ABSTRACT The gut microbiota is crucial in Alzheimer's disease (AD) progression. This study investigated the effects of milk fat globule membrane (MFGM) on AD‐related cognitive deficits and mechanisms involving the gut microbiota–brain axis using APP/PS1 mice. Behavior, physiological indicators, neuroinflammation, and microRNAs (miRNAs) in the hippocampus were examined. Then, serum differential metabolites were explored and used to evaluate anti‐neuroinflammatory and neuroprotective effects in vitro. To further clarify the reasons for alterations in serum metabolites, the role of MFGM on gut microbiota was explored. Then, APP/PS1 mice (AD COH ) were co‐housed with MFGM‐fed APP/PS1 mice (AD+MFGM COH ) to allow microbiota transfer via coprophagy. MFGM mitigated learning and memory deficits, neuronal damage, synaptic dysfunction, and blood–brain barrier leakage, associated with suppression of β‐amyloid (Aβ) accumulation and Tau phosphorylation (p‐Tau Ser396 ). It alleviated neuroinflammation via suppressing expression of inflammatory factors, microglial activation marker ionized calcium‐binding adaptor molecule 1 (IBA‐1) and NLRP3 pathway, which might be correlated with the modulation of miRNA profile in the hippocampus. Moreover, metabolomic analysis identified resolvin D1 (RVD1) and anandamide (AEA) were enriched due to MFGM supplementation. These metabolites regulated miRNAs, suppress neuroinflammation via inhibiting inflammatory factors, IBA‐1 expression, and NLRP3 pathway in BV2 cells, and attenuate p‐Tau Ser396 in SH‐SY5Y cells. Furthermore, MFGM modulated gut microbiota and effects of MFGM on cognitive impairment were proved to be associated with increased serum RVD1 and AEA mediated by gut microbiota. In summary, MFGM attenuated AD‐related cognitive impairment through suppressing neuroinflammation, correlated with the modulation of gut microbiota‐serum RVD1/AEA–brain axis, indicating it could delay AD progression.

Abstract Although intravenous lipid emulsions are routinely administered to preterm infants, their specific effects on skeletal muscle development remain unclear. In this study, a soybean oil‐based lipid emulsion (Intralipid 20®) was administered via intravenous infusion to fetal sheep (gestational day 88–90) at a dose rising from 1 g/kg/day (day 0) to 3 g/kg/day (days 2–8). Intralipid infusion did not alter overall fetal body weight, tibialis anterior (TA) muscle mass or serum testosterone levels. Histological analyses revealed no significant differences in muscle fibre diameter or collagen content in TA muscles between groups. However, Intralipid significantly upregulated the expression of key myogenic regulatory genes, including Myog (myogenin) and Myod (myogenic differentiation 1), while downregulating the expression of several genes associated with fibrogenesis: Col1a1 (collagen type I α1 chain), Col3a1 (collagen type III α1 chain), Lh2b (lysyl hydroxylase 2b) and P4ha (prolyl 4‐hydroxylase α). In contrast, Intralipid had no significant effect on the expression of genes associated with intramuscular adipogenesis, including Pparg (peroxisome proliferator‐activated receptor γ), Pdgfra (platelet‐derived growth factor receptor α), Zfp423 (zinc finger protein 423), Slc27a1 (solute carrier family 27 member 1), C/ebpa (CCAAT/enhancer‐binding protein α) and Fasn (fatty acid synthase). Similarly, genes related to inflammation, such as Tnfa (tumour necrosis factor α), Il‐6 (interleukin 6), Tlr4 (Toll‐like receptor 4) and Tlr2 (Toll‐like receptor 2), were unaffected. In conclusion, these findings indicate that short‐term lipid exposure alters gene expression patterns without measurable structural changes, suggesting that transcriptional responses may precede overt morphological remodelling in fetal skeletal muscle.

