The mode of white adipose tissue (WAT) expansion in response to positive energy balance greatly impacts obesity-related metabolic abnormalities. Pathologic WAT remodeling, characterized by adipocyte hypertrophy and reduced differentiation capacity, results in chronic inflammation, ectopic fat accumulation and insulin resistance. Conversely, healthy adipogenesis is characterized by adipocyte hyperplasia, reduced inflammation and limited fat spill-over in other organs. Pan-deletion of the monoacylglycerol lipase alpha/beta hydrolase domain-6 (ABHD6) demonstrated the therapeutic potential of ABHD6 inhibitors against obesity and type-2-diabetes. However, the role of ABHD6 in diet-induced adipogenesis and adipose inflammation remains unexplored.
Here we present evidence, employing pharmacological and genetic approaches, that ABHD6 suppression maintains AT immunometabolic health during high fat diet (HFD)-induced obesity. ABHD6 expression increases in mouse adipocytes during differentiation, and correlates with the adiposity in WAT of HFD-fed mice and in visceral fat of patients with obesity. Treatment of adipocytes with the ABHD6 inhibitor (KT203) prior to induction of differentiation increases the expression of adipogenic markers and the number of smaller lipid droplets. In addition, ABHD6 deletion in mice enhances differentiation capacity of primary inguinal pre-adipocytes. HFD-fed whole-body ABHD6-KO mice exhibit lower expression of proinflammatory cytokines, and less fibrosis and hypoxia parameters in all fat depots. Proinflammatory M1 macrophages in the visceral and brown fat depots are also reduced in HFD-fed KO mice. Furthermore, the stromal vascular fraction from WAT of HFD-fed KO mice display reduced glycolytic and increased oxidative rates. Interestingly, other tissues of KO mice, including liver, heart and spleen, show reduced weight, decreased proinflammatory markers and lower fat content, compared to wild type mice on HFD.
The results suggest that inhibition/deletion of ABHD6 in HFD fed mice enhances AT capacity to recruit new fat cells through differentiation of pre-adipocytes, reduces lipid spill-over in other organs and ameliorates inflammation. These findings provide insight into the role of ABHD6 in the immunometabolic pathways during WAT expansion, and suggest ABHD6 as a therapeutic target for inflammation and obesity-related complications.
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