Leptin Action Research Articles

The role of leptin in endometrium disorders: literature review

Leptin is not only the main regulator of energy balance, but also it affects the reproductive and immune systems. Leptin and its receptors are expressed in the endometrium and are actively involved in the embryo implantation. According to numerous studies, expression and level changes of leptin are associated with the inflammatory and autoimmune diseases, including endometriosis and chronic endometritis. Hyperplastic and inflammatory diseases of the uterus are accompanied by a violation of the receptivity of the endometrium due to the dysregulation of many factors involved in proliferation, vascularization and decidualization of cells. Activity of most of these factors is due to the leptin action, however, there are no studies of the direct effect of leptin in the pathogenesis of disorders of the endometrium in hyperplastic and inflammatory diseases.Thus, the purpose of this literature review was to describe the putative molecular mechanisms of the effect of leptin on the development of endometrial pathology.Literature search was carried out from 03/20/2023 to 05/11/2023 using scientific literature databases: NCBI PubMed, Google Scholar (foreign sources), Cyberleninka, Elibrary (domestic sources): references for the period 1995-2023 were analyzed. The following keywords were used for the search: leptin, endometrial dysfunction, endometrial receptivity, inflammation, pelvic inflammatory disease.

Leptin-activated hypothalamic BNC2 neurons acutely suppress food intake.

Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass by regulating the activity of specific neural populations controlling appetite and metabolism1. Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons2. However, whereas AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect3-5. This has raised the possibility that there is a heretofore unidentified leptin-regulated neural population that rapidly suppresses appetite. Here we report the discovery of a new population of leptin-target neurons expressing basonuclin 2 (Bnc2) in the arcuate nucleus that acutely suppress appetite by directly inhibiting AGRP neurons. Opposite to the effect of AGRP activation, BNC2 neuronal activation elicited a place preference indicative of positive valence in hungry but not fed mice. The activity of BNC2 neurons is modulated by leptin, sensory food cues and nutritional status. Finally, deleting leptin receptors in BNC2 neurons caused marked hyperphagia and obesity, similar to that observed in a leptin receptor knockout in AGRP neurons. These data indicate that BNC2-expressing neurons are a key component of the neural circuit that maintains energy balance, thus filling an important gap in our understanding of the regulation of food intake and leptin action.

12248 Leptin Signaling Deficiency At The Central Nervous System Reduces Hepatic Glucagon Sensibility Disturbing Liver Amino Acid Metabolism Leading To Hyperaminoacidemia And Hyperglucagonemia In Male Adult Rats

Abstract Disclosure: C. Pintado Losa: None. L. Mazuecos Fernández-Pacheco: None. Ó. Gómez Torres: None. S. Artigas Jerónimo: None. E. Burgos Ramos: None. I. Ramos: None. J. Poveda Colado: None. C. Arribas Mocoroa: None. A. Andres: None. N. Gallardo: None. Leptin regulates glucagon secretion, but the contribution of central leptin resistance to circulating glucagon levels and hepatic glucagon signaling is poorly studied. To analyze the effects of deficient hypothalamic leptin signaling on glucagon levels and hepatic glucagon signaling, we infused intracerebroventricularly a rat-specific leptin receptor antagonist SLA (0,2 µg/day) for 21 days to male 3-month-old Wistar rats (n=12) or PBS (n=12). At day 21 of treatment and 30 min before sacrifice, a glucagon challenge (100 µg/kg) was performed in 16h fasted rats. After sacrifice, blood and liver samples were collected for analysis. Serum hormones, urea, and total and branched-chain amino acids (BCAA) levels were determined using commercial kits and by RP-HPLC. Hepatic neutral lipid was extracted and quantified using an enzymatic kit and the hepatic content of mRNA and proteins involved in lipid and amino acid metabolism were measured by RT-PCR and Western-Blot. Additionally, the HOMA-IR and glucagon-alanine index were determined in all rats. Blocking central leptin signaling led to impaired fat oxidation and triglyceride export capacity in the liver, resulting in a 50% increase in hepatic triglyceride content in SLA-treated rats. Glucagonemia increased in SLA-treated rats, indicating impaired hepatic glucagon sensitivity. In fact, in response to exogenous glucagon, the hepatic phosphorylation of CREB was reduced by 55% in SLA-infused compared to control rats. Importantly, SLA treatment significantly decreases the expression and the activity of BCKDH (branched-chain alpha-keto acid dehydrogenase) in the liver, leading to a reduction in the BCAA degradation in SLA-treated rats, hyperaminoacidemia, and decreased serum urea levels. In conclusion, deficient hypothalamic leptin signaling alters glucose, lipid, and amino acid homeostasis, highlighting the relevance of central leptin action in the control of peripheral metabolism and glucagon sensitivity. Funding: Work supported by Ministerio de Ciencia, Innovación y Universidades under project grants RTI2018-098643-B-I00, PID2021-128243OB-I00, and from the University of Castilla-La Mancha and the European Regional Development Fund (FEDER) under project grant 2023- GRIN-34280. Presentation: 6/1/2024

