Zewei Zhao, Longyun Hu, Bigui Song, Qian Wu, Jiejing Lin, Qingqing Liu, Siqi Liu, Jin Li, Jin Li, Molin Wang, Jin Li, Jin Li, Zhonghan Yang
BACKGROUND: Obesity has emerged as a global health challenge. Although GLP-1 receptor agonists are showing considerable promise in weight loss, their clinical utility is partly limited by gastrointestinal adverse reactions and non-fat weight loss side effects. UCP1-mediated adipose thermogenesis is a critical process for body temperature maintenance and weight management. However, the lack of effective and specific adipose thermogenesis therapies has restricted its clinical application. We aimed to explore the potential of inducing adipose-specific UCP1 overexpression via modified plasmids as an innovative therapeutic approach for obesity. METHODS: We replaced the cytomegalovirus (CMV) promoter in the plasmids with two types of adipose-specific promoters: mouse adiponectin (mADP) promoter and human adiponectin (hADP) promoter, to selectively overexpress UCP1 in adipocytes. The expression level of UCP1, weight loss, metabolic homeostasis and adipose thermogenesis effects were evaluated by immunohistochemistry, western blot, weight measurements, thermography, and comprehensive lab animal monitoring system. RESULTS: The experiments demonstrated that the mADP promoter-modified plasmids failed to drive UCP1 overexpression. In contrast, the hADP promoter-modified Ucp1 overexpression (hADP-Ucp1 OE) plasmids achieved robust adipose-specific UCP1 protein expression both in vitro and in vivo. In vitro experiments revealed that delivery of the hADP promoter-modified UCP1 overexpression (hADP-UCP1 OE) plasmids reduced lipid droplet size and enhanced energy consumption in human adipocytes. In obese mice, administration of the hADP-Ucp1 OE plasmids resulted in significant weight loss and improved metabolic homeostasis. CONCLUSIONS: These findings highlight the therapeutic potential of hADP-UCP1 OE plasmids in obesity management. KEY POINTS: The hADP promoter-modified plasmids selectively overexpress protein in adipose tissue. Overexpression of UCP1 driven by hADP promoter induces thermogenesis in mouse and human adipocytes in vitro. The hADP-Ucp1 OE treatment promotes thermogenesis and energy expenditure in mice. The hADP-Ucp1 OE treatment restrains the development of obesity and glucose intolerance in mice.