet. LepRbf1077/f1077 (f/f) mice had modestly increased body weight and food intake on both diets. Both, male and female f/f mice had increased adiposity, and mutant females presented larger pancreas and ovaries than controls. Interestingly, we found that LepRb-Tyr1077 seems to be mostly important for the regulation of reproduction and glucose homeostasis given that f/f female mice have delayed or absent estrous cycling together with improved glucose clearance. These results suggest novel pathways by which leptin regulates neuronal firing, reproduction and glycemic control. This information not only extends our understanding of leptin action, but could be crucial as we seek to understand the basis of conditions linking metabolism to reproduction and glucose homeostasis.