Search Results (64)

Leptin (LEP) is an adipocyte-derived cytokine that integrates nutritional status, metabolism, and reproduction in cattle, with particular relevance for modern high-producing dairy cows. In ruminants, LEP and its receptors are widely expressed in metabolic and reproductive tissues, including adipose tissue, liver, hypothalamus, pituitary, ovary, uterus, and placenta, where LEP modulates energy homeostasis, neuroendocrine function, and local tissue responses. Changes in circulating LEP concentrations during the transition period reflect changes in body fat reserve, insulin and GH-IGF-1 dynamics, thyroid hormones, and inflammation and contribute to coordinated metabolic adaptations supporting the onset of lactation. At the reproductive level, LEP influences the hypothalamic–pituitary–gonadal axis, affects the pulsatility of luteinizing hormone (LH) under nutritional stress, and exerts direct effects on ovarian steroidogenesis, folliculogenesis, oocyte competence, embryo development, and uterine immune function. New evidence also links LEP profiles to major peripartum disorders, including subclinical ketosis, insulin resistance, postpartum ovarian inactivity, and uterine inflammatory diseases, and emphasises its potential as part of a panel evaluating the risk of metabolic and reproductive disorders. Furthermore, polymorphisms within the bovine LEP gene and its signalling network have been associated with milk production, feed efficiency, body condition, and fertility traits, suggesting opportunities to incorporate markers into genomic selection schemes aimed at improving robustness and reproductive performance. This review summarises current knowledge on LEP biology in cattle, with an emphasis on dairy cows, and discusses perspectives on translating this information into practical tools for nutritional management, health monitoring, and genetic improvement in bovine production systems. Full article

Metabolic state strongly shapes social and reproductive behaviors, yet the neural circuits that convert internal energy signals into behavioral responses remain poorly defined. The ventral premammillary nucleus (PMv) of the hypothalamus has been implicated in this process, particularly through leptin receptor-expressing (LepRb) neurons, but its brain-wide circuit organization is still unclear. Here, we used Cre-dependent retrograde (RV) and anterograde (HSV) viral tracing techniques in LepRb-Cre mice to construct a comprehensive, single-cell-resolution input–output map of PMv^LepRb neurons. 3D reconstruction showed that these neurons receive dense convergent inputs, mainly from hypothalamic and forebrain regions involved in energy balance, motivation, and limbic processing. In contrast, their outputs extend not only back to several input regions but also prominently to midbrain and pontine autonomic centers, including the periaqueductal gray (PAG) and parabrachial nucleus (PB). Quantitative analysis revealed that forebrain regions were more likely to participate in reciprocal connectivity, whereas brainstem regions were dominated by outgoing projections. This organization suggests that PMv^LepRb neurons are positioned to integrate metabolic and motivational signals and relay them to downstream systems controlling instinctive behavioral and autonomic responses. These findings provide a structural basis for understanding how energy state can influence decisions related to social competition and reproduction. Full article

Background and Aims: Anemia is seen in nearly >70% of patients with cirrhosis and is often non-responsive to nutritional supplements; therefore, we assessed the erythropoiesis and associated alteration in bone marrow (BM). Methods: It is a cross-sectional study. Flow cytometry was performed to assess the hematopoietic stem cells (HSCs) and erythroid population of 60 patients with cirrhosis compared with patients with 7 non-cirrhotic portal fibrosis (NCPF) and 3 controls. Proteomics were performed of the pure CD71 erythroid population taken from patients with cirrhosis to decipher the internal abnormalities supported by validation experiments. Real Time PCR, colony assay and heme quantification, cytokine array, and ELISA were performed to assess erythropoietic stimulating agents (ESA), inflammatory cytokines, and growth factors as an external factor affecting erythropoiesis. Results: We found a decrease in intermediate erythroid progenitors [IEPs; CD71+ CD235a+], conversely early erythroid precursors [EEP; CD71+ CD235a−] and late erythroid progenitors [LEP; CD71− CD235a+] were increased (p < 0.05) in cirrhotic and NCPF as compared to control. However, unlike NCPF, cirrhosis exhibited decreased CD71+ transferrin receptor (TfR1) expression over erythroid cells and increased immature erythrocytes (p < 0.05) in peripheral circulation. In vitro culture of erythroid precursors showed impaired differentiation and maturation that was confirmed by the reduced (p < 0.05) number of erythroid colonies (BFU-E). Proteomics analysis showed downregulated proteins associated with hemoglobin synthesis, ROS detoxification, translation, and mitochondrial activity. Furthermore, we found an altered expression of genes related to erythropoiesis and hemoglobin synthesis and increase (p < 0.05) in inflammatory cytokines such as IL-5, TRAIL-R2, TGF-α, and TGF-β in BM. Conclusions: This study suggests that the dysregulated erythropoiesis observed in patients with cirrhosis having anemia is maintained despite adequate nutrition. Full article

