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Leptin regulates energy balance via leptin receptors expressed in central and peripheral tissues, but little is known about leptinsensitive kidney genes and the role of the tubular leptin receptor (Lepr) in response to a high-fat diet (HFD). Quantitative RT-PCR analysis of Lepr splice variants A, B, and C revealed a ratio of ~100:10:1 in the mouse kidney cortex and medulla, with medullary levels being ~10 times higher. Leptin replacement in ob/ob mice for 6 days reduced hyperphagia, hyperglycemia, and albuminuria, associated with normalization of kidney mRNA expression of molecular markers of glycolysis, gluconeogenesis, amino acid synthesis, and megalin. Normalization of leptin for 7 h in ob/ob mice did not normalize hyperglycemia or albuminuria. Tubular knockdown of Lepr [Pax8-Lepr knockout (KO)] and in situ hybridization revealed a minor fraction of Lepr mRNA in tubular cells compared with endothelial cells. Nevertheless, Pax8-Lepr KO mice had lower kidney weight. Moreover, while HFD-induced hyperleptinemia, increases in kidney weight and glomerular filtration rate, and a modest blood pressure lowering effect were similar compared with controls, they showed a blunted rise in albuminuria. Use of Pax8-Lepr KO and leptin replacement in ob/ob mice identified acetoacetyl-CoA synthetase and gremlin 1 as tubular Lepr-sensitive genes that are increased and reduced by leptin, respectively. In conclusion, leptin deficiency may increase albuminuria via systemic metabolic effects that impinge on kidney megalin expression, whereas hyperleptinemia may induce albuminuria by direct tubular Lepr effects. Implications of Lepr variants and the novel tubular Lepr/acetoacetyl-CoA synthetase/gremlin 1 axis remain to be determined. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence has suggested a strong association of Q223R (rs1137101) and K109R (rs1137100) polymorphisms in leptin receptor (LEPR) gene with susceptibility of breast cancer (BC), but inconsistent results were obtained. To provide a quantitative assessment of this association, a systematic review and meta-analysis was performed. Methods: A literature search of PubMed, EMBASE, Google Scholar, and the Chinese National Knowledge Infrastructure was collected. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results: A total of 20 case-control studies for Q223R polymorphism and 8 case-control studies for K109R polymorphism were included. Significant association between Q223R polymorphism and BC risk was not found in total, Asian or Caucasian population, but in African population: allelic model, OR = 0.72, 95% CI = 0.60-0.86, p < 0.001; recessive model, OR = 0.67, 95%CI = 0.52-0.87, P = 0.003; dominant model, OR = 1.58, 95% CI = 1.15-2.17, p = 0.004; homozygous model, OR = 0.51, 95% CI = 0.36-0.78, p < 0.001. Significant association between K109R polymorphism and BC risk was not found in total or Caucasian population, but in Asian population: dominant model, OR = 0.24, 95% CI = 0.07-0.84, p = 0.03; heterozygous model, OR = 1.87, 95% CI = 1.07-3.26, p = 0.03. Conclusion: The available evidence suggests that Q223R polymorphism may be significantly associated with BC risk in African population. K109R polymorphism may be significantly associated with BC risk in Asian population. [ABSTRACT FROM AUTHOR]

Obesity has been recognized as one of the most significant risk factors for the deterioration and mortality associated with COVID-19, but the significance of obesity itself differs among ethnicity. Multifactored analysis of our single institute-based retrospective cohort revealed that high visceral adipose tissue (VAT) burden, but not other obesity-associated markers, was related to accelerated inflammatory responses and the mortality of Japanese COVID-19 patients. To elucidate the mechanisms how VAT-dominant obesity induces severe inflammation after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, we infected two different strains of obese mice, C57BL/6JHamSlc-ob/ob (ob/ob), C57BLKS/J-db/db (db/db), genetically impaired in the leptin ligand and receptor, respectively, and control C57BL/6 mice with mouse-adapted SARS-CoV-2. Here, we revealed that VAT-dominant ob/ob mice were extremely more vulnerable to SARS-CoV-2 due to excessive inflammatory responses when compared to SAT-dominant db/db mice. In fact, SARS-CoV-2 genome and proteins were more abundant in the lungs of ob/ob mice, engulfed in macrophages, resulting in increased cytokine production including interleukin (IL)-6. Both an anti-IL-6 receptor antibody treatment and the prevention of obesity by leptin replenishment improved the survival of SARS-CoV-2-infected ob/ob mice by reducing the viral protein burden and excessive immune responses. Our results have proposed unique insights and clues on how obesity increases the risk of cytokine storm and death in patients with COVID-19. Moreover, earlier administration of antiinflammatory therapeutics including anti-IL-6R antibody to VAT-dominant patients might improve clinical outcome and stratification of the treatment for COVID-19, at least in Japanese patients. [ABSTRACT FROM AUTHOR]

