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

Lin Jiang, Haoran Su, Xiaoyin Wu, Hong Shen, Min-Hyun Kim, Yuan Li, Martin G. Myers, Chung Owyang and Liangyou Rui ()
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Lin Jiang: University of Michigan Medical School
Haoran Su: University of Michigan Medical School
Xiaoyin Wu: University of Michigan Medical School
Hong Shen: University of Michigan Medical School
Min-Hyun Kim: University of Michigan Medical School
Yuan Li: University of Michigan Medical School
Martin G. Myers: University of Michigan Medical School
Chung Owyang: University of Michigan Medical School
Liangyou Rui: University of Michigan Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15328-3

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