Adipocytes control food intake and weight regain via Vacuolar-type H+ ATPase

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. Energy metabolism is dysregulated in obesity, and some if these changes persist after weight loss and may contribute to weight regain. Here the authors report that a vacuolar-type H+ ATPase, ATP6v0a1, is induced in adipocytes during obesity and persists after weight loss, and regulates food intake and weight gain in C. elegans and mice.

Automated summary

Energy metabolism remains dysregulated after weight loss in individuals with obesity, known as "metabolic memory". Using mouse and C. elegans models, this study identified ATP6v0a1 as a key gene involved in regulating food intake and weight gain, persisting even after weight loss.