IntroductionWeaned piglets face growth challenges due to low feed intake and weaning stress. Palm oil (PO) rich in long-chain saturated fatty acids may optimize nutrition, but appropriate replacement ratios and mechanisms remain unclear.Methods144 weaned piglets were randomly assigned to four groups (CON: 4% soybean oil (SO); T1-T3: 25%, 50%, 100% SO replaced by PO) for 35 days. Growth performance, nutrient digestibility, intestinal health, gene expression, and gut microbiota were measured.ResultsT1 and T3 improved average daily gain (ADG) and reduced feed/gain ratio (0-14 d, p<0.05); T3 increased ADG (0-28 d) and average daily feed intake (ADFI, p<0.05). PO reduced ether extract digestibility (p<0.05), upregulated ZO-1/Claudin-1 mRNA (T3, p<0.05), and increased hypothalamic NPY/AGRP expression. Gut microbial diversity (OTU abundance) and beneficial bacteria (Roseburia) were enhanced in T3.DiscussionModerate PO replacement (25%) balances growth promotion and digestibility, while high replacement (100%) improves gut barrier function and appetite. PO regulates growth via fatty acid composition, appetite-related genes, and gut microbiota

Heat stress (HS) severely impairs boar reproductive function by inducing oxidative stress and inflammatory responses, while lycopene (LYC), as a potent antioxidant, exerts a potential protective effect on the male reproductive system. This study aimed to clarify the mechanism underlying LYC-mediated alleviation of HS-induced decline in semen quality in Rongchang boars, identify the most affected tissues, and explore its regulatory role in the Nrf2 (Nuclear factor E2-related factor 2) pathway. A total of 18 Rongchang boars with an initial body weight of 15.81 ± 1.07 kg were randomly assigned to three groups (6 boars per group): the control group (CON, 26 ± 1 °C), the heat stress group (HS, exposed to 35 ± 1 °C for 8 h daily), and the heat stress + 100 mg/kg lycopene group (HS + LYC). After 28 days of adaptive feeding and 14 days of HS treatment, samples were collected for semen quality analysis, testicular histological analysis, antioxidant index detection, transcriptome analysis, Nrf2 pathway detection, and inflammatory index detection. The results showed that HS significantly increased the sperm abnormality rate (p < 0.05), damaged the testicular structure, and induced oxidative stress in serum, lung, liver, left ventricle, testis, and epididymis (caput epididymis, corpus epididymis, cauda epididymis), with varying degrees of oxidative stress observed in these samples. Among these tissues, the testis and cauda epididymis exhibited the most significant responses to HS and LYC, with the comprehensive impact magnitudes of 317% and 514%, respectively. Enrichment analysis of differentially expressed genes (DEGs) in these two tissues revealed that the pathways mediating oxidative stress response displayed distinct tissue specificity, and all of them were closely associated with the Nrf2 antioxidant signaling pathway. HS significantly downregulated the mRNA expressions of Nrf2, Quinone Oxidoreductase (NQO1), Heme Oxygenase 1 (HMOX1) and Glutamate-Cysteine Ligase Catalytic Subunit (GCLC) genes as well as the protein level of Nrf2 in the testis and cauda epididymis, increased the protein level of Keap1, and significantly elevated the levels of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in these two tissues (p < 0.05). Compared with the HS group, dietary supplementation of LYC significantly improved sperm motility and the proportion of rapidly progressive sperm, reduced the proportion of immotile sperm and sperm abnormality rate (p < 0.05), alleviated testicular damage and oxidative stress in various tissues, upregulated the mRNA expressions of Nrf2 and HMOX1 genes in the testis as well as the mRNA expressions of Nrf2, NQO1, HMOX1 and GCLC genes in cauda epididymis (p < 0.05), significantly increased the Nrf2 protein level and decreased the Keap1 protein level in these two tissues, and simultaneously decreased the levels of the aforementioned inflammatory factors (p < 0.05). In conclusion, dietary supplementation with 100 mg/kg LYC can alleviate HS-induced decline in semen quality and testicular damage by regulating the oxidative status and inflammatory level of relevant tissues (e.g., testis and cauda epididymis) in boars, and this protective effect may be associated with the regulation of the Nrf2 signaling pathway.