Background/Objectives: Obesity is a global health emergency with a complex etiology, in which monogenic forms, although rare, are significantly underdiagnosed. In our clinical setting, first-tier genetic screening panels targeting LEP, LEPR, BDNF, FTO, and MC4R often fail to identify a causative variant, leaving a significant diagnostic gap. This study aimed to assess the prevalence of variants in other critical genes of the melanocortin pathway to improve diagnostic yield. Methods: We analyzed 88 patients with non-syndromic obesity (Body Mass Index, BMI > 30 kg/m²), who were first screened for our standard obesity-related genes. In those testing negative, we expanded the analysis to include the MC3R and POMC genes. In silico bioinformatic tools were used to predict the functional consequences of identified variants on protein structure and splicing. Results: We found several variants in POMC, specifically within the regions coding for alpha-, beta-, and gamma-MSH peptides. A bioinformatic analysis suggests that these variants disrupt the melanocortin signaling pathway, likely contributing to an intermediate susceptibility phenotype in our adult cohort. Additionally, a clinical follow-up of a patient carrying the rare BDNF p.Thr2Ile variant revealed a suboptimal response to high-dose tirzepatide treatment (9% weight loss over 72 weeks), notably inferior to the average response observed in clinical trials. Conclusions: Our findings demonstrate that expanding first-level routine testing to include POMC and MC3R is essential to maximize diagnostic yield and improve clinical management. Full article

Bone metastases mark a critical and often terminal phase in cancer progression, where disseminated tumor cells (DTCs) manage to infiltrate and exploit the complex microenvironments of the bone marrow. While most current therapies focus on the well-known late-stage “vicious cycle” of osteolysis, they often overlook the earlier stages, namely, tumor cell colonization and dormancy. During these early phases, cancer cells co-opt hematopoietic stem cell (HSC) niches, using them as sanctuaries for long-term survival. In this review, we bring together emerging insights that highlight a trio of underappreciated cellular players in this metastatic takeover: megakaryocytes, erythroid lineage cells, and perivascular stromal subsets. Far from being passive bystanders, these cells actively shape the metastatic niche. For instance, megakaryocytes and platelets go beyond their role in transport; they orchestrate immune evasion and dormancy through mechanisms such as transforming growth factor-β1 (TGF-β1) signaling and the physical shielding of tumor cells. In parallel, we uncover a distinct “erythroid-immune” axis: here, stress-induced CD71⁺ erythroid progenitors suppress T-cell responses via arginase-mediated nutrient depletion and checkpoint engagement, forming a potent metabolic barrier against immune attack. Furthermore, leptin receptor–positive (LepR⁺) perivascular stromal cells emerge as key structural players. These stromal subsets not only act as anchoring points for DTCs but also maintain them in protective vascular zones via CXCL12 chemokine gradients. Altogether, these findings reveal that the metastatic bone marrow niche is not static; it is a highly dynamic, multi-lineage ecosystem. By mapping these intricate cellular interactions, we argue for a paradigm shift: targeting these early and cooperative crosstalk, whether through glycoprotein-A repetitions predominant (GARP) blockade, metabolic reprogramming, or other niche-disruptive strategies, could unlock new therapeutic avenues and prevent metastatic relapse at its root. Full article