Maternal high-fat diet (HFD) during pregnancy is associated with rapid weight gain and fetal fat mass increase at an early stage. Also, HFD during pregnancy can cause the activation of proinflammatory cytokines. Maternal insulin resistance and inflammation lead to increased adipose tissue lipolysis, and also increased free fatty acid (FFA) intake during pregnancy (˃35% of energy from fat) cause a significant increase in FFA levels in the fetus. However, both maternal insulin resistance and HFD have detrimental effects on adiposity in early life. As a result of these metabolic alterations, excess fetal lipid exposure may affect fetal growth and development. On the other hand, increase in blood lipids and inflammation can adversely affect the development of the liver, adipose tissue, brain, skeletal muscle, and pancreas in the fetus, increasing the risk for metabolic disorders. In addition, maternal HFD is associated with changes in the hypothalamic regulation of body weight and energy homeostasis by altering the expression of the leptin receptor, POMC, and neuropeptide Y in the offspring, as well as altering methylation and gene expression of dopamine and opioid-related genes which cause changes in eating behavior. All these maternal metabolic and epigenetic changes may contribute to the childhood obesity epidemic through fetal metabolic programming. Dietary interventions, such as limiting dietary fat intake <35% with appropriate fatty acid intake during the gestation period are the most effective type of intervention to improve the maternal metabolic environment during pregnancy. Appropriate nutritional intake during pregnancy should be the principal goal in reducing the risks of obesity and metabolic disorders. [ABSTRACT FROM AUTHOR]

Obesity promotes endothelial dysfunction. Endothelial cells not only respond, but possibly actively promote the development of obesity and metabolic dysfunction. Our aim was to characterize the role of endothelial leptin receptors (LepR) for endothelial and whole body metabolism and diet-induced obesity. Mice with tamoxifen-inducible, Tie2.Cre-ERT2-mediated deletion of LepR in endothelial cells (End.LepR knockout, KO) were fed high-fat diet (HFD) for 16 weeks. Body weight gain, serum leptin levels, visceral adiposity and adipose tissue inflammation were more pronounced in obese End.LepR-KO mice, whereas fasting serum glucose and insulin levels or the extent of hepatic steatosis did not differ. Reduced brain endothelial transcytosis of exogenous leptin, increased food intake and total energy balance were observed in End.LepR-KO mice and accompanied by brain perivascular macrophage accumulation, whereas physical activity, energy expenditure and respiratory exchange rates did not differ. Metabolic flux analysis revealed no changes in the bioenergetic profile of endothelial cells from brain or visceral adipose tissue, but higher glycolysis and mitochondrial respiration rates in those isolated from lungs. Our findings support a role for endothelial LepRs in the transport of leptin into the brain and neuronal control of food intake, and also suggest organ-specific changes in endothelial cell, but not whole-body metabolism. [ABSTRACT FROM AUTHOR]

Despite its important role in numerous physiological functions, including regulation of appetite and body weight, immune function and normal sexual maturation, raised leptin levels could result in significant damaging effects on sperm. The adverse effects of leptin on the male reproductive system result from its direct actions on the reproductive organs and cells instead of the hypothalamus–pituitary–gonadal axis. Binding of leptin to the receptors in the seminiferous tubular cells of the testes increases free radical production and decreases the gene expression and activity of endogenous enzymatic antioxidants. These effects are mediated via the PI3K pathway. The resultant oxidative stress causes significant damage to the seminiferous tubular cells, germ cells and sperm DNA leading to apoptosis, increased sperm DNA fragmentation, decreased sperm count, increased fraction of sperm with abnormal morphology, and decreased seminiferous tubular height and diameter. This review summarises the evidence in the literature on the adverse effects of leptin on sperm, which could underlie the often-reported sperm abnormalities in obese hyperleptinaemic infertile males. Although leptin is necessary for normal reproductive function, its raised levels could be pathologic. There is, therefore, a need to identify the cut-off level in the serum and seminal fluid above which leptin becomes pathological for better management of leptin associated adverse effects on male reproductive function. Sperm abnormalities are commonly reported in men with high leptin levels. This review examines the literature to ascertain a link between leptin and abnormal sperm parameters. Evidence suggests that leptin impacts sperm, and is probably responsible for the sperm abnormalities in men with raised leptin levels. [ABSTRACT FROM AUTHOR]

