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 2

Loss of Lexis leads to lean phenotype.

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Loss of Lexis leads to lean phenotype. (A) Body mass after 3 weeks of WD...
(A) Body mass after 3 weeks of WD feeding of Lexis WT or Lexis-KO mice (WT, n = 9; KO, n = 8). (B) Gross appearance and iWAT depot from WT or Lexis-KO mice. (C) Body fat composition determined by EchoMRI (WT, n = 9; KO, n = 8). (D) H&E staining of iWAT and eWAT from WT mice or Lexis-KO mice. Scale bars: 100 μm. (E) Glucose tolerance test (GTT) performed on male mice (n = 6 per group). (F) Energy expenditure from WT or Lexis-KO mice measured by indirect calorimetry (P = 0.0106, n = 6 per group). (G) Body weight and percentage changes of body mass from baseline of male mice treated with ASO control (Ctrl) or ASO Lexis placed on WD (Ctrl, n = 8; ASO Lexis, n = 7). (H) Body fat composition of mice in G determined by EchoMRI (Ctrl, n = 8; ASO Lexis, n = 7). (I) Fat depot mass after WD feeding (Ctrl, n = 8; ASO Lexis, n = 7). (J) GTT performed on mice after WD feeding (n = 9 per group). (K) Energy expenditure in ASO Ctrl or ASO Lexis mice using indirect calorimetry after WD feeding (n = 9 per group, P < 0.05 using either total body mass or lean body mass as covariates). Data in A, C, E, and G–J are represented as mean ± SD. Data in F and K are represented as mean ± SEM. P values were calculated by unpaired t test (A, C, G, H, and I) or by 2-way ANOVA (E and J). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Analysis of covariance (ANCOVA) was used for F and K.