Search Results (2,080)

Adipocytes produce the hormone leptin, a hormone that links energy availability to reproductive function by permitting activation of the hypothalamic–pituitary–gonadal (HPG) axis. Loss-of-function mutations in the long leptin receptor isoform (LEPRb) disrupt intracellular signaling pathways, including the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways, resulting in central leptin resistance and impaired neuroendocrine control of reproduction. Evidence from human monogenic obesity syndromes, animal models, and neuroendocrine studies indicates that LEPRb mutations disrupt hypothalamic circuitry upstream of gonadotropin-releasing hormone (GnRH) neurons, impairing GnRH pulsatility and leading to hypogonadotropic hypogonadism (HH) and infertility. This review synthesizes molecular, translational, and clinical data highlighting the central role of kisspeptin-mediated signaling in leptin-dependent reproductive regulation. Current therapeutic limitations are discussed alongside emerging approaches, including kisspeptin-based therapies and receptor-targeted strategies. Elucidating how LEPRb dysfunction disrupts metabolic–reproductive integration may provide insights into both rare monogenic conditions and common obesity-associated reproductive dysfunction. Full article

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine–metabolic disorder associated with insulin resistance (IR), visceral adiposity, and increased cardiometabolic risk. The visceral adiposity index (VAI) is a validated surrogate marker of adipose tissue dysfunction, but its relationship with circulating neurotrophins and adipokine balance in PCOS remains incompletely understood. In this study, 100 women with PCOS were stratified into lower- (n = 50) and higher-risk (n = 50) groups according to VAI. Anthropometric measures, fasting glucose and insulin concentrations, lipid profile, and serum levels of brain-derived neurotrophic factor (BDNF), nerve growth factor-β (NGFβ), leptin, adiponectin, and resistin were assessed. HOMA-IR, adipokine ratios and atherogenic indices were calculated. Multivariate regression showed that BDNF was independently associated with VAI and non-HDL cholesterol, whereas NGFβ was independently linked to HDL cholesterol and estradiol, highlighting neurotrophin relationships with metabolic and endocrine parameters beyond general adiposity. Correlation heatmap and network analyses demonstrated interconnected clusters linking visceral adiposity, IR, dyslipidemia, adipokine imbalance, and neurotrophins, with the leptin/adiponectin ratio emerging as a central integrative marker. These findings suggest that within a PCOS population, VAI-defined cardiometabolic risk is associated with distinct neurotrophin–adipokine signatures, highlighting neurotrophin–adipokine networks underlying visceral adiposity-driven cardiometabolic and endocrine risk. Full article

Background/Objectives: Fetal growth restriction (FGR) represents a model of adverse intrauterine programming associated with an increased risk of cardiometabolic disorders later in life. We examined the relationships between birth weight, catch-up growth, adipokine signaling, and early cardiometabolic risk in adolescents. Methods: This cross-sectional study included 80 term-born adolescents (40 FGR, 40 controls) matched for age and sex. Anthropometry, blood pressure, lipid profile, fasting glucose, adipokines (leptin, adiponectin), and ghrelin levels were assessed. Associations between birth weight, growth rate, adipokines, and cardiometabolic outcomes were analyzed. Results: Birth weight was not associated with adiposity, lipid profile, blood pressure, or glycemic status (p > 0.05). In contrast, catch-up growth in the FGR group was correlated with increased BMI (ρ = 0.680, p < 0.001), central adiposity (ρ = 0.714, p < 0.001), systolic blood pressure (ρ = 0.448, p = 0.0037) and diastolic blood pressure (ρ = 0.325, p = 0.0409). Mediation analyses showed that the current BMI largely explains the associations between catch-up growth and cardiometabolic risk, systolic blood pressure, and waist circumference (β = 2.832 kg/m² per 1-unit increase in ΔZ; p < 0.001). The hypertensive effect of catch-up growth was amplified in overweight/obese adolescents (β = 8.13 mmHg; p = 0.006). Catch-up growth was independently associated with higher leptin (β = 220 ng/L; p = 0.022) and a higher leptin/ghrelin ratio (β = 2.330; p = 0.034). Conclusions: Postnatal growth acceleration, rather than fetal size alone, drives early cardiometabolic susceptibility following FGR through adiposity-mediated and endocrine pathways. Full article

