Weight loss is not easy to achieve and is even harder to maintain. Approximately 80% of people who lose 10% of their body weight will regain the weight within one year. The new setpoint hypothesis suggests that the dysregulated signals controlling food intake and energy expenditure in the obese state undergo further adaptive changes after weight loss to encourage weight regain.
We investigated the “metabolic memory of obesity' that may play a role in weight regain. Using RNA sequencing, we measured transcriptional changes in key metabolic tissues in lean, obese and formerly obese mice. We then used a novel and innovative C. elegans based high throughput food intake assay to investigate the effects of the deletion of these genes on food intake in a whole organism setting. In follow-up studies, we used a combination of genetic and drug-based inhibition to investigate the role of one of these genes in energy balance and glucose homeostasis in mice.
Our studies show that the “metabolic memory of obesity” resides predominantly in the adipose tissue. Specifically, 752 genes in adipocytes were induced by obesity and persistently dysregulated after weight loss in comparison with just 26 genes in liver.We studied the effect of deletion of these adipocyte genes on food intake in worm mutants. Worm mutants lacking Atp6v0a1, a subunit of the lysosomal vacuolar H+ ATPase, had decreased food intake prompting us to generate and study an adipocyte specific Atp6v01 mutant mouse. Adipocyte specific ablation of Atp6v0a1 decreased weight gain and food intake, and improved glucose tolerance in HFD fed mice. In addition, drug-based inhibition of the wider V-ATPase family (using bafilomycin) reduced food intake and retarded weight rebound after weight loss.
These studies provide new mechanistic insights into the dysregulated pathways involving adipocyte vacuolar H+ ATPase which can be targeted to prevent weight rebound and improve diabetic control.