Abstract
Background: White adipose tissue (WAT) browning is a promising target for obesity prevention and treatment. 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. 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.Methods: Eight-week-old male KKAy mice were administered empagliflozin or saline for 8 weeks and compared with control C57BL/6J mice. Mature 3T3-L1 adipocytes were treated in the presence or absence of empagliflozin. Mitochondrial biosynthesis, dynamics, and function were evaluated by gene expression analyses, fluorescence microscopy, and enzymatic assays. 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.Results: Empagliflozin substantially reduced the bodyweight of KKAy mice. 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. 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) [p-DRP1 (Ser616)] in epididymal and perirenal WAT. Empagliflozin also increased mitochondrial biogenesis and fusion, improved mitochondrial integrity and function, and promoted browning of 3T3-L1 adipocytes. 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. Whether empagliflozin activates AMPK by inhibition of SGLT2 or by independent mechanisms remains to be tested.Conclusion: Our results suggest that empagliflozin is a promising anti-obesity treatment, which can immediately induce WAT browning mitochondrial biogenesis, and regulate mitochondrial dynamics.
Highlights
Obesity is a growing threat to public health due to its association with various metabolic diseases
The White adipose tissue (WAT) of empagliflozin-treated KKAy mice contained smaller multilocular lipid droplets than that of their untreated counterparts (a 57% decrease in the perirenal WAT of empagliflozin-treated KKAy mice, P = 0.018; a 36% decrease in the epididymal WAT of empagliflozin-treated KKAy mice, P = 0.024), and these morphological features typical of brown adipose tissue (BAT) were most evident in eWAT and perirenal white adipose tissue (pWAT) (Supplementary Figures 2A,B, and Figures 1F,H)
The transcriptional profiles of genes involved in lipolysis (Plin1, Adrb3, and Pparg), lipogenesis (Fasn and Srebf1), and glucose uptake (Glut4), as well as those of inflammation-related genes (MCP1, Tnf α, and F4/80), which were dysregulated in KKAy mice, were restored by empagliflozin treatment (Figures 2I,J). These results suggest that empagliflozin induces browning and adaptive metabolic reprogramming in the pWAT and eWAT of KKAy mice
Summary
Obesity is a growing threat to public health due to its association with various metabolic diseases. The rise in obesity has prompted the investigation of novel effective treatments to combat the condition (Pilitsi et al, 2019). Obesity arises due to excess energy storage relative to energy expenditure in adipocytes. Two established types of adipose tissue are present in mammals: white and brown adipose tissue (WAT and BAT, respectively) (Frontini and Cinti, 2010). They can be distinguished from each other by their morphology, biochemical characteristics, and function. 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
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