NAD+ repletion enhances mammary lactogenesis and improves offspring development in a sow model

Long Huang; Chenglin Pan; Wei Zhang; Liu He; Lulu Ma; Yingjie Li; Ruilan Zhang; Ying Li; Yong Zhuo; Xuemei Jiang; Lianqiang Che; Yan Lin; Shengyu Xu; Zhengfeng Fang; Bin Feng; De Wu; Lun Hua

doi:10.1016/j.tjnut.2025.06.013

NAD⁺ repletion enhances mammary lactogenesis and improves offspring development in a sow model

J Nutr. 2025 Jun 30:S0022-3166(25)00373-6. doi: 10.1016/j.tjnut.2025.06.013. Online ahead of print.

Authors

Long Huang¹, Chenglin Pan¹, Wei Zhang¹, Liu He¹, Lulu Ma¹, Yingjie Li¹, Ruilan Zhang¹, Ying Li², Yong Zhuo¹, Xuemei Jiang¹, Lianqiang Che¹, Yan Lin¹, Shengyu Xu¹, Zhengfeng Fang¹, Bin Feng¹, De Wu³, Lun Hua⁴

Affiliations

¹ Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, PR China, 611130; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, PR China, 611130; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China, 611130.
² Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, College of Life Science and Engineering Foshan University Foshan China, 528000.
³ Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, PR China, 611130; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, PR China, 611130; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China, 611130. Electronic address: wude@sicau.edu.cn.
⁴ Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, PR China, 611130; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, PR China, 611130; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, PR China, 611130. Electronic address: hualun@sicau.edu.cn.

PMID: 40602725
DOI: 10.1016/j.tjnut.2025.06.013

Abstract

Background: Breastfeeding provides bidirectional biosocial benefits for maternal-neonatal dyads, yet lactation insufficiency remains a major clinical challenge due to incomplete understanding of lactogenesis mechanisms. Emerging evidence has identified nicotinamide adenine dinucleotide (NAD+) as a critical modulator of reproductive physiology.

Objectives: We characterized mammary gland (MG) NAD+ metabolism and evaluated maternal nicotinamide riboside (NR), an NAD+ precursor supplementation in orchestrating mammary lactogenesis.

Methods: Twenty multiparous sows were randomly allocated into either a control group fed a basal diet (CON, n = 10) or an NR treatment group (NR, n = 10) that was administered 25mg NR/kg body weight/d in split-feed doses. Sow MG biopsies obtained under local anesthesia were analyzed for NAD+ metabolites (NAD+ and NR), histology/ultrastructure, and lactogenesis genes. MG microenvironment glucose substances in vivo were monitored using microdialysis. Milk metabolomics/composition (fat and protein) and offspring growth rate, rectal temperature (after cold stress) and intestine function (after lipopolysaccharide challenge) were assessed. Data were analyzed using t-tests and two-factor ANOVA.

Results: About 17-fold NAD+ levels and NAD+ metabolic enzymes were increased in lactating MG (P < 0.05). NR upregulated mammary and milk NAD+ levels (+ 38% and + 256%, P < 0.05), alongside 31% more milk daily yield (18.0 vs 13.7 kg, P < 0.05). NR increased MG alveolar lumen area (+ 46%) and lactogenesis genes (P < 0.05), paralleled by elevated pyruvate and lactate to glucose ratios (+ 53% and +157%) in microdialysis (P < 0.10). Offspring from NR group demonstrated 23% higher weaning weight (P < 0.05) with a reduction of hypothermia and gut barrier dysfunction (P < 0.05). Mechanistically, NAD⁺-SIRT1 signaling increased mitochondrial density (+ 60%) and biogenesis indices (P < 0.05).

Conclusions: NR supplementation meets lactating mammary NAD⁺ demands, restoring NAD+ levels to potentiate secretory differentiation and milk biosynthesis, identifying novel biomarkers and therapeutic targets for lactation insufficiency.

Keywords: NAD+; lactation; mammary; mitochondrial; nicotinamide riboside.