Effect of leptin and adiponectin on the expression of cytokine genes IL-1β, IL-6 AND TNFα in lymphocytes

Metabolic syndrome (MS) is one of the world’s topical health problems. Large-scale epidemiological studies on the prevalence of MS in the world have not been conducted, but according to different authors, depending on the region of residence, the composition of the study population and the diagnostic criteria used, the incidence of MS is at least 10%, and according to estimates of the International Diabetes Federation IDF – up to 25% of the adult population. The metabolic changes in MS are explained by a disturbance in the balance of mediators synthesized by adipose tissue (adiponectin, leptin, resistin, visfatin, vaspin and others); MS is also considered as a subclinical chronic inflammatory process characterized by excessive synthesis of proinflammatory and deficiency of anti-inflammatory cytokines. According to modern ideas, changes in the cellular and humoral immunity in MS are largely due to the imbalance of adipokines: leptin and adiponectin. Increased functional activity of immune cells, including lymphocytes, leads to changes in cytokine gene expression. In the present work, we studied in vitro the expression of IL-1â, IL-6 and TNFá genes in peripheral blood lymphocytes under the influence of adipokines at concentrations characteristic of MS. As a result, differential effects of adipokines on lymphocytes of MS patients and conditionally healthy individuals were found. In conditionally healthy individuals, incubation of lymphocytes with adipokines leptin, adiponectin and their combination, as well as in the presence of physiological solution causes an increase in IL-6 gene expression. The most noticeable effect was observed when cultured with adiponectin. Thus, in norm, with a decrease in the physiological concentration of adiponectin, the expression of IL-6 in lymphocytes increases, indicating insufficient realization of the anti-inflammatory effect of adiponectin. In MS, IL-6 gene expression increases in lymphocytes isolated from peripheral blood in vitro after incubation with adiponectin, a combination of adiponectin and leptin, as well as in the presence of physiological solution. No changes in IL-6 gene expression under the effect of high concentration of leptin were detected. Probably, our results reflect the phenomenon of lymphocyte resistance to leptin action in MS, as under its influence there is not activation of lymphocytes characteristic in vivo, but on the contrary, decrease of activated subpopulations, also there is no change in IL-6 gene expression. Thus, adipokines in concentrations characteristic of metabolic syndrome influence the functional activity of peripheral blood lymphocytes.