Maternal obesity (MO) is a growing global problem, which poses significant risks to fetal neurodevelopment and long-term neurological functions of offspring, but the underlying molecular mechanisms remain to be established. To address this female mice were fed either a control diet or a high-fat diet (HFD) for 2 months to induce obesity, and the same dietary treatments were maintained during pregnancy. Embryos were sampled at E11.5 and E13.5. Single-cell RNA sequencing revealed reduced proportions of neurons and neural progenitors in embryos from obese mothers. The downregulation of neurogenesis, nervous system development and synaptic organization pathways were further confirmed by Gene Ontology analysis. Key neurogenic transcription factors, including Neurod1, Neurog2 and Ascl1, were suppressed in MO embryos, accompanied by increased expression of inflammatory markers, including tumour necrosis factor-α (TNF-α) and Cxcl2, and inflammatory signalling mediators, Fos, Jun and Jund. Single-cell ATAC sequencing revealed the activator protein 1 (AP-1) binding sites in the promoter regions of Tnf and Cd68, with MO-enhancing AP-1 transcription factor motif activity and increased chromatin accessibility in the loci of Tnfa and Cd68 genes. Furthermore, TNF-α treatment of neurogenic cells suppressed Neurod1 and Neurog2 expression, suggesting a direct link between inflammatory signalling and impaired neurogenesis. Our findings suggest that MO creates a pro-inflammatory environment that disrupts neurogenesis during early embryonic development, providing new insights into the neurodevelopmental disorders in offspring born to obese mothers. KEY POINTS: Maternal obesity (MO) suppresses neurogenesis in the early embryos. Single-cell RNA sequencing (scRNA-seq) reveals decreased neurogenic cells and neurogenic factors in MO embryos. MO elevates activator protein 1 (AP-1) transcription factor accessibility to the promoters of inflammatory genes. Inflammation induced by tumour necrosis factor-α (TNF-α) suppresses Neurod1 and Neurog2 expression and neurogenesis in vitro.

Worldwide, both adults and children continue to develop metabolic diseases at an alarming rate. Metabolic syndrome (MetS) refers to a cluster of risk factors associated with an increased risk of noncommunicable diseases. The development of MetS is complex, and its mitigation requires multiple complementary strategies. One promising approach is dietary intervention with nutraceutical-rich foods that strengthen metabolic organs such as the liver and intestines against oxidative stress and inflammation. Potatoes are a widely consumed crop grown globally and are rich in macronutrients and bioactive secondary metabolites, including phenolic acids, carotenoids, and anthocyanins. They also provide resistant starch and dietary fiber that reach the colon undigested, where they positively modulate the gut microbiome, enhance short-chain fatty acid production, and reinforce the intestinal epithelial barrier. This review summarizes how different potato varieties and their chemical constituents mitigate hallmarks of MetS through both direct and indirect mechanisms. Additionally, it discusses molecular pathways induced by potato polyphenols and microbial metabolites that may underlie these effects, with particular emphasis on mediators linking metabolism to intestinal epithelial homeostasis. Current limitations and knowledge gaps are also highlighted, emphasizing the need for standardized potato-based interventions and expanded evaluation of skeletal muscle outcomes.

For proper locomotion, bone and muscle development must be tightly coordinated. Skeletal muscle secretes myokines that affect tissues, including bone. We previously showed that maternal exercise (ME) enhances fetal muscle development through apelin signaling. However, whether mitochondrial dysfunction impairs fetal skeletal development and whether ME mitigates these defects remain unclear. Heterozygous POLG mutant (Polgmut/+) mice were used to examine the effects of ME and apelin signaling on fetal osteogenesis. Pregnant Polgmut/+ females underwent treadmill exercise, and apelin receptor knockdown (ApjKD) mice and maternal apelin supplementation were used to evaluate apelin signaling. POLG mutation impaired fetal osteogenesis and disrupted skeletal morphology. RNA-seq revealed downregulation of pathways related to cytoskeletal organization and mitochondrial function. ME was associated with upregulation of osteogenesis and development. ME increased apelin abundance in maternal-fetal circulation and tissues, including fetal muscle and bone. Importantly, apelin administration increased fetal osteogenesis in POLG mutation, whereas ApjKD reduced osteogenic signaling in fetal bone and myogenic gene expression in fetal muscle. Apelin also enhanced mitochondrial respiration in fetal bone-derived osteogenic cells. Mechanistically, ME-induced apelin signaling was associated with increased mitochondrial biogenesis and enhanced ATF4-RUNX2 regulatory signaling. Collectively, these findings suggest that ME-induced apelin signaling contributes to fetal skeletal development under mitochondrial dysfunction.

