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박주만Jooman Park

University of Illinois at Chicago

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Sci. Adv., 7 Jan 2026 Vol 12, Issue 2 | DOI: 10.1126/sciadv.adz1385 ERα activates NAMPT/IL-33 signaling to enhance beige thermogenesis and metabolic fitness

Ruoci Hu^1,2†, Jooman Park^1*†, Yanyu Qian^1†, Shaolei Xiong¹, Ahmad Hamza Elsabbagh¹, Aditya Chhikara¹, Huailing Fan ^1,3, Zuoxiao Shi^1,2, Lifeng Liu¹, Yanhui Li⁴, Zhenyuan Song ⁴, Abeer M. Mahmoud⁵, Jiwang Chen⁶, Joseph A. Baur⁷, Yanlin He⁸, Brian T. Layden ^5,9, Zhenqi Zhou ^10,11, Pingwen Xu ⁵, Sang-Ging Ong^12,13, Zilai Wang¹⁴, Yuwei Jiang^1,2,5*

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

*Corresponding authors: Y.J.;J.P.
^†These authors contributed equally to this work.

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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