Cancer-associated fibroblast-derived exosome Leptin promotes malignant biological lineage in pancreatic ductal adenocarcinoma by regulating ABL2 via miR-224-3p

BackgroundCancer-associated fibroblasts, as a major component of the tumor microenvironment, have been shown to exhibit protumorigenic effects in pancreatic ductal adenocarcinoma. Moreover, cancer-associated fibroblasts-derived exosomes have been reported to promote tumor development, but exact mechanisms have not been elucidated. The purpose of this study was to investigate the processes by which exosomes generated from cancer-associated fibroblasts promote tumor growth.Methodstwenty-one patients with pancreatic ductal adenocarcinoma who evaluated preoperatively as potentially surgically resectable without distant metastasis and pathologically examined postoperatively as pancreatic ductal cell carcinoma were included. We determined the expression of Leptin as well as downstream proteins at the clinical and cellular levels. Cancer-associated fibroblast-derived exosomes were characterised by nanoparticle transmission electron microscopy and tracking analysis. To ascertain the mechanism mediating the action of exosomal Leptin in pancreatic ductal adenocarcinoma, we performed CCK-8 assay, colony formation assays, transwell and wound healing assays in PSN1 cells to evaluate cell proliferation, migration and invasion. Western blotting was used to detect the level of Leptin, ABL2 and exosome markers. qRT-PCR was employed to evaluate miR-224-3p. Cancer-associated fibroblasts markers and exosome uptake were verified by immunofluorescence.ResultsWestern blotting assays show that Leptin is present inside tissues and cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Cancer-associated fibroblasts stimulated PSN1 cells growth, migration and invasion in vitro by secreting the exosomal Leptin. Exosomal Leptin could regulate miR-224-3p, which targets negative regulation of ABL2. Inhibiting Leptin significantly limited PSN1 cells growth, migration and invasion. In vitro analyses revealed that miR-224-3p mimics mitigate the inhibitory effect of cancer-associated fibroblasts knockdown of Leptin on PSN1 cells development, but overexpression of ABL2 partly abolished the tumor-promoting phenotype of miR-224-3p mimics.ConclusionOur results revealed that cancer-associated fibroblasts mediate pancreatic ductal adenocarcinoma development by regulating the miR-224-3p/ABL2 molecular axis through the secretion of the exosomal Leptin.

The adipose tissue melanocortin 3 receptor is targeted by ghrelin and leptin and may be a therapeutic target in obesity

ObjectiveObesity is linked to perturbations in energy balance mechanisms, including ghrelin and leptin actions at the hypothalamic circuitry of neuropeptide Y (NPY) and melanocortin. However, information about the regulation of this system in the periphery is still scarce. Our objective was to study the regulation of the NPY/melanocortin system in the adipose tissue (AT) and evaluate its therapeutic potential for obesity and type 2 diabetes. MethodsThe expression of the NPY/melanocortin receptors’ levels was assessed in the visceral AT of individuals with obesity and altered metabolism. Protein levels of these receptors were evaluated in cultured adipocytes incubated with ghrelin (30 and 100 ng/mL) and leptin (1 and 10 nM) and in the AT of an animal model with a mutation in the leptin receptor (ZSF1 rat), to understand their regulation by leptin and ghrelin. The vertical sleeve gastrectomy animal model was used to evaluate the putative therapeutic potential of the NPY/melanocortin system. ResultsIn this study, we unravelled that leptin (1 nM and 10 nM) selectively reduced the levels of NPY5R and MC3R but no other NPYR/MCRs in cultured adipocytes. In turn, acylated ghrelin (100 ng/mL) significantly increased NPY1R, but the inhibition of its receptor also abrogates MC3R levels. However, in the Lepr-deficient ZSF1 rat, both NPY5R and MC3R levels were reduced, along with other NPYRs and MCRs, suggesting that leptin resistance negatively affects NPY and melanocortin signalling. In human adipose tissue, we found a downregulation of genes encoding the NPY and melanocortin receptors in the visceral AT of individuals with obesity and insulin resistance, being correlated with genes regulating metabolic activity. Additionally, diabetic obese rats submitted to vertical sleeve gastrectomy showed increased levels of NPY, melanocortin, ghrelin, and leptin receptors in the AT, including MC3R, suggesting it may constitute a therapeutic target in obesity. ConclusionsOur results suggest that the AT NPY/melanocortin system, particularly the MC3R, may be involved in the neuroendocrine regulation of adipocyte metabolism. Altogether, our work shows MC3R is under the control of the ghrelin/leptin duo, is reduced in patients with obesity and prediabetes, and may constitute a therapeutic target in obesity.

