Division of Endocrinology and Metabolism, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
Department of Molecular Medicine and Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Nat Commun. 2022 Aug 30;13(1):5092. doi: 10.1038/s41467-022-32764-5.
Energy metabolism becomes dysregulated in individuals with obesity and many of these changes persist after weight loss and likely play a role in weight regain. In these studies, we use a mouse model of diet-induced obesity and weight loss to study the transcriptional memory of obesity. We found that the 'metabolic memory' of obesity is predominantly localized in adipocytes. Utilizing a C. elegans-based food intake assay, we identify 'metabolic memory' genes that play a role in food intake regulation. We show that expression of ATP6v0a1, a subunit of V-ATPase, is significantly induced in both obese mouse and human adipocytes that persists after weight loss. C. elegans mutants deficient in Atp6v0A1/unc32 eat less than WT controls. Adipocyte-specific Atp6v0a1 knockout mice have reduced food intake and gain less weight in response to HFD. Pharmacological disruption of V-ATPase assembly leads to decreased food intake and less weight re-gain. In summary, using a series of genetic tools from invertebrates to vertebrates, we identify ATP6v0a1 as a regulator of peripheral metabolic memory, providing a potential target for regulation of food intake, weight loss maintenance and the treatment of obesity.
在肥胖人群中，能量代谢会失调，其中许多变化在减肥后仍然存在，并且可能在体重反弹中起作用。在这些研究中，我们使用饮食诱导肥胖和减肥的小鼠模型来研究肥胖的转录记忆。我们发现肥胖的“代谢记忆”主要局限于脂肪细胞中。利用基于秀丽隐杆线虫的食物摄入测定法，我们鉴定出在食物摄入调节中起作用的“代谢记忆”基因。我们表明，V-ATPase 亚基 ATP6v0a1 的表达在肥胖的小鼠和人类脂肪细胞中均显著诱导，并且在减肥后仍然存在。Atp6v0A1/unc32 缺失的秀丽隐杆线虫突变体的食物摄入量少于 WT 对照。脂肪细胞特异性 Atp6v0a1 敲除小鼠对 HFD 的反应性食物摄入量减少，体重增加减少。用 V-ATPase 组装的药理学破坏导致食物摄入量减少和体重反弹减少。总之，我们使用从无脊椎动物到脊椎动物的一系列遗传工具，鉴定出 ATP6v0a1 是外周代谢记忆的调节剂，为调节食物摄入、减肥维持和肥胖治疗提供了潜在的靶标。
