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JCI Insight. 2016 Oct 6;1(16):e89908.

Adipocyte-specific loss of PPARγ attenuates cardiac hypertrophy.

Author information

1
Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, China.; Department of Medicine, School of Medicine, UCSD, La Jolla, California, USA.
2
Department of Medicine, School of Medicine, UCSD, La Jolla, California, USA.
3
Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, China.
4
Institute of Bioinformatics and Systems Biology, Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan.
5
Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, China.; The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.

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.

PMID:
27734035
PMCID:
PMC5053146
DOI:
10.1172/jci.insight.89908
[Indexed for MEDLINE]
Free PMC Article

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