Central Actions of Leptin Induce an Atrophic Pattern and Improves Heart Function in Lean Normoleptinemic Rats via PPARβ/δ Activation.

Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARβ/δ activation. Here, we assessed the impact of central leptin administration and PPARβ/δ inhibition on cardiac function. Various cardiac properties, including QRS duration, R wave amplitude, heart rate (HR), ejection fraction (EF), end-diastolic left ventricular mass (EDLVM), end-diastolic volume (EDV), and cardiac output (CO) were analyzed. Central leptin infusion increased cardiac PPARβ/δ protein content and decreased HR, QRS duration, and R wave amplitude. These changes induced by central leptin suggested a decrease in the ventricular wall growth, which was confirmed by MRI. In fact, the EDLVM was reduced by central leptin while increased in rats co-treated with leptin and GSK0660, a selective antagonist of PPARβ/δ activity. In summary, central leptin plays a dual role in cardiac health, potentially leading to ventricular atrophy and improving heart function when PPARβ/δ signaling is intact. The protective effects of leptin are lost by PPARβ/δ inhibition, underscoring the importance of this pathway. These findings highlight the therapeutic potential of targeting leptin and PPARβ/δ pathways to combat cardiac alterations and heart failure, particularly in the context of obesity.

Low Testosterone and High Leptin Activate PPAR Signaling to Induce Adipogenesis and Promote Fat Deposition in Caponized Ganders.

Low or insufficient testosterone levels caused by caponization promote fat deposition in animals. However, the molecular mechanism of fat deposition in caponized animals remains unclear. This study aimed to investigate the metabolomics and transcriptomic profiles of adipose tissues and study the effect of testosterone and leptin on the proliferation of adipocytes. We observed a significant enlargement in the areas of adipocytes in the abdominal fat tissues in capon, as well as increased luciferase activity of the serum leptin and a sharp decrease in the serum testosterone in caponized gander. Metabolomics and transcriptomic results revealed differentially expressed genes and differentially expressed metabolites with enhanced PARR signal pathway. The mRNA levels of peroxisome proliferators-activated receptor γ, fatty acid synthase, and suppressor of cytokine signaling 3 in goose primary pre-adipocytes were significantly upregulated with high leptin treatment and decreased significantly with increasing testosterone dose. Hence, reduced testosterone and increased leptin levels after caponization possibly promoted adipocytes proliferation and abdominal fat deposition by altering the expression of PPAR pathway related genes in caponized ganders. This study provides a new direction for the mechanism through which testosterone regulates the biological function of leptin and fat deposition in male animals.