42% of American women of childbearing age are obese, impacting offspring muscle and metabolism. The IGF2 pathway is vital for muscle growth, but its regulation by maternal obesity (MO) remains unclear. H19, a long non-coding RNA, is reciprocally regulated with Igf2, which has multiple promoters (P0-P3). H19 interacts with EZH2, the catalytic subunit of Polycomb Repressive Complex 2 depositing H3K27me3. We found that MO increased fetal H19 expression and investigated how H19 epigenetically regulates Igf2 in offspring muscle. C57BL/6J female mice were fed a control (10% fat) or high-fat diet (45% fat) to induce obesity before mating, continuing through pregnancy and lactation. Neonates were sampled for biochemical analysis, and 3-month-old offspring were used for assessing muscle function and metabolism. MO increased H19 expression, enhancing H19-EZH2 interaction and H3K27me3-mediated repression of Igf2 in the P3 promoter, leading to hypermethylation and impaired muscle function in offspring. In addition, offspring with myogenic cell-specific H19 overexpression were also used. Weaning offspring with H19 overexpression showed reduced muscle mass, strength, endurance, and altered structure. Primary myogenic cells from H19 overexpressing neonates showed suppressed Igf2 expression, promoter activity, and myotube formation, which were recovered upon IGF2 treatment. In C2C12 and human skeletal myoblast cells, H19 overexpression disrupted IGF2 signaling, increased EZH2 recruitment, and reduced myotube formation, while its knockdown had opposite effects. Additionally, EZH2 inhibition reduced H3K27me3 deposition and methylation in the Igf2 P3 promoter. These data show that MO impairs muscle development by disrupting IGF2 signaling through H19-EZH2 interaction, affecting offspring muscle function.

Marbling or intramuscular fat (IMF) is one of the major quality attributes of beef. Intramuscular adipocytes develop later than subcutaneous, visceral, and intermuscular fat depots during early development. The variation in developmental timing among fat depots can be leveraged as a targeted strategy to enhance marbling. Vitamin A regulates cell proliferation and differentiation via its active metabolite retinoic acid. Recent studies indicate that vitamin A supplementation to beef cattle during the late gestation and neonatal stages promotes the formation of IMF adipocytes (adipogenesis/ adipocyte hyperplasia), which provide sites for IMF accumulation during the fattening stage. On the other hand, vitamin A promotes lipid oxidation, and its restriction during the finishing stage increases IMF deposition and achieves a higher ratio of prime-grade carcasses. In conclusion, the stage-specific vitamin A management strategy can be effectively utilized to maximize IMF deposition and improve beef quality.

