Obesity arises due to excess energy storage relative to energy expenditure in adipocytes. The rise in obesity has prompted the investigation of novel effective treatments to combat the condition ( Pilitsi et al., 2019). Obesity is a growing threat to public health due to its association with various metabolic diseases. Whether empagliflozin activates AMPK by inhibition of SGLT2 or by independent mechanisms remains to be tested.Ĭonclusion: Our results suggest that empagliflozin is a promising anti-obesity treatment, which can immediately induce WAT browning mitochondrial biogenesis, and regulate mitochondrial dynamics. Further, we found that AMPK signaling activity played an indispensable role in empagliflozin-induced browning and mitochondrial biogenesis, and that PGC-1α was required for empagliflozin-induced fusion. Empagliflozin also increased mitochondrial biogenesis and fusion, improved mitochondrial integrity and function, and promoted browning of 3T3-L1 adipocytes. At the same time, empagliflozin enhanced fusion protein mitofusin 2 (MFN2) expression, while decreasing the levels of the fission marker phosphorylated dynamin-related protein 1 (Ser616) in epididymal and perirenal WAT. Mice treated with empagliflozin exhibited elevated cold-induced thermogenesis and higher expression levels of uncoupling protein 1 (UCP1) and other brown adipose tissue signature proteins in epididymal and perirenal WAT, which was an indication of browning in these WAT depots. Results: Empagliflozin substantially reduced the bodyweight of KKAy mice. The roles of adenosine monophosphate–activated protein kinase (AMPK) and peroxisome proliferator–activated receptor-γ coactivator-1-alpha (PGC-1α) were determined through AICAR (5-Aminoimidazole-4-carboxamide1-β-D-ribofuranoside)/Compound C and RNA interference, respectively. Mitochondrial biosynthesis, dynamics, and function were evaluated by gene expression analyses, fluorescence microscopy, and enzymatic assays. Mature 3T3-L1 adipocytes were treated in the presence or absence of empagliflozin. Methods: Eight-week-old male KKAy mice were administered empagliflozin or saline for 8 weeks and compared with control C57BL/6J mice. Here, we investigated whether empagliflozin could induce WAT browning and mitochondrial alterations in KK Cg-Ay/J (KKAy) mice, and explored the mechanisms of its effects. Empagliflozin has emerged as an agent with weight-loss potential in clinical and in vivo studies, but the mechanisms underlying its effect are not fully understood. iWAT, inguinal white adipose tissue sWAT, subcutaneous white adipose tissue.īackground: White adipose tissue (WAT) browning is a promising target for obesity prevention and treatment. pWAT, perirenal white adipose tissue eWAT, epididymal white adipose tissue.
Western blot and quantitation of PGC-1α, p-DRP1 (S616), DRP1, MFN2, UCP1, and CYTO C, with GAPDH used as a loading control. (I–L) Eight-week-old male KKAy mice ( n = 6 per group) were treated with (DM + Empa) or without empagliflozin (DM), or treated with insulin (Ins). (G,H) Western blot and quantitation of SGLT2 in different fat depots in 16-week-old C57BL/6J mice. (E,F) Western blot and quantitation of SGLT2 in different organs of 16-week-old KKAy mice. (C,D) Western blotting and quantitation of SGLT2 in different organs of 16-week-old C57BL/6J mice. (A,B) Representative images of hematoxylin staining in iWAT and sWAT. Supplementary Figure 2: Insulin does not induce the expression of UCP1 or proteins related to mitochondrial biogenesis, fusion, and fission in KKAy mice.
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