Active thermogenesis in the brown adipose tissue (BAT) facilitating the utilization of lipids and glucose is critical for maintaining body temperature and reducing metabolic diseases, whereas inactive BAT accumulates lipids in brown adipocytes (BAs), leading to BAT whitening. Although cellular crosstalk between endothelial cells (ECs) and adipocytes is essential for the transport and utilization of fatty acid in BAs, the angiocrine roles of ECs mediating this crosstalk remain poorly understood. Using single-nucleus RNA sequencing and knock-out male mice, we demonstrate that stem cell factor (SCF) derived from ECs upregulates gene expressions and protein levels of the enzymes for de novo lipogenesis, and promotes lipid accumulation by activating c-Kit in BAs. In the early phase of lipid accumulation induced by denervation or thermoneutrality, transiently expressed c-Kit on BAs increases the protein levels of the lipogenic enzymes via PI3K and AKT signaling. EC-specific SCF deletion and BA-specific c-Kit deletion attenuate the induction of the lipogenic enzymes and suppress the enlargement of lipid droplets in BAs after denervation or thermoneutrality in male mice. These data provide insight into SCF/c-Kit signaling as a regulator that promotes lipid accumulation through the increase of lipogenic enzymes in BAT when thermogenesis is inhibited. Although it is known that cellular crosstalk between endothelial cells and brown adipocytes is essential, it remains poorly understood. Here the authors show that SCF derived from the surrounding endothelial cells promotes lipid accumulation in BAT by enhancing lipogenic enzymes in through c-Kit activation. [ABSTRACT FROM AUTHOR]

The melanocortin-4 receptor agonist setmelanotide is now recommended for the treatment of genetic obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency in patients aged 6 years and older. Here, we describe the clinical benefit of setmelanotide administration in a 5-year-old child with severe hyperphagia and obesity due to POMC deficiency. Daily administration of 0.5 mg setmelanotide for 12 months resulted in significant weight loss of −30 kg from baseline (−36% of weight loss) and improvements in hyperphagia and metabolic status. No major side effects were observed, except for hyperpigmentation and transient spontaneous erections. Interestingly, the clinical improvement of the child was associated with a remarkable improvement in the quality of life of the parents, along with a decrease in their emotional scores. This observation supports the early use of setmelanotide in young children with melanocortin pathway variants, in order to limit the adverse consequences of early and extreme weight gain, and to improve the quality of life of patients and of their relatives. [ABSTRACT FROM AUTHOR]

Simple Summary: This article is mainly about that molecular characterization and expression pattern of leptin in yellow cheek carp (Elopichthys bambusa) and its transcriptional changes in response to fasting and refeeding. In this study, the authors used PCR to clone the CDS of leptin in yellow cheek carp, and analyzed the sequence differences of the gene with other species, constructed the phylogenetic tree, used real-time PCR for analyzing the expression of leptin in different tissues, including the expression of leptin in the brain and liver after fasting–refeeding of yellow cheek carp. This paper found that the full-length cDNA sequence of Eblep was 1140 bp and the length of the open reading frame (ORF), which can encode a protein of 174 amino acids, was 525 bp. The Eblep mRNA transcript was detected in all tested tissues, with the highest expression in the liver and lowest expression in the spleen. It was found that the change in the mRNA expression of EbLep may be an adaptive strategy for different energy levels by studying the expression of EbLep mRNA in the brain and liver under fasting and refeeding. Leptin, a secretory protein encoded by obese genes, plays an important role in regulating feeding and energy metabolism in fish. To study the structure and function of the Leptin gene in yellow cheek carp (Elopichthys bambusa), the full-length cDNA sequence of leptin was cloned, named EbLep. The full-length cDNA of Eblep was 1140 bp, and the length of the open reading frame (ORF), which can encode a protein of 174 amino acids, was 525 bp. The signal peptide was predicted to contain 33 amino acids. Sequence alignment showed that the amino acid sequence of Leptin was conserved in cyprinid fish. Despite large differences between primary structures, the tertiary structure of the EbLep protein was similar to that of the human protein and had four α-helices. The EbLep mRNA transcript was detected in all tested tissues, with the highest expression in the liver and lowest expression in the spleen. In this study, short-term fasting significantly increased the mRNA expression of EbLep in the liver, which returned to a normal level after 6 days of refeeding and was significantly lower than the normal level after 28 days of refeeding. In the brain, the mRNA expression of EbLep significantly decreased during short-term fasting and significantly increased to a higher value than the control group after 1 h of refeeding. It then rapidly decreased to a lower value than the control group after 6 h of refeeding, returning to the normal level after 1 day of refeeding, and significantly decreasing to a lower value than the control group after 28 days of refeeding. To sum up, the change in the mRNA expression of EbLep in the brain and liver may be an adaptive strategy for different energy levels. [ABSTRACT FROM AUTHOR]