Background/Objectives: Obesity-associated hyperleptinemia has been linked to breast cancer (BC) progression via mechanisms that remain incompletely understood. This study explores the role of leptin and its receptor (LEPR) in facilitating BC cell proliferation, migration, epithelial–mesenchymal transition (EMT), and STAT3 signaling pathway activation. Methods: We analyzed gene expression and survival data from TCGA BRCA dataset. MCF-7 and MDA-MB-231 BC cells were exposed to leptin at 10 ng/mL (lean-associated levels) and 100 ng/mL (elevated levels linked to obesity). MTT assays, colony formation tests, wound-healing and tumor spheroid dissemination experiments evaluated cell proliferation and migration. Immunofluorescence and Western blot analysis assessed changes in EMT markers and cytoskeletal alterations, while Western blotting and qPCR assessed STAT3 and NCOA1 expression and activation levels. Results: Elevated LEPR expression was linked with unfavorable prognosis in BC patients. Higher doses of leptin (100 ng/mL) significantly enhanced cellular proliferation rates and migratory capabilities, in both cell lines, and promoted EMT characteristics marked by downregulated E-cadherin and cytoskeleton structural changes. Whereas heightened JAK2/STAT3 signaling correlated with elevated leptin dosages, STAT3 inhibition using AG490 reversed leptin-induced migration while reinstating E-cadherin levels to baseline. Furthermore, leptin upregulated NCOA1, an essential STAT3 coactivator, facilitating increased expression of Cyclin D1 and VEGF target genes. Clinical positive relationships were seen between LEP/LEPR expressions and NCOA1 levels and between NCOA1 and various gene signatures related to STAT3/P-STAT3 within BC specimens. Conclusions: Obesity-associated hyperleptinemia enhances aggressiveness in BC through a mechanism involving LEPR-mediated activation pathways encompassing NCOA1/STAT3, which drive proliferation, migration, and EMT. This assigns a potential therapeutic utility for obesity-related advancements found within BC pathology. Full article

This study evaluated the protective role of farnesoid-X-receptor (FXR) agonist INT-787 in the control of mitochondrial changes using a metabolic dysfunction-associated steatohepatitis (MASH) model. Lep-ob/ob mice were fed a control diet (CD) for 21 weeks (wks), or a high-fat diet (HFD) for 9 or 21 wks; in the 21 wk HFD groups, INT-787 (30 mg/kg/day) dosed via HFD admixture was added. The hepatic ATP, ROS, GSH and MIC19, which stabilizes the structure of inner mitochondrial membrane (IMM), were quantified. Transmission electron microscopy (TEM) analysis was also performed. INT-787 increased hepatic ATP, which was downregulated after HFD 9 and 21 wks. Hepatic ROS increased and GSH decreased after 21 wks and were recovered by INT-787. MIC19 mRNA level decreased after HFD 21 wks, and it was completely restored after INT-787 administration. TEM analysis showed that INT-787 reverted the mitochondrial alterations as documented by restored mitochondrial length, number of mitochondrial cristae junctions (CJs), and distance between endoplasmic reticulum (ER) and outer mitochondrial membrane (OMM) when compared with HFD groups. These results underline the involvement of the FXR pathway in the control of mitochondrial damage, thus revealing a previously undiscovered mechanism mediated by FXR activation: the upregulation of IMM protein MIC19, which is essential for maintaining cristae integrity and mitochondrial function. Full article

Background/Objectives: The causes and mechanisms underlying the development of leptin resistance (LR) in patients with cardiovascular disease (CVD) remain unknown. Investigating the characteristics of adipose tissue in patients with CVD is a relevant scientific problem that may help to uncover the missing links in the pathogenesis of LR. This study aimed to evaluate systemic and local markers of LR in patients with different forms of CVD, and to determine the prevalence and tissue-specific expression patterns that contribute to LR. Methods: The study included 108 patients with myocardial infarction (MI), 96 patients with chronic coronary heart disease (CHD), and 96 patients with acquired heart disease (AHD). On day 1 of admission to the hospital, leptin and leptin receptor concentrations and the serum-free leptin index (FLI) were measured. Leptin resistance (LR) was defined as a leptin level of >6.45 ng/mL and FLI of >25. In chronic CHD and AHD patients, LEP, LEPR1, LEPR2, LEPR2/2, LEPR3, LEPR3/2, and LEPR4 expression as well as leptin and soluble leptin receptor secretion were assessed in subcutaneous (SAT), epicardial (EAT), and perivascular (PVAT) adipose tissue. Results: MI and chronic CHD patients are characterized by elevated leptin levels and high FLI values in the blood serum, which indicates a high prevalence of LR, in contrast to AHD patients. In chronic CHD, the LR level was highest in EAT and moderate in SAT. Reduced leptin sensitivity in EAT is underlied by decreased expression of LEPR1, LEPR2, LEPR2/2, LEPR3, LEPR3/2, and LEPR4, and increased leptin production by epicardial adipocytes, which contributes to enhancement of leptin resistance at the systemic level. Conclusions: A high LR rate was detected in patients with MI and chronic CHD. The identified changes in EAT lead to the development of leptin resistance in chronic CHD patients. Full article

