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

Kelly L. Stromsdorfer, Shintaro Yamaguchi, Myeong Jin Yoon, Anna C. Moseley, Michael P. Franczyk, Shannon C. Kelly, Nathan Qi, Shin ichiro Imai, Jun Yoshino

Research output: Contribution to journalArticlepeer-review

75 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1851-1860
Number of pages10
JournalCell Reports
Volume16
Issue number7
DOIs
Publication statusPublished - 2016 Aug 16

Keywords

  • NAD
  • NAMPT
  • PPARγ
  • adipocyte
  • insulin resistance
  • obesity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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