70 Circulating leptin and immune-related transcriptomic patterns in clear cell renal cell carcinoma

Abstract Background Obesity has been associated with better outcomes in localized and metastatic clear cell renal cell carcinoma (ccRCC), as well as improved survival on immunotherapy treatment. However, the mechanisms underlying this association remain unclear. Leptin is an adipokine secreted by adipocytes, and circulating levels of leptin are higher in individuals with obesity. Additionally, leptin promotes inflammation and angiogenesis and has been proposed as pro-tumorigenic in colorectal and breast cancer. In this study, we examined how circulating leptin levels relate to both tumor and perinephric fat transcriptomic patterns in a cohort of ccRCC patients by evaluating the associations with body mass index (BMI), sex, and immune-related gene expression patterns. Methods We conducted a retrospective cohort study of 92 treatment-naïve ccRCC patients undergoing nephrectomy at Memorial Sloan Kettering Cancer Center. Available data included circulating leptin from fasting blood samples, clinical characteristics from medical records, and, in a subset of patients, RNA sequencing from tumor and perinephric fat specimens. We analyzed differentially expressed genes (DEG) according to circulating leptin levels using Gene Set Enrichment Analysis (GSEA) to describe pathways that were enriched in patients with high levels of leptin. We performed analysis for the whole cohort and stratified by sex based on differences in leptin levels. Results From the 92 patients with available peripheral leptin measurements, 51 and 44 had available tumor and perinephric fat RNA sequencing data, respectively. Of these, 64 (70%) were male, the median age was 60 years old, and most tumors were low grade and stage. Leptin distribution was significantly different in males than females, with circulating leptin levels of 7 ng/ml (IQR 4-14) and 22 ng/ml (IQR 9-52), respectively. Higher BMI was associated with higher leptin levels, with a correlation coefficient of 0.63 (p<0.001) in males and 0.77 (p<0.001) in females. GSEA of tumor DEGs by circulating leptin, showed upregulation of pathways related to adaptive immune activity in patients with higher leptin levels across sexes, although this association was attenuated in females. Strikingly, in the perinephric fat there were stark differences in opposite directions in female and male specimens, with females showing significantly enriched transcription of genes associated with B cell signaling, humoral and adaptive immune responses. Conclusions Higher leptin levels were associated with a modest increase of immune-related gene expression in the tumors in both males and females, but significantly different directional changes were observed in the perinephric fat. Circulating leptin may be involved in peritumoral immune responses which may link host factors to sex related tumor outcomes. Further studies should aim to address the relationship between leptin activity and the tumor and fat microenvironment. DOD CDMRP Funding: yes

Glutamate neurotransmission from leptin receptor cells is required for typical puberty and reproductive function in female mice.

The hypothalamic ventral premammillary nucleus (PMv) is a glutamatergic nucleus essential for the metabolic control of reproduction. However, conditional deletion of leptin receptor long form (LepRb) in vesicular glutamate transporter 2 (Vglut2) expressing neurons results in virtually no reproductive deficits. In this study, we determined the role of glutamatergic neurotransmission from leptin responsive PMv neurons on puberty and fertility. We first assessed if stimulation of PMv neurons induces luteinizing hormone (LH) release in fed adult females. We used the stimulatory form of designer receptor exclusively activated by designer drugs (DREADDs) in LeprCre (LepRb-Cre) mice. We collected blood sequentially before and for 1 hr after intravenous clozapine-N-oxide injection. LH level increased in animals correctly targeted to the PMv, and LH level was correlated to the number of Fos immunoreactive neurons in the PMv. Next, females with deletion of Slc17a6 (Vglut2) in LepRb neurons (LeprΔVGlut2) showed delayed age of puberty, disrupted estrous cycles, increased gonadotropin-releasing hormone (GnRH) concentration in the axon terminals, and disrupted LH secretion, suggesting impaired GnRH release. To assess if glutamate is required for PMv actions in pubertal development, we generated a Cre-induced reexpression of endogenous LepRb (LeprloxTB) with concomitant deletion of Slc17a6 (Vglut2flox) mice. Rescue of Lepr and deletion of Slc17a6 in the PMv was obtained by stereotaxic injection of an adeno-associated virus vector expressing Cre recombinase. Control LeprloxTB mice with PMv LepRb rescue showed vaginal opening, follicle maturation, and became pregnant, while LeprloxTB;Vglut2flox mice showed no pubertal development. Our results indicate that glutamatergic neurotransmission from leptin sensitive neurons regulates the reproductive axis, and that leptin action on pubertal development via PMv neurons requires Vglut2.

Glutamate neurotransmission from leptin receptor cells is required for typical puberty and reproductive function in female mice

