1760-P: Brain Sh2b1 Protects against Obesity and Insulin Resistance through Multiple Hypothalamic Neural Circuits

Abstract

Sh2b1 is a SH2 and PH domain-containing adaptor protein and enhances signal transduction in response to leptin, insulin, brain-derived neurotrophic factor (BDNF), and other ligands. Leptin, insulin and BDNF are known to activate the hypothalamic neural circuitry that controls energy balance, body weight, and metabolism. Genome-wide studies have identified numerous SH2B1 single nucleotide polymorphisms linked to human obesity and diabetes. SH2B1 nonsense and missense mutations have also been reported to be associated with obesity and type 2 diabetes in humans. We previously reported that global deletion of Sh2b1 results in hyperphagia, obesity, and type 2 diabetes in mice. Here, we attempted to identify Sh2b1 target cells, using conditional Sh2b1 knockout mice. We ablated Sh2b1 in the ventromedial hypothalamus (VMH) of Sh2b1flox/flox mice (Sh2b1ΔVMH) either by transducing the VMH with AAV-Cre vectors or using Sf1-Cre drivers. Both Sh2b1ΔVMH males and females, like global Sh2b1 knockout mice, developed obesity, insulin resistance, and liver steatosis. To further map Sh2b1 neurons, we generated leptin receptor (LepR) neuron-specific Sh2b1 knockout (Sh2b1ΔLepR) mice using LepR-Cre drivers. Sh2b1ΔLepR males and females also developed obesity, insulin resistance, glucose intolerance, and liver steatosis. Brown adipose tissue (BAT) thermogenic programs were severely impaired in Sh2b1ΔLepR mice, leading to decreased core body temperature and cold intolerance. Remarkably, Sh2b1 deficiency completely abrogated the ability of leptin to stimulate sympathetic nerves projecting to BAT in Sh2b1ΔLepR mice, indicating that Sh2b1 mediates leptin actions on sympathetic-controlled energy expenditure and metabolism. Collectively, our data suggest that hypothalamic Sh2b1 influences multiple neural circuits controlling food intake, energy expenditure, and metabolic processes by integrating leptin, insulin, BDNF, and/or other nutritional signals. Disclosure Y. Li: None. M. Kim: None. L. Jiang: None. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc. L. Rui: None.