[HTML][HTML] Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease

L Jiang, H Su, X Wu, H Shen, MH Kim, Y Li… - Nature …, 2020 - nature.com
L Jiang, H Su, X Wu, H Shen, MH Kim, Y Li, MG Myers Jr, C Owyang, L Rui
Nature communications, 2020nature.com
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 …
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.
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