Three experiments were conducted to evaluate the energy value and apparent total tract digestibility (ATTD) of nutrients in 11 sorghum samples (S1–S11) fed to sows at different physiological stages, and to assess the feasibility of predicting energy value and nutrient digestibility using fecal and ingredient near-infrared reflectance spectroscopy (NIRS). In Exp. 1, 36 gestating sows (Landrace × Yorkshire; parity 2) at day 50 of gestation were allotted to 12 dietary treatments, including one basal diet and 11 sorghum test diets, in a replicated 12 × 2 Youden square design. Test diets contained 30% sorghum and digestible energy (DE), metabolizable energy (ME), and ATTD of nutrients were determined using the total collection method. In Exp. 2, 36 lactating sows (Landrace × Yorkshire; parity 2) were assigned to the same 12 dietary treatments in a replicated 12 × 2 Youden square design. Digestible energy and ATTD of nutrients were determined using the indicator method. In Exp. 3, fecal and sorghum ingredient samples were used to develop partial least squares regression (PLSR) models based on NIRS. Results showed that sorghum source significantly affected energy value and nutrient digestibility in both stages (P < 0.001). In gestating sows, DE and ME of sorghum ranged from 15.84 to 17.29 MJ/kg and from 15.50 to 17.04 MJ/kg, respectively, whereas DE ranged from 14.98 to 17.18 MJ/kg in lactating sows. Tannin concentration was negatively correlated with DE in both gestating and lactating sows (r = −0.93 and −0.90, respectively; P < 0.01). For NIRS prediction, fecal chemical composition was predicted with good accuracy, whereas DE and nutrient digestibility showed moderate predictive performance. Ingredient spectra also showed moderate potential for predicting DE and nutrient digestibility, with performance similar to that obtained from fecal spectra. These results demonstrate that tannin is a major contributor to the variation in energy and nutrient utilization of sorghum fed to sows, and that NIRS combined with PLSR has potential as a rapid and practical tool for evaluating sorghum energy utilization in sows.

Although fenugreek is used clinically for lactation disorders, its effects on sow reproduction and mechanisms remain unclear. We investigated the effects of fenugreek extract (FE) on sow lactation performance, plasma metabolites, and gut microbiota. A total of 140 crossbred sows were randomly assigned to a basal diet or a diet supplemented with 0.07% FE from gestation day 90 to lactation day 23. FE did not alter total born or birth weight but shortened farrowing duration (P < 0.01). It increased piglet weaning weight (P < 0.10), estimated milk yield (P < 0.05), and lactation feed intake (P < 0.05). FE also elevated dry matter in colostrum and milk, crude fat in colostrum, and lactose in milk (P < 0.05). Maternal plasma T-AOC, CAT, and GSH-Px increased, while TNF-α and IL-6 decreased (P < 0.05). Metabolomics revealed that FE-derived trigonelline and 4-hydroxyisoleucine entered plasma and modulated amino acid and energy metabolism, including arginine/proline, glycine/serine, propanoate, and riboflavin pathways. FE altered gut microbiota composition, enriching Treponema, Lachnospiraceae, Spirochaetota, and Solobacterium, and reducing Ruminococcus bicirculans and Enterococcus. These findings indicate that dietary FE supplementation enhances milk quality and piglet growth, likely by improving maternal antioxidant capacity, plasma metabolism, and gut microbiota.