The hypothalamic ventral premammillary nucleus (PMv) is a glutamatergic nucleus essential for the metabolic control of reproduction. However, conditional deletion of leptin receptor long form (LepRb) in vesicular glutamate transporter 2 (Vglut2) expressing neurons results in virtually no reproductive deficits. In this study, we determined the role of glutamatergic neurotransmission from leptin responsive PMv neurons on puberty and fertility. We first assessed if stimulation of PMv neurons induces luteinizing hormone (LH) release in fed adult females. We used the stimulatory form of designer receptor exclusively activated by designer drugs (DREADDs) in LeprCre (LepRb-Cre) mice. We collected blood sequentially before and for 1 hr after intravenous clozapine-N-oxide injection. LH level increased in animals correctly targeted to the PMv, and LH level was correlated to the number of Fos immunoreactive neurons in the PMv. Next, females with deletion of Slc17a6 (Vglut2) in LepRb neurons (LeprΔVGlut2) showed delayed age of puberty, disrupted estrous cycles, increased gonadotropin-releasing hormone (GnRH) concentration in the axon terminals, and disrupted LH secretion, suggesting impaired GnRH release. To assess if glutamate is required for PMv actions in pubertal development, we generated a Cre-induced reexpression of endogenous LepRb (LeprloxTB) with concomitant deletion of Slc17a6 (Vglut2flox) mice. Rescue of Lepr and deletion of Slc17a6 in the PMv was obtained by stereotaxic injection of an adeno-associated virus vector expressing Cre recombinase. Control LeprloxTB mice with PMv LepRb rescue showed vaginal opening, follicle maturation, and became pregnant, while LeprloxTB;Vglut2flox mice showed no pubertal development. Our results indicate that glutamatergic neurotransmission from leptin sensitive neurons regulates the reproductive axis, and that leptin action on pubertal development via PMv neurons requires Vglut2.

Placental apoptosis increased by hypoxia inducible factor-1 stabilization is counteracted by leptin†.

During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed toward the relevance of hypoxia as modulator of trophoblast cell death. Previous reports have shown that leptin, a placental cytokine, promotes cell survival in both cell culture and placental explant models. The aim of this work is to establish the role of leptin in apoptosis under hypoxic condition in trophoblast cells. In this study, we evaluated the effect of cobalt chloride, a hypoxia mimicking agent that stabilizes the expression of hypoxia-inducible factor-1 alpha, on Swan-71 and human placental explants. Hypoxia chamber was also used to generate 2% oxygen. Apoptosis was determined by the presence of apoptotic nucleus, fragmentation of DNA and Caspase-3 and PARP-1 cleavage. The pro-apoptotic proteins BAX, BID, BAD, and BAK and the anti-apoptotic effectors BCL-2, B-cell lymphoma-extra-large, and myeloid cell leukemia-1 were also analyzed. We found that hypoxia-inducible factor-1 alpha stabilization increased the appearance of apoptotic nucleus, fragmentation of DNA, and Caspase-3 and PARP-1 cleavage. Hypoxia mimicking conditions enhanced the expression of pro-apoptotic effectors BAX, BID, BAD, and BAK. Hypoxia-inducible factor-1 alpha stabilization also downregulated the level of BCL-2, B-cell lymphoma-extra-large, and myeloid cell leukemia-1. All these apoptotic parameters changes were reversed with leptin treatment. Moreover, we showed that leptin action on apoptosis modulation involves PI3K and MAPK signaling pathways. Obtained data demonstrate that hypoxia-inducible factor-1 alpha stabilization induces apoptosis in human placenta and leptin counteracts this effect, reinforcing its role as a survival cytokine.

Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans

Mitochondrial-secreted growth differentiation factor-15 (GDF-15) promotes weight loss in animals. Its effects in humans remain unclear, due to limited research and potential measurement interference from the H202D-variant. Our post-hoc analysis investigates total (irrespective of genetic variants) and H-specific GDF-15 (detected only in H202D-variant absence) in humans under acute and chronic energy deprivation, examining GDF-15 interaction with leptin (energy homeostasis regulator) and GDF-15 biologic activity modulation by the H202D-variant. Total and H-specific GDF-15 increased with acute starvation, and total GDF-15 increased with chronic energy deprivation, compared with healthy subjects and regardless of leptin repletion. Baseline GDF-15 positively correlated with triglyceride-rich particles and lipoproteins. During acute metabolic stress, GDF-15 associations with metabolites/lipids appeared to differ in subjects with the H202D-variant. Our findings suggest GDF-15 increases with energy deprivation in humans, questioning its proposed weight loss and suggesting its function as a mitokine, reflecting or mediating metabolic stress response.

