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 ATP6v0al, 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 ATP6v0al as a regulator of peripheral metabolic memory, providing a potential target for regulation of food intake, weight loss maintenance and the treatment of obesity.

Rizaldy C. Zapata, Maria Carretero, Felipe Castellani Gomes Reis, Besma S. Chaudry, Jachelle Ofrecio, Dinghong Zhang, Roman Sasik, Theodore Ciaraldi, Michael Petrascheck, Olivia Osborn