期刊
NATURE MEDICINE
卷 23, 期 12, 页码 1444-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4432
关键词
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资金
- Baylor College of Medicine Mouse Metabolism Core - NIH [P30 DK079638]
- Protein and Monoclonal Antibody Production Core - NIH [P30 CA125123]
- Mouse Phenotyping Core - NIH [UM1HG006348]
- NIH [P30 CA016086]
- American Heart Association [16POST29630010, 16POST27260254]
- American Diabetes Association [1-17-PDF-138, 1-17-JDF-009]
- NIDDK [1R01DK111631, DK075087, DK101379, 1K08DK102529]
- NLM grant [LM012806]
- NHGRI Baylor-Johns Hopkins Center for Mendelian Genomics [UM1 HG006542]
- R.P. Doherty, Jr.-Welch Chair in Science [Q-0022]
- Intramural Research Program of the NIH
- USDA-CRIS [3092-5-001-059]
- Chao Physician-scientist Award
- Caroline Wiess Law scholar award
- departmental laboratory startup package
Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP+ neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.
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