Obesity is a multifaceted disorder influenced by various factors, with heredity being a significant contributor. Bariatric surgery is the most effective long-term intervention for morbid obesity and associated comorbidities, while outcomes vary significantly across individuals. Recent studies indicate that genetic and molecular determinants, particularly alterations in the leptin–melanocortin signalling pathway involving the fat mass and obesity-associated gene (FTO), pro-opiomelanocortin (POMC), melanocortin 4 receptor (MC4R), leptin (LEP), and leptin receptor (LEPR), influence the efficacy of weight loss and metabolic adaptations post-surgery. This narrative review consolidates evidence from peer-reviewed papers available in PubMed and Scopus until July 2025. The emphasis was on novel research and systematic reviews examining genetic polymorphisms, gene–environment interactions, and outcomes following bariatric procedures such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). Recent research emphasised the integration of genetic screening and precision medicine models into clinical bariatric workflows. Variants in FTO (e.g., rs9939609), MC4R (e.g., rs17782313), LEPR, and POMC are associated with diminished weight loss post-surgery, an increased likelihood of weight regain, and reduced metabolic enhancement. Patients with bi-allelic mutations in MC4R, POMC, or LEPR exhibited poor long-term outcomes despite receiving effective physical interventions. Furthermore, genes regulating mitochondrial metabolism (such as PGC1A), adipokine signalling (such as ADIPOQ), and glucose regulation (such as GLP1R) have been demonstrated to influence the body’s response to sugar and the extent of weight gain or loss. Two recent systematic reviews elucidate that candidate gene investigations are beneficial; however, larger genome-wide association studies (GWAS) and machine learning techniques are necessary to enhance predictive accuracy. Integrating genetic and molecular screening with bariatric surgery planning possesses significant therapeutic potential. Genotyping can assist in patient selection, procedural decisions, and medication additions, particularly for those with variants that influence appetite regulation or metabolic flexibility. Advancements in precision medicine, including the integration of polygenic risk scores, omics-based profiling, and artificial intelligence, will enhance the customisation of surgical interventions and extend the lifespan of individuals with severe obesity. The epigenetic regulators of energy balance DNA methylation, histone changes, and microRNAs that may affect individual differences in weight-loss patterns after bariatric surgery are also briefly contextualised. We discuss the concept that epigenetic modulation of gene expression, mediated by microRNAs in response to food and exercise, may account for variations in metabolic outcomes post-surgery. Full article

Background/Objectives: Most genes involved in the pathogenesis of Metabolic Syndrome (MS) and Type 2 Diabetes Mellitus (T2DM) are regulated by peroxisome proliferator-activated receptors (PPARs), which modulate the production of pro-inflammatory cytokines, with interleukin-6 (IL-6) playing a crucial role. The associations of single-nucleotide polymorphisms (SNPs) with MS and T2DM remain uncertain across populations. Therefore, we aimed to investigate the associations of PPAR-related SNPs in IL-6, LEP, ADIPOQ, ADIPOR1, and ADIPOR2 with MS and T2DM clinical features. Methods: Polymorphism analysis of IL-6, LEP, ADIPOQ, ADIPOR1, and ADIPOR2 genes was performed on isolated DNA from individuals diagnosed with T2DM and from healthy controls using real-time polymerase chain reaction (qPCR). Results: The IL-6-174G/C polymorphism shows that the CC genotype is associated with higher MS risk, whereas the GG genotype appears protective against metabolic disturbances. When the IL6 CC genotype is combined with ADIPOR2 GA or ADIPOR2 219 A/T, hyperglycemia is 1.3 times more frequent than with other IL6/ADIPOR2 genotype combinations. Conclusions: To develop informative genetic risk scores, future studies should include additional polymorphisms in key immune–metabolic pathway genes, such as AP-1, NF-κB, and FFAs. Full article

