Nuclear Nicotinamide Adenine Dinucleotide Deficiency by Nmnat1 Deletion Impaired Hepatic Insulin Signaling, Mitochondrial Function, and Hepatokine Expression in Mice Fed a High-Fat Diet

Abstract

Metabolic syndrome (MetS) is a worldwide challenge that is closely associated with obesity, nonalcoholic liver disease, insulin resistance, and type 2 diabetes. Boosting nicotinamide adenine dinucleotide (NAD⁺) presents great potential in preventing MetS. However, the function of nuclear NAD⁺ in the development of MetS remains poorly understood. In this study, hepatocyte-specific Nmnat1 knockout mice were used to determine a possible link between nuclear NAD⁺ and high-fat diet (HFD)-induced MetS. We found that Nmnat1 knockout significantly reduced hepatic nuclear NAD⁺ levels but did not exacerbate HFD-induced obesity and hepatic triglycerides accumulation. Interestingly, loss of Nmnat1 caused insulin resistance. Further analysis revealed that Nmnat1 deletion promoted gluconeogenesis but inhibited glycogen synthesis in the liver. Moreover, Nmnat1 deficiency induced mitochondrial dysfunction by decreasing mitochondrial DNA (mtDNA)-encoded complexes Ⅰ and Ⅳ, suppressing mtDNA replication and mtRNA transcription and reducing mtDNA copy number. In addition, Nmnat1 depletion affected the expression of hepatokines in the liver, particularly downregulating the expression of follistatin. These findings highlight the importance of nuclear NAD⁺ in maintaining insulin sensitivity and provide insights into the mechanisms underlying HFD-induced insulin resistance.

Keywords: NAD+; glucose metabolism; hepatokines; insulin resistance; metabolic syndrome; mitochondrial dysfunction.