Dietary fat quality, determined by fatty acid composition, plays a central role in regulating adipose tissue function and metabolic homeostasis in obesity. This study examined whether different dietary fat sources modulate the secretory activity, antioxidant capacity, and metabolomic profiles of visceral adipose tissue (VAT) in mice with established high-fat diet (HFD)-induced obesity. Male C57BL/6J mice were rendered obese by long-term feeding with a lard-based HFD and subsequently maintained on isocaloric HFDs containing lard, coconut oil, olive oil, or fish oil. Antioxidant capacity, redox enzyme activities, adipokine levels, and untargeted metabolomic profiles of VAT were analyzed. Fish oil-enriched HFD significantly improved antioxidant potential and partially restored redox enzyme activity compared with the lard-based diet. It preserved adiponectin levels and reduced leptin accumulation in VAT. Multivariate metabolomic analyses showed clear separation of dietary groups and distinct metabolic signatures related to fat quality. Replacement of lard with fish oil induced a coordinated remodeling of the lipid and amino acid metabolism and reduced metabolites linked to mitochondrial overload and oxidative stress, whereas saturated fat-rich diets promoted patterns consistent with metabolic dysfunction. These findings indicate that dietary fat quality reshapes adipose tissue metabolism in obesity and highlights fish oil as a strategy to attenuate adipose tissue dysfunction. Full article

Osteoarthritis (OA) is a prevalent degenerative joint disease which affects millions of patients across the globe. The infrapatellar fat pad (IPFP) harbors diverse cell types with intricate intercellular interactions. Its mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) possess significant biological functions and hold promising applications in regenerative medicine. IPFP exhibits active secretory capacity, releasing adipokines including leptin and adiponectin, along with various cytokines. Furthermore, it contains a rich neural network playing a crucial role in knee pain perception and sensation. Moreover, IPFP and synovium can be considered an integrated unit, exhibiting interactions both with each other and with cartilage. In imaging applications, IPFP is gaining widespread attention as an emerging biomarker. In clinical practice, the decision to resect or preserve IPFP remains a controversial topic. This article will review the latest research regarding the mechanism of IPFP in OA, and discuss its clinical applications, providing a theoretical basis for the prevention and treatment of OA. Full article

While PCOS research has extensively explored genomic, transcriptomic, proteomic, and metabolomic milieus, our study examines the plasma glycome, comparing women with PCOS to age-matched healthy controls. In this observational study, n = 47 women with PCOS were screened and enrolled at the UC Davis Health campus; the comparator group constituted of n = 25 age-matched healthy women. During a study visit, body weight and body composition were measured, and fasted plasma samples were obtained to measure glucose, insulin, circulating lipids, and leptin, among other parameters, in both groups. In addition, in the PCOS group, circulating androgens and other endocrine hormones were measured. The plasma glycome was measured using a UHPLC-MS protocol. As expected, women with PCOS had higher body weight (p < 0.01), body fat (p = 0.004), fasting leptin (p = 0.01), insulin (p = 0.003), and glucose (p = 0.004). Hybrid-type glycans were reduced (p = 0.019), while tetraantennary (glycans with four branches) were modestly increased (p = 0.05) in women with PCOS compared to healthy controls. SVEM–LASSO (bootstrapped) regression models further supported a higher tetraantennary and lower hybrid glycan profile as representative of women with PCOS (AUROC: 0.81, accuracy: 82), even when adjusted for body weight (AUROC: 0.89, accuracy: 80) and body fat mass (AUROC: 0.89, accuracy: 86). Furthermore, in women with PCOS, total testosterone was positively correlated with tetraantennary glycans (r = 0.322, p = 0.029). We report novel findings of elevated tetraantennary and reduced hybrid-type N-glycans in PCOS, and a potential association between circulating androgens and protein glycosylation. Given the pilot nature of this study, larger cohort investigations are required to validate these observations. Full article

Studies conducted in first-episode psychosis (FEP) patients have shown alterations in inflammation and metabolism. Our objective was to investigate potential treatment-related effects on these systems in Italian FEP patients undergoing either an experimental treatment consisting of a multi-element psychosocial intervention (EXP), including cognitive–behavioural therapy, or treatment as usual (TAU). A total of 191 FEP patients with first contact between April 2010 and March 2011 were clinically assessed at baseline and after 9 months of treatment, and the serum levels of 19 analytes were determined through single or multiplex enzyme-linked immunosorbent assays (ELISAs). A significant increase was observed in leptin levels and a significant decrease in Glucagon-Like Peptide-1 (GLP-1) levels during the treatment (time effect, p < 0.001 for both), with no significant interaction between time and treatment type. Although ghrelin levels changed significantly over time in the whole cohort (p = 0.008), a significant decrease was observed only in the EXP group (post hoc test: p = 0.001). None of the biomarkers measured at baseline showed a predictive effect on treatment efficacy, and no significant associations were identified between changes in clinical scores and changes in biomarker levels. These results suggest that early-phase psychosis treatments are associated with possible effects on metabolic regulation. Full article

