Adipocyte-specific loss of PPARγ attenuates cardiac hypertrophy
Xi Fang, … , Ju Chen, Nanping Wang
Xi Fang, … , Ju Chen, Nanping Wang
Published October 6, 2016
Citation Information: JCI Insight. 2016;1(16):e89908. https://doi.org/10.1172/jci.insight.89908.
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Research Article Cardiology Cell biology

Adipocyte-specific loss of PPARγ attenuates 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

Xi Fang, Matthew J. Stroud, Kunfu Ouyang, Li Fang, Jianlin Zhang, Nancy D. Dalton, Yusu Gu, Tongbin Wu, Kirk L. Peterson, Hsien-Da Huang, Ju Chen, Nanping Wang

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Figure 4

miR-200a activates the mTOR pathway to promote cardiomyocyte hypertrophy.

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miR-200a activates the mTOR pathway to promote cardiomyocyte hypertrophy...
(A) Comparison of the seed region of miR-200a with putative target sequences of the 3ˇ-UTR conserved regions in human, chimpanzee, mouse, rat, dog, and chicken TSC1 mRNA. (B) HEK293 cells were cotransfected with either miR-200a mimic or scrambled RNA oligo (control) in combination with a TSC1 3ˇ-UTR-luciferase reporter construct. Note that the luciferase activity was significantly reduced in cells expressing the miR-200a mimic compared with the control RNA oligo. The experiment was replicated 3 times. (C) Neonatal rat cardiomyocytes were infected with miR-200a or GFP (control) adenovirus, and the levels of phosphorylated mTOR (S2448), total mTOR, and TSC1 were detected. Note that the levels of phosphorylated mTOR increased and the levels of TSC1 decreased in miR-200a–overexpressing cells. The experiment was replicated 3 times. (D and E) Neonatal rat cardiomyocytes were infected with miR-200a or GFP (control) adenovirus, as in C, and were subsequently treated with or without rapamycin. Cells were fixed and stained for DNA using DAPI (blue) and Phalloidin (red) after 36 hours. Note that cell size increased when infected with miR-200a adenovirus, and this effect was reversible when cells were treated with the mTOR inhibitor rapamycin (Rapa). The experiment was replicated 3 times. Scale bar: 10 μm. (F and G) Neonatal rat cardiomyocytes were infected with miR-200a or GFP (control) adenovirus, as in C, and were treated with or without rapamycin. RNA was isolated from cells and levels of cardiac hypertrophy markers atrial natriuretic peptide (Anp) and B-type natriuretic peptide (Bnp) were quantified using quantitative real-time PCR. Note that levels of both Anp and Bnp increased when cells were infected with miR-200a, and this was reversible when treated with rapamycin. The experiment was replicated 5 times. Data are represented as mean ± SEM; *P < 0.05 according to 2-tailed Student’s t test for B and 1-way ANOVA for E–G.