eNAMPT actions through nucleus accumbens NAD⁺/SIRT1 link increased adiposity with sociability deficits programmed by...

Obesity is frequently associated with impairments in the social domain, and stress at puberty can lead to long-lasting changes in visceral fat deposition and in social behaviors. However, whether stress-induced changes in adipose tissue can affect fat-to-brain signaling, thereby orchestrating behavioral changes, remains unknown. We found that peripubertally stressed male-but not female-mice exhibit concomitant increased adiposity and sociability deficits. We show that reduced levels of the adipokine nicotinamide phosphoribosyltransferase (NAMPT) in fat and its extracellular form eNAMPT in blood contribute to lifelong reductions in sociability induced by peripubertal stress. By using a series of adipose tissue and brain region-specific loss- and gain-of-function approaches, we implicate impaired nicotinamide adenine dinucleotide (NAD⁺)/SIRT1 pathway in the nucleus accumbens. Impairments in sociability and accumbal neuronal excitability are prevented by normalization of eNAMPT levels or treatment with nicotinamide mononucleotide (NMN), a NAD⁺-boosting compound. We propose NAD⁺ boosters to treat social deficits of early life stress origin.