NAD replenishment restores mitochondrial function and thermogenesis in the brown adipose tissue of mice with obesity

Brown adipose tissue (BAT) is a highly specialized thermogenic tissue and plays a critical role in controlling energy expenditure and metabolic homeostasis. BAT dysfunction is associated with body weight gain and metabolic disorders in mice models. Here, we investigated the influence of the NAD-biosynthesis pathway in the control of BAT metabolism and function. Using a wide multi-omics and phenotypic panel of isogenic strains of BXD mice, we found that the NAD-biosynthesis pathway in BAT is closely associated with body weight gain, adiposity, insulin resistance, oxygen consumption, exercise capacity and mitochondrial metabolism. Interestingly, the high-fat diet (HFD) treatment disrupted the NAD-biosynthesis pathway, reducing Nampt and NMNat3 protein contents and inducing severe mitochondrial dysfunction in BAT of mice. Finally, the oral treatment with nicotinamide riboside (NR), an NAD⁺ precursor, significantly boosted NAD⁺ levels and preserved the morphofunctional mitochondria aspects of mitochondria, and the thermogenesis capacity of BAT in HFD-fed mice. These data point to the NAD synthesis pathway as a promising therapeutic adjuvant target in body thermogenesis management. KEY POINTS: Obesity impairs the NAD⁺ biosynthesis pathway, leading to mitochondrial dysfunction and reduced thermogenic capacity. NAD⁺ metabolism enzymes Nampt and NMNat3 are crucial for mitochondrial function in BAT. Nicotinamide riboside treatment increases the expression of key thermogenic proteins and NAD⁺-related enzymes in BAT, optimizing adaptive thermogenesis and mitochondria function.