Reducing dietary nutrient density may lower the feed cost but compromise the growth performance in piglets. Given the ability of lysolecithin (LPI) to enhance nutrient utilization, its supplementation may help piglets adapt to a low-nutrient (LN) diet. This study aimed to investigate the effects of dietary LPI supplementation on growth performance, nutrient utilization, metabolism, and muscle development in piglets fed a LN diet. A total of 96 nursery piglets (17.0 ± 0.2 kg in initial body weight [BW] and 50 d of age) were randomly assigned to three groups in a randomized complete block design and received either the normal-nutrient diet (CON), a LN diet, or the LN diet supplemented with 400 mg/kg lysolecithin (LN-LPI) for 28 d. Each dietary treatment included 8 replicates of 4 piglets each. Results showed that the LN-LPI diet improved the average daily gain (ADG; P = 0.040) during the first two weeks, feed-to-gain ratio (F:G; P = 0.032), and BW (P = 0.065) throughout the experimental period, reaching levels comparable to those of piglets in the CON group. Compared with the LN diet, the growth-promoting effect of LPI may be attributed to its role in increasing the digestibility of ether extract (EE; P < 0.001) and gross energy (GE; P = 0.022) in diets, as well as increasing the relative weight of psoas major muscles (PMM) and the EE (P = 0.049) and crude protein (CP) content (P = 0.007) in muscle. Accordingly, compared with the LN diet, LPI supplementation decreased the blood urea nitrogen (P = 0.003) and total cholesterol (TC) concentrations (P = 0.017), and increased total superoxide dismutase (T-SOD) levels in plasma (P = 0.005) and liver (P = 0.006), along with the lower malondialdehyde (MDA) levels in blood (P < 0.001) and liver (P = 0.003). In addition, microarray analysis indicated that dietary LPI supplementation promoted expression of lipid synthesis and transport-related genes in the liver (FAS, P = 0.040; FABP5, P = 0.001; and SLC27A6, P = 0.025), and amino acid (AA) transport and synthesis-related genes (LAT, P = 0.021; LAMC3, P = 0.004), compared with the LN diet in muscle. In conclusion, this study demonstrated that the LN-LPI diet mitigated the compromised growth performance commonly observed under nutrient restriction, potentially mediated by improving nutrient utilization and redox status, and modulating lipid and protein metabolism.

Abnormal placental angiogenesis contributes significantly to fetal growth restriction (FGR) and related complications. Methionine adenosyl-transferase 2A (MAT2A) can regulate the process of embryonic development; however, the role of MAT2A in placental angiogenesis during fetal development remains poorly understood. In this study, placentas from paired normal birth weight (NBW) and FGR piglets were used to quantify placental vascular density and biochemical indexes, while porcine trophoblast cells (pTrs) and porcine vascular endothelial cells (PVECs) were used to investigate the regulatory mechanism of MAT2A on placental angiogenesis. Here, we found that FGR placentas exhibited reduced vascular density and increased glycogen levels. Moreover, FGR placentas showed reduced S-adenosylmethionine (SAM) levels and downregulated protein expression of MAT2A and CD31. Placental SAM levels were positively correlated with vascular density, while MAT2A expression was positively correlated with CD31 expression. Further study showed that MAT2A knockdown disrupted the metabolism of methionine, glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation, and hindered protein synthesis, thereby impairing cell proliferation and migration in pTrs and/or PVECs, and inhibited angiogenesis in a co-culture system. In contrast, SAM supplementation promoted phosphorylation of ribosomal protein S6 kinase 1 (S6K1), downstream of the mammalian target of rapamycin complex 1 signalling pathway, and upregulated vascular endothelial growth factor-A protein expression, thereby increasing endothelial cell tube formation. In conclusion, our study demonstrates the potential of MAT2A in interventional therapy for placental development of FGR. KEY POINTS: Placental vascular density is correlated with decreased S-adenosylmethionine (SAM) levels caused by downregulated adenosyl-transferase 2A (MAT2A) expression. MAT2A regulates the placental mTORC1 signalling pathway and protein synthesis. MAT2A knockdown disrupts methionine metabolism, glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation. MAT2A regulates the proliferation and migration capacity of placental trophoblast and endothelial cells. MAT2A regulates placental angiogenesis via the SAM-mTORC1-S6K1-VEGF-A signalling pathway.

