Obesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis.

Researchers show that the p75 neurotrophin receptor (p75^NTR) controls energy expenditure in obese mice on a high-fat diet (HFD). Despite no changes in food intake, p75^NTR-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.

p75^NTR 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 p75^NTR or transplantation of p75^NTR-null white adipose tissue (WAT) into wild-type mice fed a HFD protected against weight gain and insulin resistance.

These results reveal that signaling from p75^NTR 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.

http://www.cell.com/cell-reports/abstract/S2211-1247(15)01452-7