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Telmisartan induces browning of fully differentiated white adipocytes via M2 macrophage polarization.

ABSTRACT: Telmisartan is a well-known anti-hypertensive drug acting as an angiotensin 2 receptor blocker (ARB), but it also possesses partial PPARγ agonistic activity and induces insulin sensitivity. In the present study, we investigated the effects of telmisartan on macrophage polarization in association with its browning capacity, because PPARγ plays a key role in M2 polarization and in the browning of white adipocytes. Telmisartan induced M2 marker expression in murine macrophages concentration dependently, which was confirmed by flow cytometry. Both PPARγ and PPARδ activations appear to be responsible for telmisartan-induced M2 polarization. Telmisartan-treated conditioned medium (Tel-CM) of RAW264.7 cells and of bone marrow derived macrophages (BMDM) induced the expressions of browning markers in fully differentiated white adipocytes with reduced lipid droplets, and increased oxygen consumption rate and mitochondrial biogenesis. Levels of catecholamines (CA) released into the conditioned medium as well as intracellular tyrosine hydroxylase (TH) mRNAs were found to be increased by telmisartan, and browning effects of Tel-CM were lessened by β3 receptor antagonist (L-748,337), suggesting CA secreted into CM play a role in Tel-CM-induced adipocyte browning. Acute administration of telmisartan (2 weeks, p.o.) to C57BL/6J mice increased the expressions of browning markers and M2 markers in white adipose tissues, whereas macrophage depletion by clodronate liposome pretreatment attenuated the telmisartan-induced expressions of browning markers. Together, telmisartan was observed to induce the browning of fully differentiated white adipocytes, at least in part, via PPAR activation-mediated M2 polarization.

SUBMITTER: Jeon EJ

PROVIDER: S-EPMC6362091 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Telmisartan induces browning of fully differentiated white adipocytes via M2 macrophage polarization.

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