The adipokine leptin plays an important role in the regulation of the reproductive system. It stimulates the activity of the hypothalamic–pituitary–gonadal axis by indirectly affecting gonadoliberin (GnRH)-secreting neurons and modulates testicular steroidogenesis via binding to leptin receptors in Leydig cells. The leptin fragment (LF) 116–122, which includes the main receptor-binding determinants of this adipokine, normalizes metabolic parameters in animals with a diet-induced obesity. However, its ability to influence the testicular steroidogenic function, including through interaction with hypothalamic GnRH neurons, has not been studied. The aim of this work was to study the effects of a single and 3-day intranasal LF administration (200 µg/rat) on blood testosterone levels and expression of steroidogenic genes in the testes of mature male Wistar rats, as well as to evaluate the steroidogenic activity of LF upon testosterone synthesis stimulation by human chorionic gonadotropin (hCG, 15 IU/rat, s.c.) and inhibition by the GnRH receptor antagonist Cetrorelix (75 µg/kg, s.c.). It was shown that a single LF administration increases blood testosterone levels, while a 3-day administration enhances the steroidogenic effect of hCG. LF and hCG increased the expression of the Star gene that encodes the key regulatory protein of steroidogenesis StAR. Cetrorelix administration reduced blood testosterone levels and Star expression, while compensatory increasing gene expression of the luteinizing hormone receptor. The potentiating effect of LF on hCG-induced stimulation of testosterone synthesis and Star expression was not detected after Cetrorelix treatment. Thus, LF is able to stimulate testicular steroidogenesis in rats by itself and potentiate the steroidogenic effects of hCG. Since its effects are suppressed in the presence of a GnRH antagonist, there are grounds to assume that they are implemented via stimulation of hypothalamic GnRH neurons. [ABSTRACT FROM AUTHOR]

Simple Summary: Mycotoxin-contaminated feed is a current, worldwide problem. Mold-contaminated cereal is rich in heat-resistant and harmful metabolites such as fumonisins. The amount of fumonisins consumed as part of animal feed, including livestock feed, is unknown, and thus their influence on animal health, the costs associated with veterinary health care and the associated economic losses in breeding are impossible to calculate. Prenatal exposure of fetuses to fumonisins, through exposure of the mothers to fumonisins during pregnancy, is an important problem during breeding, often resulting in disturbed development of offspring in the postnatal period as a result. Thus, studies focused on the effects of fumonisin-exposure during the prenatal period on postnatal development are required. Animal feed is very frequently contaminated with different types of mold, the metabolites of which are toxic to living organisms. Mold-contaminated cereal is rich in heat-resistant and harmful metabolites such as fumonisins (FBs). The amount of FBs consumed as part of animal feed, including livestock feed, is unknown. Therefore, this study aimed to evaluate the effects of maternal oral FB intoxication on basal duodenum morphology and the immunolocalization of gut hormones responsible for food intake (leptin and ghrelin), as well as their receptors, in newborn rat offspring. Pregnant Wistar rats were randomly allocated to one of three groups: a control group or one of two FB-intoxicated groups (60 or 90 mg FB/kg b.w., respectively). Basal morphological duodenal parameters changed in a dose- and sex-dependent manner. The intensity of the ghrelin immunoreaction was unchanged in females, while in males it increased after FB exposure (60 mg/kg b.w.), with a simultaneous decrease in expression of the ghrelin receptor. Leptin and its receptor immunoreaction intensity was decreased in both sexes following FB exposure. The current study highlighted the potential involvement of intestinal ghrelin and leptin in the metabolic disturbances observed later in life in offspring that were prenatally exposed to fumonisins. [ABSTRACT FROM AUTHOR]