1543-P: Feeding Regulatory Mechanism of Leptin Action in the Nucleus of the Solitary Tract and Area Postrema

1543-P: Feeding Regulatory Mechanism of Leptin Action in the Nucleus of the Solitary Tract and Area Postrema

Air pollution accelerates the development of obesity and Alzheimer's disease: the role of leptin and inflammation -a mini-review.

Air pollution is an urgent concern linked to numerous health problems in low- and middle-income countries, where 92% of air pollution-related deaths occur. Particulate matter 2.5 (PM2.5) is the most harmful component of air pollutants, increasing inflammation and changing gut microbiota, favoring obesity, type 2 diabetes, and Alzheimer's Disease (AD). PM2.5 contains lipopolysaccharides (LPS), which can activate the Toll-like receptor 4 (TLR4) signaling pathway. This pathway can lead to the release of pro-inflammatory markers, including interleukins, and suppressor of cytokine signaling-3 (SOCS3), which inhibits leptin action, a hormone that keeps the energy homeostasis. Leptin plays a role in preventing amyloid plaque deposition and hyperphosphorylation of tau-protein (p-tau), mechanisms involved in the neurodegeneration in AD. Approximately 50 million people worldwide are affected by dementia, with a significant proportion living in low-and middle-income countries. This number is expected to triple by 2050. This mini-review focuses on the potential impact of PM2.5 exposure on the TLR4 signaling pathway, its contribution to leptin resistance, and dysbiosis that exacerbates the link between obesity and AD.

Influence of leptin administration to pregnant mice on fetal gene expression and adaptation to sweet and fatty food in adult offspring of different sexes.

Elevated leptin in pregnant mice improves metabolism in offspring fed high-calorie diet and its influence may be sex-specific. Molecular mechanisms mediating leptin programming action are unknown. We aimed to investigate programming actions of maternal leptin on the signaling function of the placenta and fetal liver and on adaptation to high-calorie diet in male and female offspring. Female C57BL/6J mice received leptin injections in mid-pregnancy. Gene expression was assessed in placentas and in the fetal brain and liver at the end of pregnancy. Metabolic parameters and gene expression in the liver, brown fat and hypothalamus were assessed in adult male and female offspring that had consumed sweet and fatty diet (SFD: chow, lard, sweet biscuits) for 2 weeks. Females had lower blood levels of leptin, glucose, triglycerides and cholesterol than males. Consuming SFD, females had increased Ucp1 expression in brown fat, while males had accumulated fat, decreased blood triglycerides and liver Fasn expression. Leptin administration to mothers increased Igf1 and Dnmt3b expression in fetal liver, decreased post-weaning growth rate, and increased hypothalamic Crh expression in response to SFD in both sexes. Only in male offspring this administration decreased expression of Fasn and Gck in the mature liver, increased fat mass, blood levels of glucose, triglycerides and cholesterol and Dmnt3a expression in the fetal liver. The results suggest that the influence of maternal leptin on the expression of genes encoding growth factors and DNA methyltransferases in the fetal liver may mediate its programming effect on offspring metabolic phenotypes.

Leptin signaling promotes blood vessel formation in the Xenopus tail during the embryo-larval transition

