NAD+ boosting by oral nicotinamide mononucleotide administration regulates key metabolic and immune pathways through SIRT1 dependent and independent mechanisms to mitigate diet-induced obesity and dyslipidemia in mice

Sirtuins are NAD+-dependent histone deacetylases that play a key role in metabolism. Sirtuin activity is compromised in aging and metabolic disorders, and pharmacological strategies that promote sirtuin function including NAD+ boosting approaches show potential as therapeutics. To study the impact of nicotinamide mononucleotide (NMN) supplementation in mice in high fat diet (HFD) induced obesity and the role of SIRT1, a sirtuin family member, in mediating the NMN response, we administered NMN to mice in drinking water to boost NAD+ in control and in inducible SIRT1 knock-out mouse models and performed a combination of metabolic phenotyping, lipid profiling and plasma proteomics in these mice. We discovered that supplementation with NMN mitigated diet induced weight gain by enhancing energy expenditure, corrected dyslipidemia, and reversed perturbations in fasting blood glucose, all in a SIRT1-dependent manner. On the other hand, NMN-induced reductions in fat mass, fluid mass, eWAT and mesenteric WAT were SIRT1 independent. Proteomic approaches in plasma samples using O-Link and mass-spectrometry provided novel insights into key obesity- and NMN-dependent changes in circulating molecules with potential relevance to inflammation, liver function, and dyslipidemia. We discovered SIRT1 dependent and independent alterations in key circulating plasma proteins and identified key metabolic and molecular pathways that were significantly affected by HFD, several of which were reverted by oral NMN administration. Glucose metabolism, cholesterol metabolism and immune-related pathways are among the most significantly affected changes. Causal analysis of proteomic data suggests that observed effects could be mediated by transcription regulators FBXW7, ADIPOR2 and PRDM16. Collectively, our data support the hypothesis that promoting SIRT1 function by boosting NAD+ levels in vivo may be a useful strategy to mitigate obesity and associated cardiovascular complications such as dyslipidemia.