Nero Siciliano (NS) is an autochthonous pig breed reared in northeastern Sicily; despite its high-quality meat products, NS is currently endangered. This study aimed to evaluate the genetic variability at nine loci within candidate genes for meat traits—Melanocortin 4 Receptor (MC4R), Ryanodine Receptor 1 (RYR1), Class 3 Phosphoinositide 3-Kinase (PIK3C3) and Leptin (LEP)—to provide useful information for preservation and exploitation of the NS pig breed. Distribution of the genetic variants was assessed in a representative sample of 87 pigs (18 boars and 69 sows) collected in nine farms located in the original breeding area. Genotypes have been determined using PCR-RFLP and Sanger sequencing. Alleles linked to different growth rates and back fat deposition showed high frequencies (MC4R c.175C—0.93; LEP g.3469T—0.91) in the whole sample. Deviations from Hardy–Weinberg equilibrium and different allele distribution in boars and sows were observed. The RYR1 g.1843T allele, associated with Malignant Hyperthermia and Pale Soft Exudative meat defect, was reported in seven heterozygote pigs (q = 0.04) with one farm exhibiting a frequency of 0.29. Our results suggest the need for continuous monitoring of the genetic variants in NS both to maintain high meat quality and eradicate the RYR1 g.1843T allele. Full article

We investigated whether the peripheral co-administration of leptin and liraglutide (a glucagon-like peptide-1 receptor agonist) improved glucose metabolism in a mouse model of insulin-dependent diabetes mellitus (IDDM). Twelve-week-old male C57BL/6J mice were injected intraperitoneally with a high dose of streptozotocin to induce IDDM or vehicle-treated. Mice with IDDM were divided into four groups: leptin treatment alone (LEP), liraglutide treatment alone (LIRA), co-administration of leptin and liraglutide treatment (LEP+LIRA), untreated mice (UNT). Vehicle-treated mice were the healthy controls (HC). The blood glucose (BG) levels were measured, and a glucose tolerance test (GTT) was performed to compare the five groups. Leptin was administered peripherally at 20 μg/day using an osmotic pump, while liraglutide was administered subcutaneously at 1000 μg/kg/day. Monotherapy with leptin or liraglutide significantly improved glucose metabolism, as assessed by comparing BG levels and GTTs with those of the UNT group. Mice in the LEP+LIRA group showed even greater improvements in glucose metabolism than the monotherapy groups. Notably, glucose metabolism in the LEP+LIRA group improved comparably with the HC group. Thus, the peripheral co-administration of leptin and liraglutide effectively improved glucose metabolism in mice with IDDM without the use of insulin. Full article

The bioactive components present in onion peel powder are a promising factor in preventing/treating obesity. Overweight/obesity causes metabolic changes, which can lead to leptin resistance in the central nervous system (CNS) and, thus, to structural and functional changes in the brain. Objectives: The presented study focused on evaluating the influence of a diet supplemented with onion peel powder on the immunoexpression of leptin receptors (LepRs) in the hippocampus in obese rats and the potential anti-obesity role of the onion in the brain. Methods: To induce obesity, the animals were given a high-energy chow containing lard and sucrose. Onion skin powder was used to modify the standard and high-energy diets (10.5 g per rat/week) of Wistar rats in a 14-week experiment followed by a brain IHC study. Results: The effect of the onion diet on the expression of neuronal LepRs and astrocytes in the hippocampus was analyzed. Obese animals receiving onion in the diet showed significant growth in the average number of immunoreactive LepR (LepR-IR) neurons (p = 0.00108) and their average size (p = 0.00168) in the CA1 field of the hippocampus. Meanwhile, in obese rats not given onion peel powder, a significant increase in the average density of astrocytes was observed (p < 0.0001). Conclusions: The increased density of astrocytes in the hippocampus of obese animals can probably have a beneficial effect on brain changes in overweight individuals. The inclusion of onion in the diet of overweight/obese individuals may lead to increased hippocampal neuroplasticity, manifested by changes in the immunoexpression of LepRs. It can be speculated that the observed changes have a protective effect on the CNS structures during obesity, but this undoubtedly requires further research. Full article

