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. doi:10.1172/jci.insight.89908.
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Categories: 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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Regulation of miR-200a expression by rosiglitazone. (A–D) WT mice were t...

Figure 1

Regulation of miR-200a expression by rosiglitazone.

(A–D) WT mice were treated for 4 weeks with either rosiglitazone (RSG) or vehicle (control). Levels of mature miR-200a and primary transcript of miR-200a (pri-miR-200a) were quantified using quantitative real-time PCR (qRT-PCR) in adipose (A and B) and cardiac tissue (C and D), respectively. Note that miR-200a and pri-miR-200a levels are both increased in RSG-treated adipose tissue, but only mature miR-200a is upregulated in cardiac tissue. n = 5 mice. (E–G) Cells were treated with RSG alone, RSG combined with GW9662 (PPARγ antagonist), or DMSO (control). Levels of mature miR-200a and pri-miR-200a were quantified using qRT-PCR. (E) Expression levels of miR-200a were measured in cardiomyocytes. Note that miR-200a is not induced in cardiomyocytes by RSG at varying concentrations after 24, 36, and 48 hours of treatment. The experiment was replicated 3 times. (F and G) Expression levels of miR-200a and pri-miR-200a were quantified in 3T3-L1–induced adipocytes and primary adipocytes treated with RSG alone, RSG combined with GW9662, or DMSO (control). Note that RSG increases both mature miR-200a and pri-miR-200a levels (F and G, respectively) in both cell types, but the effect is ablated when RSG is combined with the PPARγ antagonist GW9662. The experiment was replicated 3 times. snoRNA 202 and Gapdh were used as internal controls for qRT-PCR experiments. Data are represented as mean ± SEM; *P < 0.05 according to 2-tailed Student’s t test for A–D and 1-way ANOVA for E–G.