Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease
Open Access
- 23 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-13
- https://doi.org/10.1038/s41467-020-15328-3
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.Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK110436, P30 DK34933, RO1 DK091591, RO1 DK094014, DK-114220)
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
- American Diabetes Association (#1-18-IBS-189)
This publication has 64 references indexed in Scilit:
- Leptin and Insulin Act on POMC Neurons to Promote the Browning of White FatCell, 2015
- The Thermogenic Effect of Leptin Is Dependent on a Distinct Population of Prolactin-Releasing Peptide Neurons in the Dorsomedial HypothalamusCell Metabolism, 2014
- Immunoaffinity Enrichment and Mass Spectrometry Analysis of Protein MethylationMolecular & Cellular Proteomics, 2014
- Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brotherEuropean Journal of Human Genetics, 2012
- Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesityGenetics in Medicine, 2010
- Large, rare chromosomal deletions associated with severe early-onset obesityNature, 2009
- Direct Innervation of GnRH Neurons by Metabolic- and Sexual Odorant-Sensing Leptin Receptor Neurons in the Hypothalamic Ventral Premammillary NucleusJournal of Neuroscience, 2009
- Genome-wide association yields new sequence variants at seven loci that associate with measures of obesityNature Genetics, 2008
- Neuronal SH2B1 is essential for controlling energy and glucose homeostasisJCI Insight, 2007
- Disruption of the SH2-B Gene Causes Age-Dependent Insulin Resistance and Glucose IntoleranceMolecular and Cellular Biology, 2004