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 6

Rosiglitazone-induced cardiac hypertrophy is attenuated in mice with PPARγ-deficient adipocytes.

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Rosiglitazone-induced cardiac hypertrophy is attenuated in mice with PPA...
Adipose-specific PPARγ knockout (AKO) and littermate control mice (Ctrl) were treated with rosiglitazone (RSG) to induce cardiac hypertrophy. (A) Representative whole-mouse heart (top) and H&E-stained sections (bottom). Scale bar: 2 mm. n = 3 mice per group. (B and C) The ratios of left ventricle weight (LV) to body weight (BW) and LV to tibia length (TL) were measured. Note that both ratios increased in the control mice; however, the effect was blunted in the AKO mice. n = 5–8 mice. (D and E) Echocardiography revealed thicknesses of the interventricular septum (IVSd) and left ventricular posterior wall (LVPWd). Note that both septal and posterior wall thicknesses increased in the control mice, but this effect was not observed in AKO mice. n = 5–8 mice. (F and G) RNA from the left ventricle was extracted, and levels of atrial natriuretic peptide (Anp) and B-type natriuretic peptide (Bnp) were quantified using quantitative real-time PCR (qRT-PCR). Note that Anp and Bnp increased in control mice but were unaffected in AKO mice. n = 5 mice. (H–K) RNA was extracted from serum, adipose tissue, and cardiac tissue from AKO and control mice, and levels of mature miR-200a (H–J) or pri-miR-200a (K) were analyzed using qRT-PCR. Note that RSG increased levels of miR-200a in tissues from control mice, whereas RSG failed to increase the level of miR-200a in serum, adipose tissue, and cardiac tissue in AKO mice. Pri-miR-200a was only increased in adipose tissue from RSG-treated WT mice. n = 5–8 per group. Data are represented as mean ± SEM; *P < 0.05 according to 1-way ANOVA.