Background: Long non-coding RNA H19 is abundantly expressed in stem cells and has emerged as a key regulator of the balance between stem cell self-renewal and differentiation. Growing evidence highlights its involvement in multiple developmental and pathological contexts; however, its role in skeletal muscle regeneration remains largely unexplored. We hypothesized that aberrant H19 expression disrupts effective muscle repair by directly inhibiting satellite cell activation, proliferation, and myogenic differentiation. Methodology: Homozygous H19 imprinting control region (ICR) floxed male mice were crossed with heterozygous Pax7-CreER female mice to generate satellite cell–specific H19 overexpression (H19 OE) and control mice respectively. Skeletal muscle injury was induced in the tibialis anterior (TA) muscle, and tissue samples were collected at 3, 7, and 14 days post-injury (dpi). Western blotting, RT-qPCR, histological staining, and immunofluorescence were used to assess gene expression, protein abundance, and regenerative outcomes. Results: H19 OE impaired muscle regeneration by reducing key trophic and pro-myogenic factors, including Igf1, Wnt1, Wnt3a, and Wnt5a, as well as decreasing desmin protein, which suppressed satellite cell proliferation and myogenic activity. H19 OE profoundly dysregulated the inflammatory response during regeneration. At 7 days post-injury (dpi), H19 OE exhibited elevated levels of pro-inflammatory cytokines accompanied by a reduction in anti-inflammatory cytokines, suggesting a failure to properly resolve inflammation. This persistent inflammatory state is known to exacerbate fibrogenesis and further suppress satellite cell-mediated repair. Importantly, H19 OE also altered the dynamics of fibro-adipogenic progenitors (FAPs), key regulators of the muscle regenerative microenvironment. At 14 dpi, H19 OE muscles displayed increased accumulation of FAPs, which was attributed to reduced FAP apoptosis rather than enhanced proliferation. The prolonged survival and accumulation of FAPs likely contributed to sustained fibrosis and impaired resolution of the regenerative process. H19 OE promoted a pronounced fibrotic response within regenerating muscle. This was evidenced by increased expression of fibrogenic markers, including collagen type I (COL1A) and TCF4, along with enhanced activation of TGF-β signaling, a central driver of extracellular matrix deposition and fibroblast activation. These changes indicate a shift in the regenerative niche toward a pro-fibrotic microenvironment that is unfavorable for myofiber regeneration. Conclusions: Overall, these findings show that H19 impairs muscle regeneration by suppressing the myogenic activity of satellite cells and prolonging inflammation, thereby promoting fibrosis. These data suggest H19 as a potential therapeutic target for improving muscle repair. Funding sources: This research was funded by the National Institute of Child Health and Human Development through research grant R01HD067449. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Maternal obesity (MO) alters the intrauterine environment and increases the risk of a variety of developmental outcomes; however, the effects on placental cell population and development remain unclear. In this study, we investigated the impact of MO on placental cellular composition, development, and morphology in C57BL/6J mice fed a control or high-fat diet. Single-cell RNA sequencing of embryonic day (E) 13.5 placentas identified 16 transcriptionally distinct cell populations and revealed a reduction in the trophoblast progenitor cell population in MO placentas. MO suppressed trophoblast genes involved in placental development and mitochondrial oxidative phosphorylation, accompanied by decreased protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key regulator of mitochondrial biogenesis. Furthermore, MO reduced the expression of Hand1 and Tfap2c, transcription factors involved in trophoblast differentiation and placental development, whereas increasing prolactin-family gene expression and STAT5 phosphorylation. At E17.5, MO caused female-specific reductions in placental weight and labyrinth zone area, along with increased Tnf expression and sustained suppression of Hand1 in female placentas. These findings suggest that MO disrupts trophoblast differentiation and placental metabolic function during midgestation, which may contribute to placental vulnerability later in pregnancy.NEW & NOTEWORTHY Using placental single-cell RNA sequencing at embryonic day (E) 13.5, we found that maternal obesity (MO) was associated with a lower observed trophoblast proportion and downregulation of placental-development and oxidative-phosphorylation programs. These changes occurred alongside reduced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) protein and activated JAK-STAT signaling. At embryonic day 17.5, female placentas from obese dams showed reduced weight and labyrinth area, revealing sex-dependent placental vulnerability.

Maternal obesity (MO) impairs immunological development in the offspring with poorly defined mechanisms. By integrating single-cell RNA sequencing datasets from placentas and fetal livers of diet-induced obese mice, data showed that MO markedly enhances inflammatory and immune activation within the placenta but induces immunosuppression in fetal liver. Inter-organ cell-cell communication analysis further revealed that placental Spp1 signaling sent by macrophage potentiates TGFβ/Smad signaling in fetal liver immune cells, which promotes Rbl2 upregulation and induces a G1 phase arrest in T cells and basophils. Finally, T cell function is inhibited by MO. Totally, this study identifies a potential placental-fetal liver Spp1-TGFβ-Rbl2 axis associated with fetal immunosuppression due to MO.

Maternal obesity alters H19 expression, disrupting epigenetic modifications during embryonic development, impairing muscle development, promoting fibrogenesis, and perturbing metabolic homeostasis, thereby predisposing offspring to fibrosis and metabolic dysfunction. Metformin in early pregnancy may mitigate these alterations by modulating placental H19 through AMP-activated protein kinase (AMPK) and epigenetic regulation, improving offspring metabolic health.

