Rho-kinase mediates the anorexigenic action of melanocortin by suppressing AMPK

ObjectiveMelanocortin action is essential for the maintenance of energy homeostasis. However, knowledge of the signaling mechanism(s) that mediates the effect of melanocortin remains incomplete.\n\nMethodsROCK1 is a key regulator of energy balance in the hypothalamus. To explore the role of ROCK1 in the anorexigenic action of melanocortin, we deleted ROCK1 in MC4R neurons in mice. Next, we studied the metabolic effects of MC4R neuron-specific ROCK1-deficiency and following treatment with -melanocyte-stimulating hormone (MSH).\n\nResultsHere we show that -MSH increases Rho-kinase 1 (ROCK1) activity in the hypothalamus. Deficiency of ROCK1 in MC4R-expressing neurons results in increased body weight in mice fed normal chow diet. This is likely due to increased food intake and decreased energy expenditure. Importantly, we find that ROCK1 activation in MC4R expressing neurons is required for melanocortin action, as evidenced by the fact that - MSHs ability to suppress food intake is impaired in MC4R neuron-specific ROCK1-deficient mice. To elucidate the mechanism by which ROCK1 mediates melanocortin action, we performed in vitro studies in hypothalamic cells expressing MC4R. We demonstrate that -MSH promotes the physical interaction of ROCK1 and G12, and this results in suppression of AMPK activity.\n\nConclusionsOur study identifies ROCK1 as a novel mediator of melanocortins anorexigenic action and uncover a new MC4R[->]G12[->]ROCK1[->]AMPK signaling pathway. Targeting Rho-kinase in MC4R-expressing neurons could provide a new strategy to combat obesity and its related complications.