Background: Rare sugar D-Allulose, a zero-calorie sweetener, markedly ameliorates obesity. It reportedly stimulates the release of endogenous glucagon-like peptide 1 (GLP-1) to activate vagal afferent and directly influences the neurons in hypothalamic arcuate nucleus (ARH), thus evoking vagal and central nervous routes. D-Allulose can now be produced substantially, being expected for diet therapy. Oral form GLP-1 receptor agonist (GLP-1RA), Oral semaglutide (O-Sema), without injection markedly ameliorates obesity. It evokes only central nervous route. Thus, these GLP-1-based substances utilize common/distinct routes, suggesting common/distinct effects on obesity and related disorders including sarcopenia. To address it, this study precisely compared their effects. Methods: O-Sema and D-Allulose were administered to diet-induced obese mice under identical conditions, equivalent doses, oral gavage, and food/water deprivation. Acute and sub-chronic effects on food intake, body weight and grip strength were measured. Results: Acutely, D-Allulose rapidly and O-Sema slowly reduced feeding. Sub-chronically, D-Allulose and O-Sema profoundly reduced food intake and weight in the early period (0–3 days) of treatment. The weight loss was diminished with O-Sema but maintained with D-Allulose in the late period (4–10 days) and after termination of treatment. D-Allulose and O-Sema increased muscle strength. Mechanistically, D-Allulose and semaglutide similarly activated anorexigenic leptin-responsive neurons while only D-Allulose significantly inhibited orexigenic ghrelin-responsive neurons in ARH. Conclusions: D-Allulose and O-Sema equally elicit weight reduction possibly via the central nervous route including ARH anorexigenic neuron activation. The weight loss is rebounded with O-Sema, while it is maintained with D-Allulose possibly via combined vagal afferent and central nervous routes including ARH orexigenic neuron inhibition. Their optimal use potentially provides precise control of obesity and related disorders. Full article

Pancreatic exocrine secretion is regulated by the physicochemical properties and nutrient composition of gastric and intestinal chyme. The present study examined integrative feedback mechanisms involved in the physiological control of pancreatic secretion, with particular emphasis on interactions between pancreatic juice, bile, and gut-derived regulatory and metabolic signals. A chronic porcine model enabling selective withdrawal and controlled reintroduction of pancreatic juice and bile into defined intestinal segments was employed. Duodenal and ileal exposure to pancreatic juice suppressed pancreatic enzyme secretion, while intraduodenal administration of pancreatin elicited a biphasic inhibitory response. Interruption of bile flow to the duodenum resulted in increased pancreatic protein output and was associated with reduced circulating cholecystokinin concentrations. In contrast, intraduodenal infusion of bile acids attenuated pancreatic exocrine secretion. Prolonged bile deprivation led to sustained pancreatic hypersecretion accompanied by a marked reduction in biliary leptin output. Collectively, these findings indicate that pancreatic exocrine secretion in pigs is regulated by multiple interacting feedback pathways operating along the gastrointestinal tract. The observed responses support functional contributions of protease-dependent luminal feedback, distal intestinal sensing, hormone-dependent regulation, and bile-associated metabolic modulation. Full article

Most dementias are preceded by mild cognitive impairment (MCI), a transitional clinical stage characterized by cognitive decline that does not yet significantly interfere with activities of daily living. Obesity and diabetes are among the major risk factors for MCI and are strongly associated with unhealthy lifestyle patterns. The growing global prevalence of obesity has intensified the need for effective dietary strategies that promote both weight control and neuroprotection. Red fruits, which are rich in bioactive compounds such as anthocyanins, have demonstrated potential roles in modulating metabolic pathways and cognitive function. This systematic review aimed to identify and synthesize evidence from human studies published over the past two decades that examined the effects of red fruit consumption on obesity-related mechanisms and cognitive outcomes, as well as its influence on key neurodegenerative biomarkers, including TAU protein, β-amyloid, and neurofilament light chain. A systematic search was conducted in major scientific databases to identify human clinical trials evaluating the metabolic and neuroprotective effects of berry-derived compounds. Eligible studies were screened for outcomes related to cognitive performance, obesity-related parameters, and relevant molecular biomarkers. The included studies reported modest improvements in cognitive domains, with the most consistent effects observed in memory-related outcomes. Berry-derived bioactive compounds demonstrated potential in attenuating TAU protein hyperphosphorylation and reducing β-amyloid accumulation; however, the available evidence remains limited and requires further confirmation. Human clinical studies remain scarce, and although some trials reported favorable metabolic effects, these findings are still inconclusive. Reported outcomes included improvements in insulin sensitivity, regulation of leptin levels, and modulation of the gut–brain axis, which may collectively contribute to a reduced risk of obesity. Based on the studies evaluated in this review, there remains a limited number of human clinical trials that robustly support the neuroprotective and complementary metabolic effects of berry-derived bioactive compounds. Nevertheless, the available evidence suggests that dietary strategies incorporating wild fruits rich in polyphenols may represent a promising complementary approach for the prevention of mild cognitive impairment (MCI) and obesity, with potential implications for reducing the risk of dementia progression. Full article

