Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Morato L

PROVIDER: S-EPMC8890725 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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eNAMPT actions through nucleus accumbens NAD<sup>+</sup>/SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress.

Morató Laia L Astori Simone S Zalachoras Ioannis I Rodrigues Joao J Ghosal Sriparna S Huang Wei W Guillot de Suduiraut Isabelle I Grosse Jocelyn J Zanoletti Olivia O Cao Lei L Auwerx Johan J Sandi Carmen C

Science advances 20220302 9

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 adipo ...[more]

PMID: 35235362

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Project description:BackgroundThe intestine of children with severe malnutrition (SM) shows structural and functional changes that are linked to increased infection and mortality. SM dysregulates the tryptophan-kynurenine pathway, which may impact processes such as SIRT1- and mTORC1-mediated autophagy and mitochondrial homeostasis. Using a mouse and organoid model of SM, we studied the repercussions of these dysregulations on malnutrition enteropathy and the protective capacity of maintaining autophagy activity and mitochondrial health.MethodsSM was induced through feeding male weanling C57BL/6 mice a low protein diet (LPD) for 14-days. Mice were either treated with the NAD+-precursor, nicotinamide; an mTORC1-inhibitor, rapamycin; a SIRT1-activator, resveratrol; or SIRT1-inhibitor, EX-527. Malnutrition enteropathy was induced in enteric organoids through amino-acid deprivation. Features of and pathways to malnutrition enteropathy were examined, including paracellular permeability, nutrient absorption, and autophagic, mitochondrial, and reactive-oxygen-species (ROS) abnormalities.FindingsLPD-feeding and ensuing low-tryptophan availability led to villus atrophy, nutrient malabsorption, and intestinal barrier dysfunction. In LPD-fed mice, nicotinamide-supplementation was linked to SIRT1-mediated activation of mitophagy, which reduced damaged mitochondria, and improved intestinal barrier function. Inhibition of mTORC1 reduced intestinal barrier dysfunction and nutrient malabsorption. Findings were validated and extended using an organoid model, demonstrating that resolution of mitochondrial ROS resolved barrier dysfunction.InterpretationMalnutrition enteropathy arises from a dysregulation of the SIRT1 and mTORC1 pathways, leading to disrupted autophagy, mitochondrial homeostasis, and ROS. Whether nicotinamide-supplementation in children with SM could ameliorate malnutrition enteropathy should be explored in clinical trials.FundingThis work was supported by the Bill and Melinda Gates Foundation, the Sickkids Research Institute, the Canadian Institutes of Health Research, and the University Medical Center Groningen.

Dataset Information

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

Publications

eNAMPT actions through nucleus accumbens NAD<sup>+</sup>/SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress.

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Dataset Information

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

Publications

eNAMPT actions through nucleus accumbens NAD<sup>+</sup>/SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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