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

Abstract

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.

The attenuation of activity-based anorexia by obese adipose tissue transplant is AgRP neuron-dependent

“…Thus, neonatal AgRP ablation might have reduced survival in OFR mice by reducing food intake, at least in part. The observed trend for OFR ablated mice to eat less during restriction is consistent with our previous work showing that obese WAT transplants contain specific factors that can encourage feeding (34).…”

“…Weight loss through dieting is frequently followed by weight regain due to compensatory changes that encourage a higher body weight (30)(31)(32)(33). Body weight recidivism following dieting was recently suggested to be driven by a "metabolic memory" of obesity, which predominantly resides in WAT (28,34). Specifically, gene expression and metabolites within metabolic tissues were compared between lean, obese, or previously obese mice; obesity induced widespread transcriptional and metabolomic changes that were reversible by weight loss across most metabolic tissues, except for WAT (34).…”

“…Body weight recidivism following dieting was recently suggested to be driven by a “metabolic memory” of obesity, which predominantly resides in WAT (28, 34). Specifically, gene expression and metabolites within metabolic tissues were compared between lean, obese, or previously obese mice; obesity induced widespread transcriptional and metabolomic changes that were reversible by weight loss across most metabolic tissues, except for WAT (34). Thus, WAT-driven metabolic memory of obesity has been implicated in weight regain.…”

An update on chronic complications of diabetes mellitus: from molecular mechanisms to therapeutic strategies with a focus on metabolic memory

“…Notably, obesity is intricately intertwined with glycemic and metabolic homeostasis, as evident in previous studies (El-Mesallamy et al 2013 ; Aboouf et al 2015 ; Khella et al 2017 ). However, Zapata et al ( 2022 ) also observed that obesity elicits a persistent metabolic imprint that persists despite weight loss, phenotypically resembling metabolic memory. Despite this, the existing literature consistently associates metabolic memory with glycemic fluctuations.…”

Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit

“…Adipogenesis plays a central role in determining AT mass and functions. Recent studies revealed vacuolar H + -ATPase (V-ATPase) subunits ATP6AP2 and ATP6V0A1 regulates adipogenesis and adipose functions 11 , 12 . V-ATPase is highly conserved and expressed in virtually all eukaryotes as a multi-subunit complex, composed of a transmembrane V o domain (subunits a, c, c', c'', d, e) that transports H + across membrane, and a cytosolic V 1 domain (subunits A-H) responsible for ATP hydrolysis.…”