Background/Objectives: Among more than 300 candidate genes for obesity, FTO, MC4R, and BDNF have been approved for DTC genetic testing. However, population-specific evidence supporting their relevance to obesity-related phenotypes in Koreans remains limited. Methods: A total of 231 healthy adults aged 19–64 years were recruited between March and May 2024. Anthropometric and clinical measurements, genotyping, dietary intake, and questionnaires on socioeconomic status, family history, and lifestyle behaviors were obtained. Associations between genotypes and obesity-related phenotypes were evaluated using ANOVA and ANCOVA, multivariable-adjusted models and multicollinearity analysis-based stepwise regression. Results: In Koreans, MAFs for FTO (3 SNPs), MC4R rs17782313 and BDNF rs6265 were 13–16%, 27.1% and 47.4%, respectively. OB frequency (%) differed significantly between BDNF GG and A allele carriers (p < 0.05). Compared to GG, BDNF A allele carriers showed higher WHR, ALT, HbA1c and sodium intake (p < 0.05). BDNF A allele carriers were observed to have higher drinking frequency and elevated ALT levels. Significant genotype–obesity interactions were identified for RMR/BW status, dietary fiber, Vit E, folate, P, K, cholesterol, and PUFA (p < 0.05). Among A allele carriers, OB-related indicators (BMI, RMR, WHR) were independently associated with age, sex, RMR, SBP, ALT, leptin, and dietary intakes of Vit A and sugars. Conclusions: These findings support the relevance of BDNF rs6265 in obesity phenotypes among Korean adults and provide Korean-specific evidence for genotype-based nutrition strategies. Given the cross-sectional study, the interpretation of personalized nutrition approaches for genetic risk carriers should be made with caution. Full article

Neuroplacentology is an emerging field of research supporting that the placenta actively contributes to the fetal brain development through the release of bioactive molecules. Recent angiogenesis-focused data showed that prenatal alcohol exposure (PAE) disrupts inter-organ gene expression between the placenta and fetal cortex. The present study aimed to perform the first comprehensive and untargeted analysis of a murine placenta–cortex transcriptomic database of PAE. Gene lists from a recently NCBI-deposited PAE Placenta–Cortex transcriptomic database were analyzed using g:Profiler for unbiased functional profiling querying Gene Ontology, KEGG, and Reactome databases. Genes intersecting with cell–cell communication terms were submitted to STRING and ShinyGO analyses to identify enriched protein–protein interactions and pathways. Several ligand or receptor candidates were then validated by Western blot. g:Profiler revealed 21 enriched GO functional maps, seven KEGG pathways, and six Reactome pathways, of which 11 were related to cell-to-cell communication. STRING analysis exhibited substantial protein–protein interaction enrichments supporting that proteins belonging to the functional maps and pathways are biologically connected. Notably, 38 ligands or receptors from endocrine families including angiotensinogen, leptin, somatostatin, or PACAP were identified. Western blot analysis of protein candidates showed different validation patterns. In particular, the PACAP receptor family confirmed transcriptomic findings and revealed sex-dependent PAE-impacted expression profiles. The present study indicates that PAE is associated with alterations in the transcriptomic placenta–cortex expression profile, including changes in the expression ratios of several ligands and/or receptors implicated in key physiological pathways such as energy balance, vascular development, and neurogenesis. These transcriptomic associations suggest that altered placenta–fetal brain signaling at the gene expression level may be involved in alcohol-induced neurodevelopmental disorders, highlighting the need for future functional validation studies. Full article