Leptin is an adipokine with a pleiotropic impact on many physiological processes, including hypothalamic-pituitary-somatotropic (HPS) axis activity, which plays a key role in regulating mammalian metabolism. Leptin insensitivity/resistance is a pathological condition in humans, but in seasonal animals, it is a physiological adaptation. Therefore, these animals represent a promising model for studying this phenomenon. This study aimed to determine the influence of leptin on the activity of the HPS axis. Two in vivo experiments performed during short- and long-day photoperiods were conducted on 12 ewes per experiment, and the ewes were divided randomly into 2 groups. The arcuate nucleus, paraventricular nucleus, anterior pituitary (AP) tissues, and blood were collected. The concentration of growth hormone (GH) was measured in the blood, and the relative expression of GHRH, SST, GHRHR, SSTR1, SSTR2, SSTR3, SSTR5, LEPR, and GH was measured in the collected brain structures. The study showed that the photoperiod, and therefore leptin sensitivity, plays an important role in regulating HPS axis activity in the seasonal ewe. However, leptin influences the release of GH in a season-dependent manner, and its effect seems to be targeted at the posttranscriptional stages of GH secretion. [ABSTRACT FROM AUTHOR]

Context: Serum soluble leptin receptor (sOb-R) may protect against future type 2 diabetes or serve as a marker for protective features, but how sOb-R is regulated is largely unknown. Objective: This work aimed to test how serum sOb-R is influenced by glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity. Methods: We performed an epidemiological triangulation combining cross-sectional, interventional, and Mendelian randomization study designs. In 5 independent clinical studies (n= 24-823), sOb-R was quantified in serum or plasma by commercial enzyme-linked immunosorbent assay kits using monoclonal antibodies. We performed mixed-model regression and 2-sample Mendelian randomization. Results: In pooled, cross-sectional data, leveling by study, sOb-R was associated inversely with BMI (β [95% CI] −0.19 [−0.21 to −0.17]), body fat (−0.12 [−0.14 to −0.10), and fasting C-peptide (−2.04 [−2.46 to −1.62]). sOb-R decreased in response to acute hyperinsulinemia during euglycemic glucose clamp in 2 independent clinical studies (−0.5 [−0.7 to −0.4] and −0.5 [−0.6 to −0.3]), and immediately increased in response to intensive exercise (0.18 [0.04 to 0.31]) and food intake (0.20 [0.06 to 0.34]). In 2-sample Mendelian randomization, higher fasting insulin and higher BMI were causally linked to lower sOb-R levels (inverse variance weighted, −1.72 [−2.86 to −0.58], and −0.20 [−0.36 to −0.04], respectively). The relationship between hyperglycemia and sOb-R was inconsistent in cross-sectional studies and nonsignificant in intervention studies, and 2-sample Mendelian randomization suggested no causal effect of fasting glucose on sOb-R. Conclusion: BMI and insulin both causally decreased serum sOb-R levels. Conversely, intensive exercise and food intake acutely increased sObR. Our results suggest that sOb-R is involved in short-term regulation of leptin signaling, either directly or indirectly, and that hyperinsulinemia may reduce leptin signaling. [ABSTRACT FROM AUTHOR]

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Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and a relative deficiency of insulin. This study aims to screen T2DM-related maker genes in the mouse extraorbital lacrimal gland (ELG) by LASSO regression.C57BLKS/J strain with leptin db/db homozygous mice (T2DM, n = 20) and wild-type mice (WT, n = 20) were used to collect data. The ELGs were collected for RNA sequencing. LASSO regression was conducted to screen marker genes with the training set. Five genes were selected from 689 differentially expressed genes by LASSO regression, including Synm, Elovl6, Glcci1, Tnks and Ptprt. Expression of Synm was downregulated in ELGs of T2DM mice. Elovl6, Glcci1, Tnks, and Ptprt were upregulated in T2DM mice. Area under receiver operating curve of the LASSO model was 1.000(1.000–1.000) and 0.980(0.929–1.000) in the training set and the test set, respectively. The C-index and the robust C-index of the LASSO model were 1.000 and 0.999, respectively, in the training set, and 1.000 and 0.978, respectively, in the test set. In the lacrimal gland of db/db mice, Synm, Elovl6, Glcci1, Tnks and Ptprt can be used as marker genes of T2DM. Abnormal expression of marker genes is related to lacrimal gland atrophy and dry eye in mice. [ABSTRACT FROM AUTHOR]

