Journal
CELL REPORTS
Volume 16, Issue 7, Pages 1851-1860Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.07.027
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Funding
- NIH [DK56341, DK37948, DK52574, UL1 TR000450, DK104995, DK20579, AG024150, AG037457, DK089503, DK020572]
- Central Society for Clinical and Translational Research Early Career Development Award
- Longer Lifer Foundation
- Sumitomo Life Welfare and Culture Foundation
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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 PPARg (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARg 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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