Abstract
Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; however, the underlying molecular mechanism remains elusive. Here, we uncover Sh2b1 in leptin receptor (LepR) neurons as a critical component of a SNS/brown adipose tissue (BAT)/thermogenesis axis. LepR neuron-specific deletion of Sh2b1 abrogates leptin-stimulated sympathetic nerve activation and impairs BAT thermogenic programs, leading to reduced core body temperature and cold intolerance. The adipose SNS degenerates progressively in mutant mice after 8 weeks of age. Adult-onset ablation of Sh2b1 in the mediobasal hypothalamus also impairs the SNS/BAT/thermogenesis axis; conversely, hypothalamic overexpression of human SH2B1 has the opposite effects. Mice with either LepR neuron-specific or adult-onset, hypothalamus-specific ablation of Sh2b1 develop obesity, insulin resistance, and liver steatosis. In contrast, hypothalamic overexpression of SH2B1 protects against high fat diet-induced obesity and metabolic syndromes. Our results unravel an unrecognized LepR neuron Sh2b1/SNS/BAT/thermogenesis axis that combats obesity and metabolic disease.
Highlights
Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; the underlying molecular mechanism remains elusive
Both gonadal and inguinal white adipose tissue (WAT) depots were significantly larger in Sh2b1ΔLepR relative to Sh2b1f/f and leptin receptor (LepR)-Cre mice (Supplementary Fig. 1a)
We identify LepR neurons as key Sh2b1 targets that mediate Sh2b1 protection against obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD)
Summary
Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; the underlying molecular mechanism remains elusive. We uncover Sh2b1 in leptin receptor (LepR) neurons as a critical component of a SNS/brown adipose tissue (BAT)/thermogenesis axis. Mice with either LepR neuron-specific or adult-onset, hypothalamus-specific ablation of Sh2b1 develop obesity, insulin resistance, and liver steatosis. Our results unravel an unrecognized LepR neuron Sh2b1/SNS/BAT/thermogenesis axis that combats obesity and metabolic disease. Sh2b1-null mice develop severe leptin resistance, obesity, and type 2 diabetes[23,24]. Sh2b1 deficiency in LepR neurons abrogates the ability of leptin to stimulate sympathetic nerves innervating brown adipose tissue (BAT), leading to BAT dysfunction and reduced core body temperature in Sh2b1ΔLepR mice. Our results unveil an unrecognized leptin/Sh2b1/ sympathetic nerve/adipose thermogenesis axis that combats obesity, type 2 diabetes, and liver steatosis
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