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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

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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 5

Adipocyte-derived miR-200a mediates cardiomyocyte hypertrophy in vitro.

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Adipocyte-derived miR-200a mediates cardiomyocyte hypertrophy in vitro.
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(A) Primary adipocytes were treated with rosiglitazone (RSG) alone, RSG and GW9662 (PPARγ antagonist), or RSG and GW4869 (exosome biogenesis inhibitor). Cardiomyocytes were subsequently cocultured in the presence or absence of the primary adipocytes for 72 hours, as in Figure 4A. Cardiomyocytes were subsequently lysed, and Western blots were performed. Note that in the absence of adipocytes, levels of TSC1, total mTOR, and phosphorylated mTOR in cardiomyocytes were unaffected when treated with RSG. Conversely, in the presence of adipocytes, RSG activated mTOR signaling and decreased protein levels of TSC1. Importantly, this effect was rescued using either PPARγ antagonist or exosome biogenesis inhibitor. The experiment was replicated 4 times. (B–D) Adipocytes and cardiomyocytes were cocultured and treated as in A, and RNA was subsequently extracted after 72 hours. The cell size and levels of atrial natriuretic peptide (Anp) and B-type natriuretic peptide (Bnp) in cardiomyocytes were quantified. Note that the cell size and levels of Anp and Bnp increased when cocultured with adipocytes, and this effect was exacerbated when treated with RSG. This effect was rescued by treating adipocytes with PPARγ antagonist and exosome biogenesis inhibitor. The experiment was replicated 3–5 times. (E and F) 3T3-L1-induced adipocytes were transfected with either miR-200a antagomir or control RNA for 24 hours followed by treatment with RSG or DMSO (control). Cardiomyocytes were subsequently cocultured, and RNA was extracted and quantified using quantitative real-time PCR after 72 hours of coculture. Note that the increased levels of Anp and Bnp were ablated when adipocytes were treated with miR-200a antagomir. The experiment was replicated 3 times. (G and H) Rat cardiomyocytes were infected with miR-200a antagomir or control RNA for 24 hours before being adenovirus cocultured with adipocytes. Adipocytes were treated with RSG and RNA was isolated from cardiomyocytes. Note the increased levels of Anp and Bnp were ablated when cardiomyocytes were treated with miR-200a antagomir. The experiment was replicated 3 times. Data are represented as mean ± SEM; *P < 0.05 according to 1-way ANOVA.

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