Journal
ENDOCRINOLOGY
Volume 158, Issue 12, Pages 4233-4245Publisher
OXFORD UNIV PRESS INC
DOI: 10.1210/en.2017-00212
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Funding
- NIH [R01 DK077097, R01DK102898]
- Joslin Diabetes Center's DRC from the National Institute of Diabetes and Digestive and Kidney Diseases [P30 DK036836]
- American Diabetes Foundation [7-12-BS-191]
- Harvard StemCell Institute
- American Diabetes Association
- NIH (National Institute of Neurological Disorders and Stroke) [NS40987]
- American Diabetes Association [1-14-JF-55]
- [NIH T32-DK007260-33]
- [NIH F32-DK091996]
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The regulation of energy balance involves complex processes in the brain, including coordination by hypothalamic neurons that contain pro-opiomelanocortin (POMC). We previously demonstrated that central bone morphogenetic protein (BMP) 7 reduced appetite. Now we show that a type 1 BMP receptor, BMPR1A, is colocalized with POMC neurons and that POMC-BMPR1A-knockout (KO) mice are hyperphagic, revealing physiological involvement of BMP signaling in anorectic POMC neurons in the regulation of appetite. Surprisingly, the hyperphagic POMC-BMPR1A-KO mice exhibited a lack of obesity, even on a 45% high-fat diet. This is because the brown adipose tissue (BAT) of KO animals exhibited increased sympathetic activation and greater thermogenic capacity owing to a reestablishment of energy balance, most likely stemming from a compensatory increase of BMPR1A in the whole hypothalamus of KO mice. Indeed, control animals given central BMP7 displayed increased energy expenditure and a specific increase in sympathetic nerve activity (SNA) in BAT. In these animals, pharmacological blockade of BMPR1A-SMAD signaling blunted the ability of BMP7 to increase energy expenditure or BAT SNA. Together, we demonstrated an important role for hypothalamic BMP signaling in the regulation of energy balance, including BMPR1A-mediated appetite regulation in POMC neurons as well as hypothalamic BMP-SMAD regulation of the sympathetic drive to BAT for thermogenesis.BMP signaling is important for the hypothalamic regulation of energy balance, and we observed an intriguing reestablishment of energy balance with loss of POMC neuron BMPR1A despite hyperphagia.
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