(LB03-20-25) Beneficial Effects of Transplantation of Human Brown Adipocytes Treated With T-AUCB in Mice on a High-Fat Diet

Objectives: Brown adipose tissue (BAT), recognized for its role in non-shivering thermogenesis, has become a promising target for boosting energy expenditure to combat obesity. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme involved in converting epoxy fatty acids to less active diols. We have previously reported that local delivery of a specific sEH inhibitor, t-TUCB, to the BAT of diet-induced obese mice, reduced serum triglycerides and enhanced the expression of key genes related to lipid metabolism in the BAT. The objectives of the current study are to investigate the effects of sEH inhibition by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) on human brown adipocyte differentiation and in nude mice transplanted with human brown adipocytes treated with t-AUCB.

Methods: Human brown preadipocytes (Hbr) were differentiated with DMSO (the vehicle control) and t-AUCB (1-20 μM) for three weeks and differentiation was assessed by brown marker gene expression. Human brown adipocytes treated with DMSO or t-AUCB (5 μM) during differentiation were collected, mixed with Matrigel, and injected into the subcutaneous thoracic-sternum area of the immunocompromised nude male mice (n=5). Mice were fed a high-fat diet (45% fat) for the first two weeks, then received the transplantation, and were kept on the high-fat diet for an additional eight weeks. Food intake and body weight gain were recorded. Glucose, insulin, and cold tolerance tests and energy expenditure assessed by the Comprehensive Lab Animal Monitoring System were performed.

Results: t-AUCB at 5 μM induced higher expression of brown marker gene UCP1 and FABP4 in the Hbr. Moreover, the AUCB-Hbr transplanted mice exhibited reduced body weight gain, increased soleus muscle mass, and decreased serum triglycerides, compared to the DMSO-Hbr transplanted mice under the high-fat diet. No apparent differences were found n glucose, insulin, and cold tolerance tests and energy expenditure between the two groups.

Conclusions: The results demonstrate some beneficial effects of transplanting human brown adipocytes differentiated in the presence of t-AUCB in mice on a high-fat diet. The beneficial effects of sEH inhibitors in human obesity treatment and prevention warrant further exploration.

Funding Sources: The work was supported by NIH.