title: NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice.
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.
authors: Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Kelly L
authors: KL
authors: Stromsdorfer
authors: Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Shintaro
authors: S
authors: Yamaguchi
authors: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Myeong Jin
authors: MJ
authors: Yoon
authors: Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Anna C
authors: AC
authors: Moseley
authors: Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Michael P
authors: MP
authors: Franczyk
authors: Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Shannon C
authors: SC
authors: Kelly
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Nathan
authors: N
authors: Qi
authors: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Shin-Ichiro
authors: S
authors: Imai
authors: 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.
authors: Jun
authors: J
authors: Yoshino
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D052242:Adiponectin; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000172:deficiency / Q000235:genetics*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009537:Nicotinamide Mononucleotide / Q000494:pharmacology; D054409:Nicotinamide Phosphoribosyltransferase / Q000172:deficiency / Q000235:genetics*; D009765:Obesity / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D016207:Cytokines; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D009537:Nicotinamide Mononucleotide; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D051360:Cyclin-Dependent Kinase 5
keywords: NAD(+); NAMPT; PPARγ; adipocyte; insulin resistance; obesity