The signals that regulate peripheral blood vessel formation during development are still under investigation. The hormone leptin promotes blood vessel formation, adipose tissue establishment and expansion, tumor growth, and wound healing, but the underlying mechanisms for these actions are currently unknown. We investigated whether leptin promotes angiogenesis in the developing tail fin using embryonic transgenic xflk-1:GFP Xenopus laevis, which express a green fluorescent protein on vascular endothelial cells to mark blood vessels. We found that leptin protein is expressed in endothelial cells of developing blood vessels and that leptin treatment via injection increased phosphorylated STAT3 signaling, which is indicative of leptin activation of its receptor, in blood vessels of the larval tail fin. Leptin administration via media increased vessel length, branching, and reconnection with the cardinal vein, while decreased leptin signaling via immunoneutralization had an opposing effect on vessel development. We also observed disorganization of major vessels and microvessels of the tail fin and muscle when leptin signaling was decreased. Reduced leptin signaling lowered mRNA expression of cenpk, gpx1, and mmp9, markers for cell proliferation, antioxidation, and extracellular matrix remodeling/cell migration, respectively, in the developing tail, providing insight into three possible mechanisms underlying leptin's promotion of angiogenesis. Together these results illustrate that leptin levels are correlated with embryonic angiogenesis and that leptin coordinates multiple aspects of blood vessel growth and development, showing that leptin is an important morphogen during embryonic development.

Leptin and ghrelin dynamics: unraveling their influence on food intake, energy balance, and the pathophysiology of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired glucose homeostasis. In recent years, there has been growing interest in the role of hunger and satiety hormones such as ghrelin and leptin in the development and progression of T2DM. In this context, the present literature review aims to provide a comprehensive overview of the current understanding of how ghrelin and leptin influences food intake and maintain energy balance and its implications in the pathophysiology of T2DM. A thorough literature search was performed using PubMed and Google Scholar to choose the studies that associated leptin and ghrelin with T2DM. Original articles and reviews were included, letters to editors and case reports were excluded. This narrative review article provides a comprehensive summary on mechanism of action of leptin and ghrelin, its association with obesity and T2DM, how they regulate energy and glucose homeostasis and potential therapeutic implications of leptin and ghrelin in managing T2DM. Ghrelin, known for its appetite-stimulating effects, and leptin, a hormone involved in the regulation of energy balance, have been implicated in insulin resistance and glucose metabolism. Understanding the complexities of ghrelin and leptin interactions in the context of T2DM may offer insights into novel therapeutic strategies for this prevalent metabolic disorder. Further research is warranted to elucidate the molecular mechanisms underlying these hormone actions and to explore their clinical implications for T2DM prevention and management.

Selection of Leptin Surrogates by a General Phenotypic Screening Method for Receptor Agonists.

There is a high demand for agonist biomolecules such as cytokine surrogates in both biological and medicinal research fields. These are typically sourced through natural ligand engineering or affinity-based screening, followed by individual functional validation. However, efficient screening methods for identifying rare hits within immense libraries are very limited. In this research article, we introduce a phenotypic screening method utilizing biological receptor activation-dependent cell survival (BRADS). This method offers a high-throughput, low-background, and cost-effective approach that can be implemented in virtually any biochemical laboratory setting. As a proof-of-concept, we successfully identified a surrogate for human leptin following a two-week cell culture process, without the need for specialized high-throughput equipment or reagents. This surrogate effectively emulates the activity of native human leptin in cell validation assays. Our findings not only underscore the effectiveness of BRADS but also suggest its potential applicability to a broad range of biological receptors, including Notch and GPCRs.

Correlation of Leptin in Patients With Type 2 Diabetes Mellitus.

The exponential increase in diabetes mellitus (DM) poses serious public health concerns. In this review, we focus on the role of leptin in type 2 DM. The peripheral actions of leptin consist of upregulating proinflammatory cytokines which play an important role in the pathogenesis of type 2 DM and insulin resistance. Moreover, leptin is known to inhibit insulin secretion and plays a significant role in insulin resistance in obesity and type 2 DM. A literature search was conducted on Medline, Cochrane, Embase, and Google Scholar for relevant articles published until December 2023. The following search strings and Medical Subject Headings (MeSH terms) were used: "Diabetes Mellitus," "Leptin," "NPY," and "Biomarker." This article aims to discuss the physiology of leptin in type 2 DM, its glucoregulatory actions, its relationship with appetite, the impact that various lifestyle modifications can have on leptin levels, and, finally, explore leptin as a potential target for various treatment strategies.