Dietary protein restriction (PR) is a well-recognized nutritional intervention that enhances metabolic health and extends lifespan. However, the mechanisms behind this phenomenon are not well understood. Here, using genetic loss-of-function models for fibroblast growth factor 21 (Fgf21) and its obligate co-receptor β-Klotho (Klb), we demonstrate that FGF21-KLB signalling in adipocytes is indispensable for the anti-senescence effects of PR. Specifically, adipocyte FGF21 signalling preserves mitochondrial integrity, maintains an anti-inflammatory milieu and sustains nicotinamide adenine dinucleotide (NAD+) homeostasis under PR. Mechanistically, FGF21 enhances adipocyte NAD+ abundance through activation of AMP-activated protein kinase to maintain mitochondrial integrity. Additionally, high-protein feeding induces adipocyte senescence and metabolic dysfunction could be mitigated by exogenous FGF21 supplementation. Together, these findings establish adipose FGF21 signalling as a pivotal endocrine axis that couples dietary protein availability to adipocyte NAD+ metabolism and identify it as a promising target for the prevention and treatment of age-related metabolic disorders. KEY POINTS: Dietary protein restriction improves metabolic health and extends lifespan, but the mechanisms responsible for these benefits are not fully understood. Fibroblast growth factor 21 (FGF21) is a hormone strongly induced by low-protein diets and has emerged as an important regulator of metabolic adaptation. We show that FGF21 signalling specifically in adipose tissue is essential for the anti-senescence effects of dietary protein restriction. FGF21 preserves mitochondrial integrity by maintaining nicotinamide adenine dinucleotide metabolism through AMP-activated protein kinase activation. Targeting the FGF21-adipose tissue pathway may provide new strategies to prevent or treat age-related metabolic dysfunction.

This study investigated the responses of growth performance, apparent nutrient digestibility, serum biochemical indices, fecal enzyme activity, short-chain fatty acids (SCFA), and fecal microbiota to a high-fiber diet in Tibetan pigs by manipulating dietary neutral detergent fiber (NDF) levels. Forty healthy Tibetan pigs with an initial body weight (IBW) of (13.46 ± 1.34) kg were randomly assigned to two groups: a control group (CON, NDF 8.80

This study was conducted to investigate the effects of dietary polyunsaturated fatty acid (PUFA) levels and FME (flavor and multiple enzymes) on the reproductive performance, nutrient digestion, and metabolism, immunity, and antioxidant capacity of sows and piglets. Forty primiparous sows [Duroc × (Landrace × York)] were randomly assigned from day 107 of gestation to day 7 post-weaning to one of four dietary treatments, low PUFA (4.6% tallow, LP), high PUFA (4.6% fish oil, HP), and LP and HP, each supplemented with 600 mg/kg FME (LP + FME, HP + FME). Results showed that dietary HP + FME supplementation significantly alleviated sow backfat loss during lactation (p < 0.05). Dietary FME supplementation significantly increased milk lactose and solids-non-fat (p < 0.05) on day 15. Meanwhile, milk protein and true protein contents were significantly lower in the LP treatment than in the LP + FME and HP treatments. The apparent total-tract digestibility (ATTD) of ash and phosphorus was improved (p < 0.05) by both HP diets and FME supplementation. The ATTD of energy and dry matter was significantly higher in LP + FME treatment than in LP and HP + FME treatments (p < 0.05). HP diets increased serum malondialdehyde (MDA, p < 0.01), total superoxide dismutase (p < 0.05) in sows, and increased serum MDA and decreased hydrogen peroxide (H2O2) contents in piglets (p < 0.05). Dietary FME supplementation decreased serum H2O2 contents and increased serum catalase activity of sows and/or piglets (p < 0.05). The serum immune markers, lipid, and protein metabolites of sows and piglets were altered (p < 0.05 or p < 0.10) by HP diets and/or FME supplementation. In conclusion, dietary fish oil (4.6% of diet replacing tallow) and FME (600 mg/kg) supplementation improved lactating performance by improving nutrient digestibility, body reserve mobilization, antioxidant capacity, and health state of sows and piglets.

