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

Area of Science:

• Adipose tissue biology
• Metabolic regulation
• Molecular endocrinology

Background:

• White adipose tissue (WAT) and beige adipocytes interplay in obesity and insulin resistance.
• Nuclear receptor PPARγ is crucial for adipocyte function.
• Mechanisms linking PPARγ to thermogenic vs. white adipose fate are unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms of PPARγ in regulating WAT fate.
• To investigate the role of a PPARγ/long noncoding RNA (lncRNA) axis in thermogenesis.
• To identify novel regulators of white adipose tissue plasticity.

Main Methods:

• Pharmacologic inhibition and genetic deletion of the lncRNA Lexis.
• Assessment of uncoupling protein 1-dependent (UCP1-dependent) and -independent thermogenesis.
• Single-nuclei transcriptomics and motif analysis.
• In vivo studies in diet-induced obesity models.

Main Results:

• Lexis deletion enhanced UCP1-dependent and -independent thermogenesis.
• Adipose-specific Lexis deletion ameliorated diet-induced obesity, improved insulin sensitivity, and increased energy expenditure.
• Lexis regulates a distinct thermogenic adipocyte population via TCF7L2, a metabolic GWAS gene and WNT modulator.

Conclusions:

• A novel PPARγ/lncRNA (Lexis) axis restrains WAT thermogenesis during thermoneutrality and obesity.
• Lexis inhibition promotes a thermogenic phenotype, offering a potential therapeutic strategy.
• This study uncovers a new crosstalk between PPARγ and WNT signaling in maintaining WAT plasticity.