The bone marrow contains various populations of skeletal stem cells (SSCs) in the stromal compartment, which are important regulators of bone formation. It is well-described that leptin receptor (LepR)+ perivascular stromal cells provide a major source of bone-forming osteoblasts in adult and aged bone marrow. However, the identity of SSCs in young bone marrow and how they coordinate active bone formation remains unclear. Here we show that bone marrow endosteal SSCs are defined by fibroblast growth factor receptor 3 (Fgfr3) and osteoblast-chondrocyte transitional (OCT) identities with some characteristics of bone osteoblasts and chondrocytes. These Fgfr3-creER-marked endosteal stromal cells contribute to a stem cell fraction in young stages, which is later replaced by Lepr-cre-marked stromal cells in adult stages. Further, Fgfr3+ endosteal stromal cells give rise to aggressive osteosarcoma-like lesions upon loss of p53 tumor suppressor through unregulated self-renewal and aberrant osteogenic fates. Therefore, Fgfr3+ endosteal SSCs are abundant in young bone marrow and provide a robust source of osteoblasts, contributing to both normal and aberrant osteogenesis. This study identified a new class of skeletal stem cells in the endosteal space of bone marrow, which are abundant in young bone marrow, express Fgfr3 with osteoblast-chondrocyte transitional identities and can turn into bone tumor-making cells. [ABSTRACT FROM AUTHOR]

Leptin inhibits food intake and reduces the size of body fat depots, changing adipocyte sensitivity to insulin to restrain lipid accrual. This adipokine may modulate the production of cytokines that could diminish insulin sensitivity, particularly in visceral adipose tissue. To explore this possibility, we examined the effects of chronic central administration of leptin on the expression of key markers of lipid metabolism and its possible relationship with changes in inflammatory- and insulin-signaling pathways in epididymal adipose tissue. Circulating non-esterified fatty acids and pro- and anti-inflammatory cytokines were also measured. Fifteen male rats were divided into control (C), leptin (L, icv, 12 μg/day for 14 days), and pair-fed (PF) groups. We found a decrease in the activity of glucose-6-phosphate dehydrogenase and malic enzyme in the L group, with no changes in the expression of lipogenic enzymes. A reduction in the expression of lipoprotein lipase and carnitine palmitoyl-transferase-1A, together with a decrease in the phosphorylation of insulin-signaling targets and a low-grade inflammatory pattern, were detected in the epididymal fat of L rats. In conclusion, the decrease in insulin sensitivity and increased pro-inflammatory environment could regulate lipid metabolism, reducing epididymal fat stores in response to central leptin infusion. [ABSTRACT FROM AUTHOR]

The hormone leptin is known to robustly suppress food intake by acting upon the leptin receptor (LepR) signaling system residing within the agouti-related protein (AgRP) neurons of the hypothalamus. However, clinical studies indicate that leptin is undesirable as a therapeutic regiment for obesity, which is at least partly attributed to the poorly understood complex secondary structure and key signaling mechanism of the leptin-responsive neural circuit. Here, we show that the LepR-expressing portal neurons send GABAergic projections to a cohort of α3-GABAA receptor expressing neurons within the dorsomedial hypothalamic nucleus (DMH) for the control of leptinmediated obesity phenotype. We identified the DMH as a key brain region that contributes to the regulation of leptin-mediated feeding. Acute activation of the GABAergic AgRP-DMH circuit promoted food intake and glucose intolerance, while activation of post-synaptic MC4R neurons in the DMH elicited exactly opposite phenotypes. Rapid deletion of LepR from AgRP neurons caused an obesity phenotype which can be rescued by blockage of GABAA receptor in the DMH. Consistent with behavioral results, these DMH neurons displayed suppressed neural activities in response to hunger or hyperglycemia. Furthermore, we identified that α3-GABAA receptor signaling within the DMH exerts potent bi-directional regulation of the central effects of leptin on feeding and body weight. Together, our results demonstrate a novel GABAergic neural circuit governing leptinmediated feeding and energy balance via a unique α3-GABAA signaling within the secondary leptinresponsive neural circuit, constituting a new avenue for therapeutic interventions in the treatment of obesity and associated comorbidities. [ABSTRACT FROM AUTHOR]