Nicotinamide riboside (NR) supplementation has been demonstrated efficacy in enhancing female reproductive outcomes, but its regulatory role in sow performance and gut microbiome remains undefined. This study systematically evaluated the impacts of dietary NR supplementation during late gestation and lactation on sow performance and gut microbiome remodeling. A total of 280 sows were randomized assigned to one of four groups: a control group fed basal diet or one of three groups receiving NR-supplemented diets (2, 4, or 8 g/d; n = 70/group). Sow reproductive performance, blood metabolic parameters, milk metabolome, and fecal 16S rRNA sequencing were measured. Maternal NR supplementation linearly shortened farrowing duration (P < 0.01) and tended to decrease the incidence of intrauterine growth restriction and the number of late gestation mummies (P < 0.1), while concurrently increasing the within-litter uniformity (P = 0.1). Litter weaning weight and average daily gain increased quadratically with NR dosage (P < 0.05). NR supplementation orchestrated plasma metabolite regulation (triglycerides and total cholesterol; P < 0.05), enhanced antioxidant biomarkers (T-AOC, GSH-Px, T-SOD; P < 0.05), and reduced inflammatory cytokines (TNF-α; P < 0.05) across gestation and lactation. Milk yield, colostrum/milk dry matter, crude protein, and crude fat were increased (P < 0.05), together with higher levels of NAD+ metabolites (NAD⁺, NR, nicotinamide) and beneficial bioactive factors (milk polar lipids, 3-aminosalicylic acid, fenugreekine; P < 0.05). Gut microbiota analyses at lactation day 14 revealed NR-enriched beneficial taxa (Bifidobacterium, Ruminococcus, Lachnospiraceae, Subdoligranulum, Clostridium butyricum, Succiniclasticum) across sow-offspring dyads, which was associated with the activation of microbial NAD⁺ enzymes (NadR/NAMPT; P < 0.05) and enhancement of systemic short-chain fatty acid flux, notably an increase in plasma butyrate acid (P < 0.05). Maternal supplementation of NR during late gestation and lactation increases sow performance and promotes gut NAD+ metabolic-associated microbiome remodeling. These findings propose maternal NR intervention as a novel strategy to enhance mammary lactogenesis and lactation metabolism in swine production, with potential applications for therapeutic strategies for lactation insufficiency.

Heat stress can severely impair male reproductive performance. Endoplasmic reticulum stress (ERS) is recognized as an early cellular response to stress, which can subsequently induce inflammation and apoptosis, thereby reducing semen quality. In this study, arginine, putrescine, and 4-phenylbutyric acid (4-PBA; an ERS inhibitor) were administered by gavage to a heat-stressed ICR mouse model subjected to seven days of heat exposure, in order to evaluate their effects on testicular function and the underlying mechanisms.Supplementation with arginine, putrescine, or 4-PBA significantly ameliorated heat stress-induced testicular damage and the decline in sperm quality in male mice. Specifically, the mRNA expression of Acrv1, Izumo3, and Tjp1 was markedly upregulated. In contrast, the number of TUNEL-positive testicular cells was significantly reduced, while the mRNA expression of apoptotic markers Bax and Caspase12 was downregulated. Moreover, the expression of ERS- and inflammation-related genes (Grp78, Perk, IRE1, XBP1s, TLR4, and NF-κB) was significantly decreased.In conclusion, heat stress induces testicular dysfunction and inflammation. Both arginine and its metabolite putrescine alleviate heat stress-induced testicular impairment by reducing ERS and inflammatory responses, with arginine showing stronger protective effects than putrescine.

