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 3

Adipose-specific deletion of Lexis counteracts DIO by increasing energy expenditure.

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Adipose-specific deletion of Lexis counteracts DIO by increasing energy ...
(A) Gross appearance of Lexis adipose tissue–specific KO mice (AdKO) or littermate control mice (AdWT) and their adipose depots after 12 weeks of WD. (B) Body weight of AdKO or AdWT on WD (male, n = 8). (C) Fat pad mass after 12-week WD feeding (n = 8). (D) Body fat composition of 12-week WD-fed mice determined by EchoMRI (n = 8). (E) H&E staining of iWAT from mice in B. Scale bars: 100 μm. (F) Intraperitoneal glucose tolerance test administered on WD (male, n = 8). (G) Intraperitoneal insulin tolerance test on WD (Male, n = 8). (H) Energy expenditure (EE) using indirect calorimetry in male mice after 3 weeks on a WD, showing the mean value per hour ± SEM (n = 10, P < 0.05 by ANCOVA using either total body mass or lean body mass as covariates). (I and J) Average OCR in electron flow (I) and coupling Figure 3 (J) assays of mitochondria isolated from differentiated SVF from iWAT of AdKO or AdWT mice (I, n = 5 for AdWT, n = 4 for AdKO; J, n = 5 per group). (K) Schematic of experiment and H&E staining of iWAT. Scale bars: 100 μm. (L) Core body temperature measured from K (AdWT, n = 7, 5 male, 2 female; AdKO, n = 8, 5 male, 3 female). Data are represented as mean ± SD (B–D, F, G, and L) or mean ± SEM in Figure 2 (H, I, and J). P values were calculated by unpaired t test (C, D, I, J, and L) or 2-way ANOVA (B, F, and G). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.