42% of American women of childbearing age are obese, impacting offspring muscle and metabolism. The IGF2 pathway is vital for muscle growth, but its regulation by maternal obesity (MO) remains unclear. H19, a long non-coding RNA, is reciprocally regulated with Igf2, which has multiple promoters (P0-P3). H19 interacts with EZH2, the catalytic subunit of Polycomb Repressive Complex 2 depositing H3K27me3. We found that MO increased fetal H19 expression and investigated how H19 epigenetically regulates Igf2 in offspring muscle. C57BL/6J female mice were fed a control (10% fat) or high-fat diet (45% fat) to induce obesity before mating, continuing through pregnancy and lactation. Neonates were sampled for biochemical analysis, and 3-month-old offspring were used for assessing muscle function and metabolism. MO increased H19 expression, enhancing H19-EZH2 interaction and H3K27me3-mediated repression of Igf2 in the P3 promoter, leading to hypermethylation and impaired muscle function in offspring. In addition, offspring with myogenic cell-specific H19 overexpression were also used. Weaning offspring with H19 overexpression showed reduced muscle mass, strength, endurance, and altered structure. Primary myogenic cells from H19 overexpressing neonates showed suppressed Igf2 expression, promoter activity, and myotube formation, which were recovered upon IGF2 treatment. In C2C12 and human skeletal myoblast cells, H19 overexpression disrupted IGF2 signaling, increased EZH2 recruitment, and reduced myotube formation, while its knockdown had opposite effects. Additionally, EZH2 inhibition reduced H3K27me3 deposition and methylation in the Igf2 P3 promoter. These data show that MO impairs muscle development by disrupting IGF2 signaling through H19-EZH2 interaction, affecting offspring muscle function.

Forty-two percent of American women of childbearing age have obesity, impacting offspring muscle and metabolism. The insulin-like growth factor 2 (IGF2) pathway is vital for muscle growth, but its regulation by maternal obesity (MO) remains unclear. H19, a long noncoding RNA, is reciprocally regulated with Igf2, which has multiple promoters (P0–P3). H19 interacts with EZH2, the catalytic subunit of polycomb repressive complex 2 depositing H3K27me3. We found that MO increased fetal H19 expression and investigated how H19 epigenetically regulates Igf2 in offspring muscle. C57BL/6J female mice were fed a control (10% fat) or high-fat diet (45% fat) to induce obesity before mating, continuing through pregnancy and lactation. Neonates were sampled for biochemical analysis, and 3-month-old offspring were used for assessing muscle function and metabolism. MO increased H19 expression, enhancing H19-EZH2 interaction and H3K27me3-mediated repression of Igf2 in the P3 promoter, leading to hypermethylation and impaired muscle function in offspring. In addition, offspring with myogenic cell-specific H19 overexpression were also used. Weaning offspring with H19 overexpression showed reduced muscle mass, strength, and endurance and altered structure. Primary myogenic cells from H19 overexpressing neonates showed suppressed Igf2 expression, promoter activity, and myotube formation, which were recovered upon IGF2 treatment. In C2C12 and human skeletal myoblast cells, H19 overexpression disrupted IGF2 signaling, increased EZH2 recruitment, and reduced myotube formation, while its knockdown had opposite effects. Additionally, EZH2 inhibition reduced H3K27me3 deposition and methylation in the Igf2 P3 promoter. These data show that MO impairs muscle development by disrupting IGF2 signaling through H19-EZH2 interaction, affecting offspring muscle function. ARTICLE HIGHLIGHTS:H19-mediated epigenetic modifications alter Igf2 promoter activity, leading to persistent Igf2 suppression in maternal obesity (MO) offspring, causing long-term muscle dysfunction. MO increases H19 expression and enhances EZH2 recruitment and H3K27me3 deposition in the Igf2 P3 promoter, leading to higher DNA methylation. H19-EZH2 axis provides a potential therapeutic target for mitigating MO-induced muscle dysfunction and improving offspring metabolic health.

Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder characterized by hyperandrogenism, inflammation, and ovarian dysfunction. Although exercise has been recognized as an effective nonpharmacological strategy for managing PCOS symptoms, the molecular mechanisms underlying its therapeutic benefits remain unclear. In this study, we used a dehydroepiandrosterone-induced PCOS mouse model to investigate how aerobic exercise ameliorates ovarian pathology. Our results demonstrated that exercise restored the estrous cycle, reduced ovarian cyst formation, and alleviated ovarian fibrosis and inflammation. Exercise upregulated ATP-dependent protease Lon peptidase 1 (LONP1) expression, accompanied by normalization of key steroidogenic protein levels, cytochrome P450 side-chain cleavage enzyme (CYP11A1), and steroidogenic acute regulatory protein (StAR). In parallel, exercise activated AMP-activated protein kinase (AMPK), which was accompanied by restoration of LONP1-associated mitochondrial proteolytic capacity and normalization of steroidogenic enzyme turnover. Exercise also enhanced mitochondrial biogenesis-related markers, including peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and peroxisome proliferator-activated receptor-α (PPARα), suggesting improved mitochondrial homeostasis in the PCOS ovary.NEW & NOTEWORTHY This study identifies mitochondrial proteostasis as an important molecular mechanism underlying the beneficial effects of aerobic exercise in improving polycystic ovary syndrome (PCOS). Exercise attenuated PCOS development and pathology through normalizing steroidogenic enzyme degradation via LONP1 upregulation, suppressing ovarian inflammation and fibrosis, and activating mitochondrial biogenesis pathways. Although the beneficial effects of exercise on PCOS have been well recognized, this study reveals the mitochondrial proteostasis pathway underlying these preventive effects.

Goat milk offers advantages such as enhanced absorption and reduced allergenicity. Its proteins are a significant source of bioactive peptides. Among these, antioxidant activity and angiotensin-converting enzyme (ACE) inhibition are the most reported bioactivities. This review summarizes the preparation, purification, identification, and activity of antioxidant peptides derived from goat milk (APs-GM) and ACE-inhibitory peptides derived from goat milk (ACEIPs-GM). Peptides with molecular weights below 3 kDa possessing a hydrophobic amino acid at the C- or N-terminus showed potent antioxidant and ACE inhibitory activities, both with inhibition rates exceeding 60%. ACEIPs-GM exerts bioactivity via non-competitive and mixed-type inhibition, utilizing hydrogen bonding and hydrophobic interactions at the ACE active site. In contrast, APs-GM functions by modulating endogenous antioxidant enzyme activity and regulating three signaling pathways: nuclear factor kappa-B (NF kappa B), Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2-antioxidant response element (Keap1-Nrf2-ARE), and mitogen-activated protein kinase (MAPK). Notably, the implementation of combination therapies based on peptides and nano-encapsulation strategies has markedly enhanced therapeutic bioactivity (by approximately 50%) and reduced bitterness. Nevertheless, the relationship between the secondary structures of peptides (R-sheet, alpha-helix, and random coil) and their bioactivities has not yet been elucidated. Additionally, the limited availability of clinical experimental data supporting these activities highlights crucial directions for future research efforts.

Maternal obesity is a major global health challenge worldwide, significantly increasing the risk of pregnancy complications and long-term metabolic disorders in offspring. Maternal obesity, including associated gestational diabetes, induces epigenetic modifications that can reprogram fetal development and predispose children to lifelong health issues. Long non-coding RNA (lncRNA) H19, one of the first and most extensively studied lncRNAs, plays a pivotal role in developmental programming by regulating gene imprinting, microRNA processing, protein stabilization, and signaling pathways critical for growth and metabolism. Dysregulation of H19 expression under maternal obesity alters the H19/Igf2 (insulin-like growth factor 2) imprinting axis, disrupts skeletal muscle development, and modifies osteogenic and neurogenic pathways, thereby contributing to systemic insulin resistance, metabolic dysfunction, and neuro-disorder in offspring. This review highlights how maternal obesity reprograms offspring health through H19-mediated epigenetic and post-transcriptional regulation, emphasizing its role in the developmental origins of health and disease framework. Understanding the role of H19 offers valuable opportunities to develop targeted interventions that may reduce the transgenerational effects of obesity.