HMBA ameliorates obesity by MYH9‐ and ACTG1‐dependent regulation of hypothalamic neuropeptides

The global epidemic of obesity remains a daunting problem. Here, we report hexamethylene bisacetamide (HMBA) as a potent anti‐obesity compound. Peripheral and central administration of HMBA to diet‐induced obese mice regulated the expression of hypothalamic neuropeptides critical for energy balance, leading to beneficial metabolic effects such as anorexia and weight loss. We found that HMBA bound to MYH9 and ACTG1, which were required for the anti‐obesity effects of HMBA in both NPY‐expressing and POMC‐expressing neurons. The binding of HMBA to MYH9 and ACTG1 elevated the expression of HEXIM1 and enhanced its interaction with MDM2, resulting in the dissociation of the HEXIM1–p53 complex in hypothalamic cells. Subsequently, the free HEXIM1 and p53 translocated to the nucleus, where they downregulated the transcription of orexigenic NPY, but p53 and acetylated histone 3 upregulated that of anorexigenic POMC. Our study points to a previously unappreciated efficacy of HMBA and reveals its mechanism of action in metabolic regulation, which may propose HMBA as a potential therapeutic strategy for obesity. Synopsis HMBA was identified as a potent anti‐obesity compound ameliorating metabolic dysfunction in high‐fat diet‐induced obese mice. HMBA binds to MYH9 and ACTG1, inducing HEXIM1 expression in hypothalamic NPY and POMC neurons. HMBA‐induced HEXIM1 downregulates the expression of NPY whereas it upregulates that of POMC. HMBA reverses energy imbalance in obesity by reducing food intake and fat mass and elevating BAT thermogenesis and energy expenditure, leading to weight loss. Graphical Abstract HMBA was identified as a potent anti‐obesity compound ameliorating metabolic dysfunction in high‐fat diet‐induced obese mice.