Heat stress (HS) has become an inevitable issue in modern livestock industry. It was universally believed that boars exhibit great reproductive susceptibility to HS, thereby prompting research into nutritional interventions for HS mitigation. Rather than conventional nutritional interventions against HS, modern studies have been concentrating on intestinal microecology. This study aimed to evaluate the prebiotic potential of fructooligosaccharides (FOS) on alleviating HS-induced semen quality impairment. The experiment was conducted as 2 × 2 factorial design and completely randomized design. 40 adult Duroc boars randomly assigned to low-fiber thermoneutral (LF-TN; average body weight = 209.8 kg) group, high-fiber thermoneutral (HF-TN; average body weight = 211.78 kg) group, low-fiber HS (LF-HS; average body weight = 209.55 kg) group and high-fiber HS (HF-HS; average body weight = 213.56 kg) group during 13-week experimental period. HF groups received additional 10% FOS, while HS groups were subjected to a 2-week HS challenge at 33 ℃ room temperature (RT) from week 7 to week 8 (W7–W8). Dietary FOS further exacerbated the rise in rectal temperature under HS conditions (PDiet × RT × time < 0.05). It also aggravated the HS-induced semen quality parameter declines, especially for progressive motility at W10, rapid progressive motility at W9 and effective sperm count at W9 (PHF-HS vs LF-HS < 0.05; HF-HS vs LF-HS < 0.05; HF-HS vs LF-HS < 0.05). Based on mediation analysis, rectal temperature had tendencies toward mediating FOS-induced aggravation in progressive motility, rapid progressive motility and effective sperm count (P < 0.10; P < 0.10; P < 0.10;). On the other hand, the microbial-metabolite target metabolomics detected promotion in fecal pyridoxamine concentration when comparing HF-HS with LF-HS, suggesting pyridoxamine may ameliorate concentration, progressive motility and effective sperm count declines after HS exposure (P HF-HS vs LF-HS< 0.01; Ppyridoxamine vs concentration < 0.05; Ppyridoxamine vs progressive motility < 0.05; Ppyridoxamine vs effective sperm count < 0.05). Collectively, Dietary FOS supplement elevated rectal temperature of pigs under HS conditions, resulting in deterioration of semen quality impairment. Nevertheless, FOS exerted beneficial prebiotic effects by elevating fecal pyridoxamine levels, which potentially mitigated semen quality impairment after HS exposure.

Betulin, a natural pentacyclic triterpenoid, demonstrates potential in combating obesity and metabolic disorders, yet its mechanisms remain incompletely understood. Here, we found that dietary betulin supplementation significantly attenuated body weight gain, improved glucose tolerance, and reduced ectopic lipid accumulation in the liver in mice fed a high-fat diet. Hepatic transcriptomics revealed enrichment of the peroxisome proliferator-activated receptor-α (PPARα) signaling pathway and identified fibroblast growth factor 21 (FGF21) as a key upregulated hepatokine. We found that betulin can regulate liver FGF21 expression via the PPARα signaling pathway both in vivo and in vitro. Our findings were further corroborated by the observation that liver-specific FGF21 knockout abolished betulin's metabolic benefits. Mechanistically, combining molecular dynamics simulations and experimental validation, we demonstrated that betulin acts as a PPARα agonist to induce FGF21 expression. These findings establish betulin as a PPARα agonist and elucidate a hepatokine-dependent pathway underlying betulin's metabolic benefits.

Against the backdrop of the global trend toward delayed childbearing, elucidating the mechanisms underlying uterine aging has emerged as a critical biomedical priority for addressing age-related implantation failure. Through unbiased global metabolomic profiling of peri-implantation uteri across different ages in mice, we identified nicotinamide adenine dinucleotide (NAD+) depletion as a hallmark metabolic feature of endometrial aging. Single-cell RNA sequencing further revealed an expansion of senescent stromal cell populations, which was accompanied by a decline in NAD+ levels. Supplementation with NAD+ precursors alleviated age-related stromal senescence and endometrial dysfunction, thereby restoring the uterus' implantation competence. Mechanically, we demonstrate that CD38 derived from myeloid serves as a principal driver of uterine NAD+ depletion; this process accelerates stromal senescence and impairs uterine receptivity. These findings establish CD38 as a central physiological integrator that links NAD+ metabolism to uterine function and highlight it as a promising target for rejuvenation strategies aimed at improving reproductive outcomes in women of advanced maternal age.

