Direct Delivery of Metformin to Subcutaneous White Adipose Tissue and Brown Adipose Tissue for Combating Obesity

Abstract

Abstract Objectives Obesity and its comorbidities are major public health problems worldwide. The transformation of white adipose tissue (WAT) to brown adipose tissue (BAT); browning of WAT, may serve as a promising strategy for combating obesity. Metformin is not only the first line of drug for type 2 diabetes but also has an anti-obesity potential. Emerging evidence suggests that metformin can reduce body weight and enhance energy expenditure via activating BAT or browning of WAT. However, metformin delivery to adipose tissue is limited due to the lack of adipocyte-specific surface markers. Thus, the direct injection might be an alternative. Methods ApoE3-Leiden.human cholesteryl ester transfer protein (E3L.CETP) mice (5 mice/group) were fed a high-fat diet (HFD) for 15 weeks. From week 10 to 15, mice were randomly divided into 3 groups as 1. Metformin inguinal WAT (IgWAT) injection, 2. Metformin delivery to interscapular BAT (IBAT) and 3. Saline IgWAT injection (HFD control). Mice received injections twice per week (40 mg/kg/week). Bodyweight (BW), body composition, food intake, energy expenditure and glucose tolerance test (GTT) were measured. Gene expression of beige or brown makers was analyzed using real time-PCR. Results Compared to HFD control mice, IgWAT- and IBAT-treated mice lost 2.16% and 1.9% more of their body fat, respectively (P-value < 0.001). IgWAT- and IBAT-treated mice had 1.09- and 1.24-fold lower area under the curve calculated from the GTT time course than HFD control mice, respectively, but the differences were not statistically significant. The metabolic cage data indicated that both IgWAT- and IBAT-treated mice compared to HFD control mice had significantly decreased respiration exchange ratio (RER) (P < 0.0001). IgWAT-treated mice had significantly lower IgWAT weight than the HFD control mice (P < 0.05). IgWAT-treated compared to HFD control mice had 1.5-, 2-, 2.7- and 3-fold higher expression of UCP1, PRDM16, TMEM26 and Elovl3 in IgWAT, respectively. Conclusions This study demonstrated that local delivery of metformin to IgWAT and IBAT decreased BW and fat mass, which were associated with reduced RER and improved glucose homeostasis. Direct delivery of metformin to IgWAT and IBAT might be an efficient approach for combating obesity via inducing IgWAT browning and enhancing IBAT activity. Funding Sources NIH 1R15AT010395 and AHA 19AIREA34480011.