Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea.
Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea.
EMBO Mol Med. 2023 Dec 7;15(12):e18024. doi: 10.15252/emmm.202318024. Epub 2023 Nov 20.
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.
全球肥胖症的流行仍然是一个令人畏惧的问题。在这里，我们报告己二酮（HMBA）是一种有效的抗肥胖化合物。HMBA 对饮食诱导肥胖的小鼠进行外周和中枢给药，调节了对能量平衡至关重要的下丘脑神经肽的表达，从而产生有益的代谢效应，如厌食和体重减轻。我们发现 HMBA 与 MYH9 和 ACTG1 结合，这对于 NPY 表达和 POMC 表达神经元中的 HMBA 抗肥胖作用是必需的。HMBA 与 MYH9 和 ACTG1 的结合提高了 HEXIM1 的表达，并增强了其与 MDM2 的相互作用，导致下丘脑细胞中 HEXIM1-p53 复合物的解离。随后，游离的 HEXIM1 和 p53 转位到细胞核，在那里它们下调了食欲刺激的 NPY 的转录，但 p53 和乙酰化组蛋白 3 上调了食欲抑制的 POMC 的转录。我们的研究指出了 HMBA 的以前未被认识到的功效，并揭示了其在代谢调节中的作用机制，这可能为肥胖症提出 HMBA 作为一种潜在的治疗策略。