Objective: We investigated whether the results of leptin gene (LEP) 2548G/A (rs7799039) and leptin receptor gene (LEPR) 668 A/G (rs1137101) variants, as well as the methylation analysis of CpG regions at nucleotides −31 and −51 of the LEP gene, showed any differences between breastfed and non-breastfed children in this study. Materials and Methods: The cross-sectional study included 100 children aged 2–5 years who were attending nursery and kindergarten and had been accepted to the Department of General Paediatrics. Infants who were exclusively breastfed for the first six months after birth constituted the study group, and those who were not only breastfeed constituted the control group. Methylation percentages at CpG islands of the LEP gene were compared between exclusively breastfed and non-exclusively breastfed infants, and the statistical significance was analyzed by looking for changes in LEP −31 and −51 nt methylation and LEP 2548G/A ve LEPR 668 A/G variants. Results: Both groups were compared by feeding, and the association of LEPR and LEP gene polymorphisms and −51 nt and −31 nt methylations were analyzed. There were no significant differences between the groups regarding genotype and allele frequency for the LEPR 668 A/G, LEP 2548 G/A gene variant, −31 nt methylation, and −51 nt methylation status. Similarly, there was no significant difference in genotype and allele frequency for the LEPR 668 A/G gene variant in terms of duration of exclusive breastfeeding, total breastfeeding, body mass index, family obesity, and satiety status. However, maternal support from family elders and physical activity increased the 51 nt methylation, but this methylation was not significantly affected by BMI, age, or satiety status. Conclusions: Maternal support from family elders and physical activity were associated with increased 51 nt methylation, but this methylation was not significantly affected by BMI, age, or satiety status. However, there are not enough studies in this area to reach a definitive conclusion, and further research is needed. Full article

In mammals, the maintenance of energy homeostasis relies on complex mechanisms requiring tight synchronization between peripheral organs and the brain. Thyroid hormones (THs), through their pleiotropic actions, play a central role in these regulations. Hypothyroidism, which is characterized by low circulating TH levels, slows down the metabolism, which leads to a reduction in energy expenditure as well as in lipid and glucose metabolism. The objective of this study was to evaluate whether the metabolic deregulations induced by hypothyroidism could be avoided through regulatory mechanisms involved in metabolic flexibility. To this end, the response to induced hypothyroidism was compared in males from two mouse strains, the wild-derived WSB/EiJ mouse strain characterized by a diet-induced obesity (DIO) resistance due to its high metabolic flexibility phenotype and C57BL/6J mice, which are prone to DIO. The results show that propylthiouracil (PTU)-induced hypothyroidism led to metabolic deregulations, particularly a reduction in hepatic lipid synthesis in both strains. Furthermore, in contrast to the C57BL/6J mice, the WSB/EiJ mice were resistant to the metabolic dysregulations induced by hypothyroidism, mainly through enhanced lipid metabolism in their adipose tissue. Indeed, WSB/EiJ mice compensated for the decrease in hepatic lipid synthesis by mobilizing lipid reserves from white adipose tissue. Gene expression analysis revealed that hypothyroidism stimulated the hypothalamic orexigenic circuit in both strains, but there was unchanged melanocortin 4 receptor (Mc4r) and leptin receptor (LepR) expression in the hypothyroid WSB/EiJ mice strain, which reflects their adaptability to maintain their body weight, in contrast to C57BL/6J mice. Thus, this study showed that WSB/EiJ male mice displayed a resistance to the metabolic dysregulations induced by hypothyroidism through compensatory mechanisms. This highlights the importance of metabolic flexibility in the ability to adapt to disturbed circulating TH levels. Full article