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

Sep 30, 2026

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Obesity impairs beige adipocyte generation, and the mechanisms behind this failure remain insufficiently understood. The study demonstrates that obesity causes loss of adipose progenitor cells (APCs) in white adipose tissue, alongside reduced estrogen (E2) and NAMPT expression. E2 or NAMPT-derived NMN restores beige adipogenesis in diet-induced obese mice. Mechanistically, ERα in APCs promotes Nampt transcription, while NAMPT drives APC proliferation and differentiation through IL-33 downstream signaling, preserving thermogenic capacity and improving metabolic fitness.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

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Introduction

Beige adipocytes and obesity-related failure

Adipose progenitor cells (APCs) and their roles

Estrogen signaling via ERα and related receptors

DISEASES AND DISORDERS ERα activates NAMPT/IL-33 signaling to enhance beige thermogenesis and metabolic fitness Ruoci Hu1,2†, Jooman Park1*†, Yanyu Qian1†, Shaolei Xiong1, Ahmad Hamza Elsabbagh1, Aditya Chhikara1, Huailing Fan1,3, Zuoxiao Shi1,2, Lifeng Liu1, Yanhui Li4, Zhenyuan Song4, Abeer M. Mahmoud5, Jiwang Chen6, Joseph A. Baur7, Yanlin He8, Brian T. Layden5,9, Zhenqi Zhou10,11, Pingwen Xu5, Sang-Ging Ong12,13, Zilai Wang14, Yuwei Jiang1,2,5* 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. copyright © 2026 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution noncommercial license 4.0 (cc BY-nc) . INTRODUCTION Energy expenditure plays a central role in body weight regulation. When energy intake exceeds energy expenditure, excess energy is stored as triglycerides in white adipose tissue (WAT), ultimately leading to obesity and its associated metabolic diseases, including insulin resistance, dyslipidemia, and type 2 diabetes (1–5) . In contrast, brown and beige adipocytes dissipate energy through thermogenesis, thereby improving glucose and lipid metabolism. Beige adipocytes, in particular, are inducible thermogenic cells that emerge within WAT depots in response to cold and other environmental or pharmacological stimuli (6–10) . Given their dynamic nature and metabolic benefits, beige adipocytes represent a promising therapeutic target for combating obesity and related disorders. However, both aging and obesity suppress beige adipocyte recruitment and reduce their thermogenic capacity in WAT, contributing to impaired energy homeostasis (11–14) . 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 Ang

FAQs

How do E2 or NMN treatments influence metabolic outcomes in obese mice?

Supplementation with E2 or NMN restores beige adipogenesis in diet-induced obese mice, supporting thermogenic capacity and metabolic fitness by reactivating the ERα/NAMPT/IL-33 axis.

Sep 30, 2026

Uploaded by SANS