2. Academic Validation
  3. ERα activates NAMPT/IL-33 signaling to enhance beige thermogenesis and metabolic fitness

ERα activates NAMPT/IL-33 signaling to enhance beige thermogenesis and metabolic fitness

  • Sci Adv. 2026 Jan 9;12(2):eadz1385. doi: 10.1126/sciadv.adz1385.
Ruoci Hu 1 2,  Jooman Park 1,  Yanyu Qian 1,  Shaolei Xiong 1,  Ahmad Hamza Elsabbagh 1,  Aditya Chhikara 1,  Huailing Fan 1 3,  Zuoxiao Shi 1 2,  Lifeng Liu 1,  Yanhui Li 4,  Zhenyuan Song 4,  Abeer M Mahmoud 5,  Jiwang Chen 6,  Joseph A Baur 7,  Yanlin He 8,  Brian T Layden 5 9,  Zhenqi Zhou 10 11,  Pingwen Xu 5,  Sang-Ging Ong 12 13,  Zilai Wang 14,  Yuwei Jiang 1 2 5
Affiliations

Affiliations

  • 1 Department of Physiology and Biophysics, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.
  • 2 Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL 60612, USA.
  • 3 Department of Clinical Medicine, Xiamen Medical College, Xiamen, Fujian 361023, China.
  • 4 Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL 60612, USA.
  • 5 Division of Endocrinology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.
  • 6 Division of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.
  • 7 Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 8 Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, USA.
  • 9 Jesse Brown Medical VA Medical Center, Chicago, IL 60612, USA.
  • 10 Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 11 Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 12 Department of Pharmacology and Regenerative Medicine, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.
  • 13 Division of Cardiology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.
  • 14 Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL 60612, USA.
PMID: 41499496 DOI: 10.1126/sciadv.adz1385
Abstract

Beige adipocytes are inducible thermogenic fat cells that emerge within white adipose tissue (WAT) in response to thermogenic stimuli and confer metabolic benefits. However, obesity impairs the generation of beige adipocytes, and the underlying mechanisms remain poorly understood. Here, we show that obesity leads to a loss of adipose progenitor cells (APCs) in WAT, accompanied by reduced estrogen (E2) levels and nicotinamide phosphoribosyltransferase (NAMPT) expression. Supplementation with E2 or nicotinamide mononucleotide (NMN), an NAMPT-derived nicotinamide adenine dinucleotide (NAD+) precursor, restores beige adipogenesis in diet-induced obese mice. Mechanistically, Estrogen receptor α (ERα) in APCs is required for beige fat formation by promoting NAMPT transcription. We further demonstrate that NAMPT is both necessary and sufficient to drive APC proliferation and differentiation, with interleukin-33 (IL-33) acting downstream to mediate these effects. These findings uncover a critical ERα/NAMPT/IL-33 axis that preserves progenitor function and thermogenic capacity, offering a potential therapeutic strategy to combat obesity-induced beige fat failure and associated metabolic dysfunction.

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