title: Adipocyte-specific loss of PPARγattenuates cardiac hypertrophy.
abstract: Adipose tissue is a key endocrine organ that governs systemic homeostasis. PPARγ is a master regulator of adipose tissue signaling that plays an essential role in insulin sensitivity, making it an important therapeutic target. The selective PPARγ agonist rosiglitazone (RSG) has been used to treat diabetes. However, adverse cardiovascular effects have seriously hindered its clinical application. Experimental models have revealed that PPARγ activation increases cardiac hypertrophy. RSG stimulates cardiac hypertrophy and oxidative stress in cardiomyocyte-specific PPARγ knockout mice, implying that RSG might stimulate cardiac hypertrophy independently of cardiomyocyte PPARγ. However, candidate cell types responsible for RSG-induced cardiomyocyte hypertrophy remain unexplored. Utilizing cocultures of adipocytes and cardiomyocytes, we found that stimulation of PPARγ signaling in adipocytes increased miR-200a expression and secretion. Delivery of miR-200a in adipocyte-derived exosomes to cardiomyocytes resulted in decreased TSC1 and subsequent mTOR activation, leading to cardiomyocyte hypertrophy. Treatment with an antagomir to miR-200a blunted this hypertrophic response in cardiomyocytes. In vivo, specific ablation of PPARγ in adipocytes was sufficient to blunt hypertrophy induced by RSG treatment. By delineating mechanisms by which RSG elicits cardiac hypertrophy, we have identified pathways that mediate the crosstalk between adipocytes and cardiomyocytes to regulate cardiac remodeling.
authors.affiliation: Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, China.|Department of Medicine, School of Medicine, UCSD, La Jolla, California, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Medicine, School of Medicine, UCSD, La Jolla, California, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Stroud
authors.affiliation: Department of Medicine, School of Medicine, UCSD, La Jolla, California, USA.
authors.forename: Kunfu
authors.initials: K
authors.lastname: Ouyang
authors.affiliation: Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Medicine, School of Medicine, UCSD, La Jolla, California, USA.
authors.forename: Jianlin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, School of Medicine, UCSD, La Jolla, California, USA.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.affiliation: Department of Medicine, School of Medicine, UCSD, La Jolla, California, USA.
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Medicine, School of Medicine, UCSD, La Jolla, California, USA.
authors.forename: Tongbin
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Medicine, School of Medicine, UCSD, La Jolla, California, USA.
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.affiliation: Institute of Bioinformatics and Systems Biology, Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan.
authors.forename: Hsien-Da
authors.initials: HD
authors.lastname: Huang
authors.affiliation: Department of Medicine, School of Medicine, UCSD, La Jolla, California, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, China.|The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics*; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D045162:Thiazolidinediones / Q000009:adverse effects; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D047495:PPAR gamma; D045162:Thiazolidinediones; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000077154:Rosiglitazone; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases