Telmisartan prevents weight gain and obesity through activation of PPAR-δ dependent lipolytic pathways

Abstract

Objective We tested the hypothesis that telmisartan prevents adipogenesis in vitro and weight gain in vivo through the activation of peroxisome proliferator-activated receptor-δ (PPAR-δ)-dependent pathways in adipose tissue. Design and methods C57BL/6J wild-type mice, PPAR-δ knockout mice and spontaneously hypertensive rats (SHR) were all randomly fed with a regular diet or a high fat diet with or without telmisartan (5 mg/kg daily) treatment for 16 to 24 weeks. Visceral fat weight was determined via dissection of epididymal, retroperitoneal, and mesenteric fat depots. Primary cultured preadipocytes from mice and 3T3-L1 preadipocytes were cultured and differentiated to mature adipocytes. Lipid droplets were shown by oil red O staining. PPAR-δ activity was determined by transactivation assays in 3T3-L1 preadipocytes. Expression of PPAR-δ, PKA, p-PKA, HSL and perilipin in tissue and adipocytes was detected by immunoblotting. Results In vitro, telmisartan significantly upregulated PPAR-δ expression by 68.2±17.3%, and PPAR-δ activity by 102.0±9.0%, increased phosphorylated protein kinase A (p-PKA), hormone sensitive lipase (HSL), but reduced perilipin expression and finally inhibited adipogenesis in 3T3-L1-preadipocytes. The telmisartan-associated reduction of adipogenesis in preadipocytes was significantly blocked after PPAR-δ gene knockout. In vivo, long-term administration of telmisartan significantly reduced visceral fat from 3.0±0.4 g to 1.2±0.2 g (P<0.01) and prevented high fat diet induced obesity in wild type mice and hypertensive rats, but not in PPAR-δ knockout mice. Telmisartan upregulated the expression of PPAR-δ and influenced several lipolytic-related proteins including PKA, HSL and perilipin in adipose tissue in wild type mice but not in PPAR-δ knockout mice. Conclusions The present study indicated that telmisartan prevented adipogenesis and weight gain through activation of PPAR-δ-dependent lipolytic pathways in adipose tissue.