A PPARγ/long noncoding RNA axis regulates adipose thermoneutral remodeling in mice
Zhengyi Zhang, … , Claudio J. Villanueva, Tamer Sallam
Zhengyi Zhang, … , Claudio J. Villanueva, Tamer Sallam
Published November 1, 2023
Citation Information: J Clin Invest. 2023;133(21):e170072. https://doi.org/10.1172/JCI170072.
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Research Article Cardiology Metabolism

A PPARγ/long noncoding RNA axis regulates adipose thermoneutral remodeling in mice

Abstract

Interplay between energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of specialized niche, adipocytes require the activity of the nuclear receptor PPARγ for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ; however, the molecular mechanisms by which PPARγ licenses white adipose tissue to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ/long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity. Pharmacologic inhibition or genetic deletion of the lncRNA Lexis enhances uncoupling protein 1–dependent (UCP1-dependent) and -independent thermogenesis. Adipose-specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT that preserves white adipose tissue plasticity.

Authors

Zhengyi Zhang, Ya Cui, Vivien Su, Dan Wang, Marcus J. Tol, Lijing Cheng, Xiaohui Wu, Jason Kim, Prashant Rajbhandari, Sicheng Zhang, Wei Li, Peter Tontonoz, Claudio J. Villanueva, Tamer Sallam

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Figure 5

Systemic identification of Lexis “interactome” shows direct contact with Atp2a2 promoter region.

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Systemic identification of Lexis “interactome” shows direct contact with...
(A) Volcano plot of RNA-Seq data in the iWAT of mice fed 12-week WD (n = 3 per group). Red dots indicate the gene highly expressed in AdWT or AdKO group (Cutoff: fold change [FC] > 1.5 and P < 0.05). (B) Gene expression by qRT-PCR in the iWAT of 12-week WD-fed mice in Figure 3 (B) (n = 8 per group). (C) Gene expression by qRT-PCR in the iWAT of mice given temperature stress in Figure 3 (I) (n = 6 for Lexis-AdWT; n = 8 for Lexis-AdWT). (D) Experimental schematic Lexis chromatin-affinity assay. (E) Top enriched pathways analyzed by Metascape using the data from Lexis RNA-Seq in A. (F) Top enriched pathways analyzed by Metascape using the data from D. (G) Representative peaks of Lexis, H3K27ac ChIP-Seq, H3K4me1 ChIP-Seq, and H3K4me2 ChIP-Seq on Atp2a2 promoter region. Lexis peaks are from this experiment and other ChIP-Seq from data sets under GEO GSE56872 and GSE95533. (H) Lexis ChIRP-qPCR using primers targeting binding sites of Lexis at Atp2a2 in 10T1/2 cells treated with 24 hours of GW1929 (n = 4 per group). (I) Motif analysis based on Lexis-enriched contact sites. The values in the circles revealed the −log10 (P value). (J) TCF7L2 ChIP-qPCR performed in TCF7L2 WT or TCF7L2 KO preadipocytes (left) or in iWAT of Lexis WT (Lexis AdWT) or Lexis-KO (Lexis-AdKO) mice with 1 week of thermoneutrality (n = 4 per group). Data are represented as mean ± SD (H and J) or mean ± SEM (B and C). P values were calculated by unpaired t test (B, C, and J). *P < 0.05; **P < 0.01; ****P < 0.0001.