NAD+ Repletion Enhances Mammary Lactogenesis and Improves Offspring Development in a Sow Model.

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 25 mg 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 2-factor analysis of variance.

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 compared with 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.