Zearalenone (ZEN), a widespread mycotoxin exhibiting estrogen-like activity, is known to impair placental function; however, the underlying mechanisms remain elusive, and effective targeted interventions are lacking. In this study, we utilized both porcine and rodent models to investigate the effects of ZEN exposure and evaluate the protective efficacy of Lactobacillus_rhamnosus GG (LGG). In pregnant sows, ZEN exposure significantly compromised placental vascular density and efficiency. Full-length 16S sequencing and bile acid-targeted metabolomics revealed that ZEN induced intestinal microbial dysbiosis and disrupted bile acid metabolism. Mechanistically, ZEN induced a pathological polarization of placental macrophages toward an M2-like phenotype, characterized by the overexpression of arginase-1 (Arg-1) and the suppression of nitric oxide (NO) and vascular endothelial growth factor (VEGF) production. Crucially, LGG supplementation reshaped the gut microbiota by enriching Ruminococcus_gnavus, which subsequently increased the production of isolithocholic acid (isoLCA). This metabolic modulation reversed the ZEN-induced aberrant macrophage polarization. Further validation in rodent models confirmed that ZEN drove aberrant hepatic M2 macrophage polarization, a phenotype that was similarly rectified by LGG administration. In conclusion, this study revealed that ZEN impaired placental function by driving pathological macrophage polarization, and indicated that LGG could mitigate this toxicity through alterations in the gut microbiota and bile acid metabolism. These findings provided a novel perspective and a promising nutritional strategy for combating ZEN-induced reproductive toxicity.

Low-birth-weight (LBW) piglets often exhibit glycolipid metabolic disorders at birth, which severely impair their postnatal growth and survival. Bile acids (BAs) act as signaling molecules that participate in the regulation of glycolipid metabolism. However, whether the hepatic metabolic abnormalities observed in LBW piglets are associated with altered BA metabolism remains largely unclear. Thus, using naturally occurring LBW fetal pigs, neonatal piglets, and hepatic cell lines as models, the present study aimed to elucidate the association between BA homeostasis and hepatic glycolipid metabolism and to further reveal the underlying molecular mechanisms through integrated analyses of BA-targeted metabolomics, 16S rRNA gene sequencing, and molecular docking. Compared with normal-birth-weight (NBW) fetal pigs, LBW fetal pigs exhibited a marked reduction in hepatic glycogen storage accompanied by excessive lipid accumulation. As key nuclear receptors governing glycolipid metabolism, farnesoid X receptor (FXR) and hepatocyte nuclear factor 4α (HNF4α) were significantly down-regulated in the liver of LBW fetal pigs at both the transcriptional and protein levels, which was coupled with impaired glycogen synthetic capacity and lipolytic capacity in these fetal pigs. Targeted BA metabolomic analysis revealed a profound alteration in the hepatic BA profile of LBW fetal pigs, characterized by an increased proportion of secondary BAs. Notably, the hepatic level of taurolithocholic acid (TLCA) was markedly decreased in LBW fetal pigs. Further analyses demonstrated that critical processes of BA metabolism, including synthesis, transport, detoxification and conjugation, were impaired in LBW fetal pigs, along with disrupted endogenous TLCA biosynthesis. Mechanistically, molecular docking results suggested that TLCA might act as a potential agonist of FXR and HNF4α. In vitro assays confirmed that TLCA modulated hepatic glycolipid metabolism by activating FXR and HNF4α. More importantly, in vivo studies indicated that exogenous supplementation of TLCA significantly ameliorated hepatic glycolipid metabolism and improved overall liver function in LBW neonatal piglets. These findings reveal crosstalk between hepatic glucose-lipid and BA metabolism via HNF4α and FXR, providing potential nutritional strategies to improve liver health in LBW piglets and a theoretical basis for using BAs as feed additives in pig production.

As delayed childbearing becomes increasingly common, elucidating the mechanisms of age-related placental senescence is critical for the development of effective therapeutic strategies. Here, we integrate metabolomics, single-cell RNA sequencing, and spatial transcriptomics to uncover conserved features of aged placentas in humans, mice, and pigs, namely, increased macrophage CD38 expression and NAD⁺ deficiency. Through pharmacological and genetic approaches, we demonstrate that macrophage CD38 depletes NAD⁺ in decidual stromal cells, thereby promoting placental senescence. Mechanistically, early-onset inflammation and senescence-associated secretory phenotype activity drive CD38 expression in macrophages via the IRF5 pathway. Importantly, treatment with NAD⁺ precursors or CD38 inhibitors attenuates age-related placental senescence, rescues intrauterine growth restriction, and improves long-term metabolic outcomes in offspring. These findings reveal a critical role for macrophage-driven metabolic dysregulation in reproductive aging and establish CD38 as a potential therapeutic target for age-associated pregnancy complications. The authors show that CD38-activated macrophages deplete NAD+ in decidual stromal cells, driving placental senescence and fetal growth restriction during aging. NAD+ restoration in animal models improves pregnancy outcomes and offspring health.