Background: Adipose tissue-derived stromal vascular fraction (SVF) harbors multipotent cells with potential therapeutic relevance. We developed a method to form adipose spheroids (AS) from the SVF with complex organoid structure and enhanced leptin secretion upon insulin stimulation. Methods: SVF was generated from the interscapular brown adipose tissue of newborn mice. Immunophenotype and stemness of cultured SVF were determined by flow cytometry and in vitro differentiation, respectively. Spheroids were generated in hanging drops and non-adherent plates and compared by morphometric methods. The adipogenic potential was compared between preadipocyte monolayers and spheroids. Extracellular leptin was quantified by immunoassay. Lipolysis was stimulated with isoprenaline and quantified by colorimetric methods. AS viability and ultrastructure were determined by confocal and transmission electron microscopy analyses. Results: Cultured SVF contained Sca1 + CD29 + CD44 + CD11b- CD45- CD90- cells with adipogenic and chondrogenic but no osteogenic potential. Culture on non-adherent plates yielded the highest quantity and biggest size of spheroids. Differentiation of AS for 15 days in a culture medium supplemented with insulin and rosiglitazone resulted in greater Pparg, Plin1, and Lep expression compared to differentiated adipocytes monolayers. AS were viable and maintained leptin secretion even in the absence of adipogenic stimulation. Glycerol release after isoprenaline stimulation was higher in AS compared to adipocytes in monolayers. AS were composed of outer layers of unilocular mature adipocytes and an inner structure composed of preadipocytes, immature adipocytes and an abundant loose extracellular matrix. Conclusion: Newborn mice adipose SVF can be efficiently differentiated into leptin-secreting AS. Prolonged stimulation with insulin and rosiglitazone allows the formation of structurally complex adipose organoids able to respond to adrenergic lipolytic stimulation. [ABSTRACT FROM AUTHOR]

The reproductive phase‐wise leptin (lep) and its receptor (lepr) expression in different parts of the brain of adult male and female spotted snakehead Channa punctata reveals sexual dimorphism in the brain leptin system. In anterior, middle and posterior parts of the brain of males, a maximum lep was observed in resting, spawning and postspawning reproductive phases, respectively. In females, a high level of lep was seen during the preparatory phase in the anterior brain, preparatory and postspawning phases in the middle brain and resting and postspawning phases in the posterior brain. Nonetheless, the transcript level of lepr was recorded highest during the spawning phase, irrespective of sex and region of the brain. Regardless of the reproductive state of fishes, lep and lepr were seen considerably high in middle and posterior parts of male brain than that of female, implying the involvement of factors other than sex steroids for sex‐related variation in the leptin system in these regions of the brain. Nonetheless, no sex difference was evidenced in the expression of either ligand or its receptor in the anterior brain. In summary, the presence of lep and lepr in different regions of the brain and variation in their expression depending on sex and reproductive phases raise the possibility of pivotal actions of leptin in influencing neuronal circuitry and thereby reproductive functions. [ABSTRACT FROM AUTHOR]

In the present study, candidate single nucleotide polymorphism (SNP) g.92450765 G > A of leptin gene was explored for Bos indicus cattle with an aim to explore its possible effect on production and reproduction traits. The genotypic and allelic frequencies of BsaA 1 genotyped SNP g.92450765 G > A indicated the predominance of AG (0.65) genotyped Sahiwal cows in our studied population. The least-squares analysis showed a significant association (p < 0.05) of identified genetic variants with total milk yield (TMY) and 305 days milk yield (MY) (p < 0.05). The GG genotyped cows were found to be associated with higher milk yields. However, for reproduction traits under study AA genotype was found to be more favorable with respect to service period and calving interval (p < 0.05). Computational analysis was also performed to predict changes if any in the transcription factor binding sites (TFBS) caused due to the identified SNP in the intronic region of the leptin gene. TFBS analysis predicted that the targeted SNP at g.92450765G > A may lead to the disappearance of TFBS such as Hypermethylated in cancer 2 protein (HIC2), Max-binding protein MNT (MNT), Cyclic AMP-dependent transcription factor −3 (ATF3), Myc-associated factor X (MAX) and Microphthalmia-associated transcription factor (MITF). It may lead to changes in transcriptional regulation. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that the activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome contributes to the pathophysiology of post-traumatic stress disorder (PTSD). Astrocytes, the homeostatic cells of the central nervous system are intimately involved into pathophysiology of various mental disorders including PTSD. We demonstrated previously that leptin exerts neuroprotection and ameliorates chronic sleep deprivation-induced depressive-like behaviours. Here, we extended the study of therapeutic effects of leptin to PTSD model mice. We discovered that PTSD is associated with significant activation of NLRP3 inflammasome in astrocytes sorted from GFAP-GFP transgenic mice, while administration of leptin markedly suppressed the activation of astrocytic NLRP3 inflammasome. Leptin effectively improved PTSD-associated behavioural alterations including fear memory, cognitive impairments, and depressive-like behaviours. Therapeutic effects of leptin were mediated by the signal transducer and activator of transcription 3 (STAT3) in astrocytes. In addition, the PTSD-related activation of NLRP3 inflammasome impairs astrocytic mitochondria suppressing ATP synthesis and leading to an increased ROS production. Leptin reversed mitochondrial inhibition by stimulating STAT3 in astrocytes. We propose leptin as a novel candidate for the pharmacological treatment of PTSD. [ABSTRACT FROM AUTHOR]

