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Cell Rep. 2016 Aug 16;16(7):1851-60. doi: 10.1016/j.celrep.2016.07.027. Epub 2016 Aug 4.

NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice.

Author information

1
Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
4
Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: jyoshino@wustl.edu.

Abstract

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.

KEYWORDS:

NAD(+); NAMPT; PPARγ; adipocyte; insulin resistance; obesity

PMID:
27498863
PMCID:
PMC5094180
DOI:
10.1016/j.celrep.2016.07.027
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

STATEMENT S.I. is a co-founder of Metro Midwest Biotech. Dr. Samuel Klein, Division Chief of Nutritional Science at Washington University in St. Louis (WUSTL), has ownership interests with Metro Midwest Biotech. WUSTL may receive royalty income based on a technology licensed by WUSTL to Metro Midwest Biotech. This technology is evaluated in this research.

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