Regulatory T cells (Tregs) are essential for establishing maternal immune tolerance during embryo implantation. Dietary fiber, composed of diverse polysaccharides, has been shown to enhance Tregs populations and improve implantation outcomes, yet the specific components responsible remain unclear. In this study, we investigated the effects of polysaccharide components of dietary fiber, inducing polygalacturonic acid (PGA), arabinoxylan, and cellulose on embryo implantation. We found that PGA significantly promoted implantation, associated with an increased number of decidual Tregs. PGA also enhanced gut microbial diversity and elevated short-chain fatty acids (SCFAs) levels, particularly butyrate, which in turn promoted Tregs differentiation. In vitro, we demonstrated that butyrate enhances Tregs differentiation via GPR43-dependent signaling, which upregulates Tregs associated genes and may activate the adaptive immune response through JAK-STAT and PI3K-Akt pathways. These findings provide new insights into the role of dietary fiber in supporting early pregnancy and suggest novel strategies for preventing embryo loss.

Heat stress (HS) induces adverse intestinal effects, including morphological damage, immune dysfunction, and microbial dysbiosis. Nicotinamide riboside (NR) supplementation has shown promise in protecting against intestinal injury. This study aimed to investigate the efficacy of NR in alleviating HS-induced intestinal damage in a porcine model. Eighteen boars were randomized into three groups (n = 6): control (CON, thermoneutral), heat stress (HS), and HS with NR supplementation (HS-NR). After an initial feeding phase, the HS and HS-NR groups were exposed to an HS environment (35 ± 1°C) for 2 weeks, while the CON group remained thermoneutral. Intestinal injury was assessed via histomorphology, biochemical parameters, transcriptomics, and microbiome sequencing. We found that NR supplementation significantly restored intestinal morphology and attenuated colonic oxidative stress compared to the HS group. Moreover, NR ameliorated HS-induced immune dysfunction and corrected gut microbial dysbiosis. These results suggest the therapeutic potential of NR as a nutritional intervention to mitigate HS-induced intestinal damage.

Long-term nutritional excess causes hepatic steatosis, endoplasmic reticulum (ER) stress, hyperglycemia, and hyperlipidemia. Mitogen-activated protein kinase phosphatase-3 (MKP-3) is a well-established stress-regulated protein and a regulator of gluconeogenesis. Our previous study revealed that acute ER stress reduced gluconeogenesis and MKP-3 protein stability. However, the expression of MKP-3 and its regulatory mechanisms in chronic ER stress remain unclear. The aim of this study was to investigate the effects of chronic ER stress on hepatic MKP-3 expression and its role in the regulation of gluconeogenesis. The results show that long-term administration of thapsigargin (Tg) or palmitic acid promoted gene expression of Mkp-3 and gluconeogenic genes Pepck, G6pc, and Pgc1α in primary mouse hepatocytes. In addition, a long-term high-fat diet (HFD) or Tg administration significantly increased hepatic ER stress and blood glucose level in mice, while inducing the expression of Mkp-3 and hepatic gluconeogenic genes Pepck, G6pc and Pgc1α. Further study revealed that liver-specific Mkp-3 knockout (Mkp-3 LKO) reversed the blood glucose level and expression levels of gluconeogenic genes those were induced by long-term HFD in mice. Moreover, activation of the PKR-like ER kinase (PERK) by its agonist increased hepatic Mkp-3 expression, whereas inhibitor of PERK suppressed the expression of Mkp-3 under Tg administration. These results suggest that chronic high-fat diet might promote hepatic gluconeogenesis via the PERK/MKP-3 pathway. Consequently, this study identified a potential therapeutic target for treating obesity-related hyperglycemia.