This study investigated the effects of a high-fat diet (HFD), particulate matter (PM) exposure, and resistance exercise training on circulating lipid profiles, adipokines, inflammatory responses, neurotrophic factors, and blood–brain barrier (BBB) permeability. Forty-eight 10-week-old male C57BL/6 mice were randomly assigned to four groups (n = 12 per group): normal diet (ND), HFD, HFD with PM exposure (HFD + PM), and HFD with PM exposure plus exercise training (HFD + PM + EX). ND and HFD were administered for 16 weeks, whereas PM exposure and exercise training interventions were initiated after 8 weeks of dietary treatment and continued for an additional 8 weeks. PM was administered via tail vein injection three times per week, and resistance exercise training consisted of a ladder-climbing exercise performed five times per week. The results indicated that body weight, total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), leptin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), S100 calcium-binding protein B (S100B), and neuron-specific enolase (NSE) levels were significantly higher in the HFD group than in the ND group (p < 0.05), whereas adiponectin and brain-derived neurotrophic factor (BDNF) levels were significantly lower (p < 0.05). In addition, the HFD + PM group exhibited significantly lower BDNF and vascular endothelial growth factor (VEGF) levels (p < 0.05) and significantly higher S100B and NSE levels (p < 0.05) than the HFD group. In contrast, the HFD + PM + EX group showed significantly lower TG, LDL-C, leptin, and IL-6 levels than the HFD group (p < 0.05). Moreover, compared with the HFD + PM group, the HFD + PM + EX group demonstrated significantly lower TG, LDL-C, leptin, S100B, and NSE levels (p < 0.05) and significantly higher high-density lipoprotein cholesterol (HDL-C), adiponectin, BDNF, and VEGF levels (p < 0.05). Collectively, these findings suggest that an HFD may contribute to dyslipidemia, heightened inflammatory responses, downregulation of neurotrophic factors, and increased BBB permeability and that concurrent PM exposure under HFD conditions may exacerbate adverse alterations in neurotrophic factors and BBB permeability. The results indicate that an HFD induces metabolic and neurovascular alterations, whereas concurrent PM exposure under HFD conditions is associated with additional changes in neurotrophic factors and BBB-related markers. Resistance exercise training attenuated these changes. Full article

Colorectal cancer (CRC) remains one of the most common malignancies worldwide with relatively high levels of morbidity and mortality. Current data demonstrate the significant role of adipokines, in particular leptin and adiponectin, in CRC pathogenesis and progression. Both adipokines exert pleiotropic activities and often possess opposing physiological effects. The main goal of this study was to provide a comprehensive overview of current knowledge regarding the complex relationship between leptin and adiponectin signaling and tumorigenesis with a specific focus on CRC. The pro-tumorigenic role of leptin in CRC has been highly emphasized by recent reports, primarily by activation of JAK2/STAT3 and PI3K/Akt/mTOR signaling pathways. In contrast, adiponectin has been shown to demonstrate an anti-tumorigenic role mainly because of activation of AMPK and PPARα signaling cascades. Focusing on the current advances in the field of adipokines’ signaling, we highlighted the latest achievements in understanding their role in colorectal malignancy. Full article

Background/Objectives: Obesity is characterized by dysregulated hypothalamic energy homeostasis and reduced central responsiveness to the anorexigenic hormones leptin and insulin. β-Hydroxybutyrate (β-HB), a major ketone body, has recently garnered attention as a signaling metabolite. However, its effects on hypothalamic leptin and insulin responsiveness remain unclear. This study aimed to investigate the effects of β-HB on hypothalamic hormone responsiveness and the associated molecular mechanisms, primarily using a high-fat diet (HFD)-induced obese mouse model. Methods: Male mice were fed an HFD to induce obesity and treated with β-HB via oral or intracerebroventricular (ICV) administration. Feeding behavior following leptin and insulin administration was evaluated, and activation of hypothalamic leptin-induced STAT3 signaling and insulin-induced Akt signaling was analyzed. In addition, mRNA expression of inflammation-related and appetite-regulating genes was assessed by quantitative PCR. Normal mice also received chronic ICV administration of β-HB from the onset of HFD feeding, and changes in body weight and cumulative food intake were measured. Results: Both oral and ICV administration of β-HB significantly enhanced the anorexigenic responses to leptin and insulin in HFD-induced obese mice. At the molecular level, leptin-induced STAT3 phosphorylation and insulin-induced Akt phosphorylation were enhanced in the hypothalamus. Gene expression analysis revealed reduced SOCS3 and TNFα expression and increased POMC expression. Furthermore, chronic ICV administration of β-HB from the onset of HFD feeding significantly suppressed body weight gain and the increase in cumulative food intake. Conclusions: This study demonstrates that β-HB improves hypothalamic leptin and insulin responsiveness in obese mice and modulates the associated molecular environment. These findings suggest that β-HB acts as a metabolically responsive signaling molecule regulating hypothalamic function, providing a basis for novel metabolic intervention strategies against obesity. Full article