Dissecting NAMPT Signaling Pathways in Beige Adipocyte Development, Impairment and Maintenance

Obesity and aging remodel adipose tissue in ways that reduce the abundance and function of thermogenic beige and brown adipocytes, lowering energy expenditure and worsening metabolic disease. Beige adipocytes arise within white adipose tissue in response to environmental and hormonal cues, whereas brown adipose tissue is a dedicated thermogenic organ; both depots display substantial plasticity and undergo “whitening” during aging, overnutrition, and thermoneutrality. The NAD(^+) biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) regulates cellular stress responses and immune–metabolic crosstalk, yet its roles in thermogenic adipocyte development, maintenance, and failure remain incompletely defined. Here, I define context-specific functions of NAMPT across aging, obesity, and thermoneutral obesogenic stress. In aging, NAMPT expression declines in smooth muscle actin (SMA)(^+) adipose progenitor cells (APCs) alongside increased endoplasmic reticulum (ER) stress and impaired cold-induced beige adipogenesis in inguinal white adipose tissue. Genetic reduction of NAMPT in SMA(^+) APCs recapitulates age-associated beige fat failure, whereas pharmacologic augmentation of NAD(^+) with nicotinamide mononucleotide (NMN) alleviates ER stress and restores beige adipocyte formation; conversely, ER stress induction is sufficient to blunt beige adipogenesis and thermogenic competence. In diet-induced obesity, NAMPT in SMA(^+) APCs is required to maintain an IL-33–rich niche that supports beige adipocyte formation: NAMPT deficiency reduces Il33 and beige markers, while progenitor NAMPT overexpression enhances beige adipogenesis and improves systemic metabolic parameters. Neutralizing IL-33 abrogates benefits of NAMPT overexpression, and recombinant IL-33 rescues beige fat formation in NAMPT-deficient settings, placing NAMPT upstream of IL-33–dependent stromal–immune signaling. In brown adipose tissue, UCP1-CreERT2–driven NAMPT overexpression preserves thermogenic gene programs, improves cold tolerance and glucose metabolism, and limits adiposity in mice housed at thermoneutrality under a high-fat, high-sucrose diet, despite tissue-level whitening. These effects coincide with increased circulating extracellular NAMPT (eNAMPT) and enrichment of IL-10–producing M2 macrophages in BAT; in vitro, eNAMPT promotes IL-10–dependent M2 polarization. Collectively, this work identifies NAMPT as a central regulator of thermogenic adipocyte competence by constraining ER stress in aging progenitors, sustaining IL-33–dependent niches in obesity, and supporting BAT maintenance via an eNAMPT–M2–IL-10 axis under thermoneutral, obesogenic stress, highlighting NAMPT-controlled stress and immune pathways as therapeutic nodes to preserve thermogenic adipose function in metabolic disease.

Author dc:creator

• Ruoci Hu (7512059)

• Adipose tissue
• beige adipocyte
• NAD+ metabolism

Statement dc:rights

• In Copyright
• Open Access after 2028-05-01

DOI dc:identifier

https://doi.org/10.25417/uic.32994983.v1

OAI identifier oai:identifier

oai:figshare.com:article/32994983