p75 Neurotrophin Receptor Regulates Energy Balance in Obesity

• p75NTR-null mice are protected from diet-induced obesity
• p75NTR regulates energy expenditure and fat oxidation
• p75NTR inhibits the dissociation of the PKA holoenzyme and suppresses cAMP
• Adipocyte-specific p75NTR knockout protects mice from diet-induced obesity

SummaryObesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis. Here, we show that the p75 neurotrophin receptor (p75NTR) controls energy expenditure in obese mice on a high-fat diet (HFD). Despite no changes in food intake, p75NTR-null mice were protected from HFD-induced obesity and remained lean as a result of increased energy expenditure without developing insulin resistance or liver steatosis. p75NTR directly interacts with the catalytic subunit of protein kinase A (PKA) and regulates cAMP signaling in adipocytes, leading to decreased lipolysis and thermogenesis. Adipocyte-specific depletion of p75NTR or transplantation of p75NTR-null white adipose tissue (WAT) into wild-type mice fed a HFD protected against weight gain and insulin resistance. Our results reveal that signaling from p75NTR to cAMP/PKA regulates energy balance and suggest that non-CNS neurotrophin receptor signaling could be a target for treating obesity and the metabolic syndrome.

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