NAMPT-Mediated NAD+ Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice
Open accessAbstract
Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD(+) biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle and adipose tissue dysfunction, manifested by increased plasma free fatty acid concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. These deleterious alterations were normalized by administering rosiglitazone or a key NAD(+) intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance.
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Multiple recent studies have shown that NAD+ supplements (NR and NMN), which can restore low NAD+ levels associated with ageing, are protective against obesity in rodent models.
“Additionally, multiple recent studies have shown that NAD+ supplements (NR and NMN), which can restore low NAD+ levels associated with ageing, are also protective against obesity in rodent models81,82,92, suggesting that these supplements could be explored as therapeutics to restore metabolic health in human patients with obesity.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [92]
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References 35 · Cited by 213
- Authors
- Stromsdorfer, K. L., Yamaguchi, S., Yoon, M. J., Moseley, A. C., Franczyk, M. P., Kelly, S. C., Qi, N., Imai, S.-I., & Yoshino, J.
- Affiliations
- Washington University in St. Louis (US)
- University of Michigan (US)
- Corresponding author
- Yoshino, Jun
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 16
- Issue
- 7
- Pages
- 1851-1860
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5094180
- OpenAlex
- W2486625910
- Cited by
- 213
- References
- 35
- Citations by year
- 2026: 10 · 2025: 22 · 2024: 29 · 2023: 25 · 2022: 23 · 2021: 21 · 2020: 23 · 2019: 22 · 2018: 24 · 2017: 14
- FWCI
- 11.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (5p60dk020579-35, KL2TR000450, UL1TR000448)
- National Institute on Aging (R01AG024150, R01AG037457, R01AG047902)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60DK020572, U2CDK110768, R01DK104995, R01DK037948, P60-DK-020579, P30DK020572, P30DK056341, P30DK089503, P30DK020579, P30DK052574)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- visfatin, NAD biosynthesis, adipocytes, adipose tissue dysfunction, insulin resistance, obesity, PPARγ phosphorylation, cyclin-dependent kinase 5, adiponectin, free fatty acids, rosiglitazone, nicotinamide mononucleotide
- MeSH terms
- Rosiglitazone, Adipose Tissue, Animals, Fatty Acids, Nonesterified, Female, Gene Expression Regulation, Hypoglycemic Agents, Insulin Resistance, Liver, Male, Nicotinamide Mononucleotide, Obesity, Phosphorylation, Signal Transduction, Cytokines, Adipocytes, Mice, Knockout, Muscle, Skeletal, Thiazolidinediones, PPAR gamma, Cyclin-Dependent Kinase 5, Mice, Adiponectin, Nicotinamide Phosphoribosyltransferase
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