Adipose Tissue Overexpression of Nicotinamide Phosphoribosyltransferase Prevents Metabolic Dysfunction in Obese Mice

Ferguson, D.; Gadson, E. I.; Markan, K. R.; Yoshino, J.; Lin, M.; Habibi, M.; Tiash, S.; Cui, X.; Kouranova, E.; Franczak, E.; Guo, Q.; Kealing, J.; Pietka, T. A.; Liss, K. H. H.; Thyfault, J. P.; Patti, G. J.; Finck, B. N.; Crewe, C.; Mukherjee, S.

doi:10.1101/2025.09.30.679563

bioRxiv · 10.1101/2025.09.30.679563

Adipose Tissue Overexpression of Nicotinamide Phosphoribosyltransferase Prevents Metabolic Dysfunction in Obese Mice

Ferguson, D.·Gadson, E. I.·Markan, K. R.·Yoshino, J.·Lin, M.·Habibi, M.·Tiash, S.·Cui, X.·Kouranova, E.·Franczak, E.·Guo, Q.·Kealing, J.·Pietka, T. A.·Liss, K. H. H.·Thyfault, J. P.·Patti, G. J.·Finck, B. N.·Crewe, C.·Mukherjee, S.

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Abstract

Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme and a central factor in energy metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) maintains the cellular NAD+ pool by synthesizing the NAD+ precursor, nicotinamide mononucleotide (NMN), and diminished adipocyte NAMPT activity has been implicated in aging- and obesity-related metabolic dysfunction. Herein, we examined the effects of overexpressing or knocking out NAMPT in adipocytes on metabolic dysfunction and interorgan communication in mice. We generated new adipocyte-specific NAMPT overexpressing(ANOV) mice model. Male ANOV mice are protected from diet-induced metabolic dysfunction including adipose tissue inflammation, glucose intolerance, and insulin resistance. In contrast female ANOV mice were less protected from metabolic dysfunction, possibly due to higher endogenous expression of NAMPT in WT female mice. Livers of ANOV mice showed improved insulin signaling, increased NAD content, and reduced steatosis, suggesting that NAMPT regulates interorgan communication between adipocytes and hepatocytes. Extracellular vesicles (EV) isolated from ANOV mice enhanced insulin signaling in HepG2 cells and improved glucose tolerance in WT obese mice. In contrast, EV from ANKO mice suppressed HepG2 insulin signaling and inhibition of EV release improved glucose tolerance in ANKO female mice. Collectively, these data highlight a novel mechanism by which adipocyte NAD+ metabolism regulates systemic metabolic dysfunction via EVs.

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Ferguson, D., Gadson, E. I., Markan, K. R., Yoshino, J., Lin, M., Habibi, M., Tiash, S., Cui, X., Kouranova, E., Franczak, E., Guo, Q., Kealing, J., Pietka, T. A., Liss, K. H. H., Thyfault, J. P., Patti, G. J., Finck, B. N., Crewe, C., Mukherjee, S.. 2025-10-02. Adipose Tissue Overexpression of Nicotinamide Phosphoribosyltransferase Prevents Metabolic Dysfunction in Obese Mice. https://doi.org/10.1101/2025.09.30.679563

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