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NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin
Kelly L Stromsdorfer1, Shintaro Yamaguchi1, Myeong Jin Yoon2
1Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
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.
Insights
Obesity causes insulin resistance by impairing adipose tissue function. Restoring nicotinamide phosphoribosyltransferase (NAMPT) activity in fat cells improved metabolic health in mice.
Area of Science:
- Metabolic disease research
- Molecular biology
- Obesity research
Background:
- Obesity is linked to adipose tissue dysfunction and systemic insulin resistance.
- The precise mechanisms driving these metabolic complications remain unclear.
- Nicotinamide phosphoribosyltransferase (NAMPT) is crucial for NAD+ biosynthesis and its levels decrease in obesity.
Purpose of the Study:
- To investigate the role of adipocyte NAMPT in systemic metabolic regulation.
- To elucidate the mechanisms underlying obesity-associated insulin resistance.
Main Methods:
- Generated mice with adipocyte-specific knockout of the Nampt gene.
- Assessed insulin sensitivity in adipose tissue, liver, and skeletal muscle.
- Analyzed adipose tissue dysfunction markers, including plasma free fatty acids and adiponectin.
- Investigated the impact of NAMPT loss on CDK5, PPARγ phosphorylation, and gene expression.
Main Results:
- Adipocyte-specific Nampt knockout mice exhibited severe multi-organ insulin resistance and adipose tissue dysfunction.
- Characterized by elevated plasma free fatty acids and reduced adiponectin levels.
- Loss of NAMPT led to increased CDK5 and PPARγ (serine-273) phosphorylation and altered PPARγ target gene expression.
- Administration of rosiglitazone or nicotinamide mononucleotide (NMN) normalized these detrimental effects.
Conclusions:
- Adipocyte NAMPT is critical for maintaining systemic metabolic homeostasis and insulin sensitivity.
- NAMPT deficiency in adipocytes contributes to multi-organ insulin resistance via PPARγ dysregulation.
- Targeting NAMPT or NAD+ metabolism presents a potential therapeutic strategy for obesity-related metabolic disorders.
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