The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity

Summary

The first preclinical demonstration that oral NR protects against diet-induced metabolic disease in mice, from the Auwerx laboratory. C57BL/6J mice fed a high-fat diet supplemented with 400 mg/kg/day NR showed markedly reduced weight gain, improved insulin sensitivity, and preserved glucose tolerance compared with high-fat-diet controls. NR-treated animals exhibited enhanced oxidative metabolism in skeletal muscle and brown adipose tissue, with increased mitochondrial biogenesis and activation of SIRT1 and SIRT3 signaling. Whole-body energy expenditure was elevated without changes in food intake or activity, consistent with increased thermogenic capacity. The effects mirrored those of resveratrol and PPAR-δ agonists but through the upstream mechanism of cosubstrate (NAD+) availability. The study directly motivated human NR trials in metabolic populations — obesity, prediabetes, NAFLD — and is the most-cited preclinical paper on NR's metabolic benefits. It also established the 400 mg/kg/day mouse dose (≈2 g/day human-equivalent) that shaped subsequent clinical trial dose selection.

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