Telmisartan prevents weight gain and obesity through activation of peroxisome proliferator-activated receptor-delta-dependent pathways.
Telmisartan shows antihypertensive and several pleiotropic effects that interact with metabolic pathways. In the present study we tested the hypothesis that telmisartan prevents adipogenesis in vitro and weight gain in vivo through activation of peroxisome proliferator-activated receptor (PPAR)-delta-dependent pathways in several tissues. In vitro, telmisartan significantly upregulated PPAR-delta expression in 3T3-L1 preadipocytes in a time- and dose-dependent manner. Other than enhancing PPAR-delta expression by 68.2+/-17.3% and PPAR-delta activity by 102.0+/-9.0%, telmisartan also upregulated PPAR-gamma expression, whereas neither candesartan nor losartan affected PPAR-delta expression. In vivo, long-term administration of telmisartan significantly reduced visceral fat and prevented high-fat diet-induced obesity in wild-type mice and hypertensive rats but not in PPAR-delta knockout mice. Administration of telmisartan did not influence food intake in mice. Telmisartan influenced several lipolytic and energy uncoupling related proteins (UCPs) and enhanced phosphorylated protein kinase A and hormone sensitive lipase but reduced perilipin expression and finally inhibited adipogenesis in 3T3-L1 preadipocytes. Telmisartan-associated reduction of adipogenesis in preadipocytes was significantly blocked after PPAR-delta gene knockout. Chronic telmisartan treatment upregulated the expressions of protein kinase A, hormone-sensitive lipase, and uncoupling protein 1 but reduced perilipin expression in adipose tissue and increased uncoupling protein 2 and 3 expression in skeletal muscle in wild-type mice but not in PPAR-delta knockout mice. We conclude that telmisartan prevents adipogenesis and weight gain through activation of PPAR-delta-dependent lipolytic pathways and energy uncoupling in several tissues.
He
Hongbo
H
Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing 400042, People's Republic of China.
Yang
Dachun
D
Ma
Liqun
L
Luo
Zhidan
Z
Ma
Shuangtao
S
Feng
Xiaoli
X
Cao
Tingbing
T
Yan
Zhencheng
Z
Liu
Daoyan
D
Tepel
Martin
M
Zhu
Zhiming
Z
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology*; D001565:Benzoates / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004041:Dietary Fats / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism / Q000517:prevention & control*; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077333:Telmisartan; D014475:Uncoupling Agents / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects*
D001562:Benzimidazoles; D001565:Benzoates; D004041:Dietary Fats; D047494:PPAR delta; D014475:Uncoupling Agents; D000077333:Telmisartan