Purpose: Infertility is the situation in which pregnancy cannot be achieved despite unprotected sexual intercourse within at least one year. Male infertility can range from the entire absence of spermatozoa in the testicles (azoospermia) to noticeable variations in sperm quality. The patients with a mutation in the leptin (LEP) gene have been reported to be infertile and the patients with a mutation in the Leptin Receptor (LEPR) gene were shown to lack pubertal development. This study was performed to state if there is a relationship between azoospermic male infertility and LEP gene -2548G>A and LEPR gene Q223R polymorphisms. Materials and Methods: One hundred thirty-seven azoospermic infertile men and a hundred fertile men were included in this study. DNAs obtained from peripheral blood of participants were analyzed by polymerase chain reaction (PCR) along with restriction fragment length polymorphism (RFLP) technics.. Results: In terms of LEP -2548G>A (rs7799039) and LEPR Q223R (rs1137101) polymorphisms, no statistically remarkable distinction was observed in the genotype and allele distributions of azoospermic infertile and fertile men. In the composite genotype analysis, it was determined that the GGQR composite genotype was approximately 9 times more common in azoospermic infertile men than in fertile men (8.8% vs. 1.0%). Conclusion: It has been determined that LEP -2548G>A and LEPR Q223R polymorphisms may have a dual effect in azoospermic male infertility. We believe that more efficient and precise results can be obtained by conducting these studies in larger populations. [ABSTRACT FROM AUTHOR]

db/db mice, which lack leptin receptors and exhibit hyperphagia, show disturbances in energy metabolism and are a model of obesity and type 2 diabetes. The geroneuroprotector drug candidate CMS121 has been shown to be effective in animal models of Alzheimer's disease and aging through the modulation of metabolism. Thus, the hypothesis was that CMS121 could protect db/db mice from metabolic defects and thereby reduce liver inflammation and kidney damage. The mice were treated with CMS121 in their diet for 6 months. No changes were observed in food and oxygen consumption, body mass, or locomotor activity compared to control db/db mice, but a 5% reduction in body weight was noted. Improved glucose tolerance and reduced HbA1c and insulin levels were also seen. Blood and liver triglycerides and free fatty acids decreased. Improved metabolism was supported by lower levels of fatty acid metabolites in the urine. Markers of liver inflammation, including NF-κB, IL-18, caspase 3, and C reactive protein, were lowered by the CMS121 treatment. Urine markers of kidney damage were improved, as evidenced by lower urinary levels of NGAL, clusterin, and albumin. Urine metabolomics studies provided further evidence for kidney protection. Mitochondrial protein markers were elevated in db/db mice, but CMS121 restored the renal levels of NDUFB8, UQCRC2, and VDAC. Overall, long-term CMS121 treatment alleviated metabolic imbalances, liver inflammation, and reduced markers of kidney damage. Thus, this study provides promising evidence for the potential therapeutic use of CMS121 in treating metabolic disorders. [ABSTRACT FROM AUTHOR]

Malic Enzyme 1 (ME1) supports lipogenesis, cholesterol synthesis, and cellular redox potential by catalyzing the decarboxylation of L-malate to pyruvate, and the concomitant reduction of NADP to NADPH. We examined the contribution of ME1 to the development of obesity by provision of an obesogenic diet to C57BL/6 wild type (WT) and MOD-1 (lack ME1 protein) female mice. Adiposity, serum hormone levels, and adipose, mammary gland, liver, and small intestine gene expression patterns were compared between experimental groups after 10 weeks on a diet. Relative to WT female mice, MOD-1 female mice exhibited lower body weights and less adiposity; decreased concentrations of insulin, leptin, and estrogen; higher concentrations of adiponectin and progesterone; smaller-sized mammary gland adipocytes; and reduced hepatosteatosis. MOD-1 mice had diminished expression of Lep gene in abdominal fat; Lep, Pparg, Klf9, and Acaca genes in mammary glands; Pparg and Cdkn1a genes in liver; and Tlr9 and Ffar3 genes in the small intestine. By contrast, liver expression of Cdkn2a and Lepr genes was augmented in MOD-1, relative to WT mice. Results document an integrative role for ME1 in development of female obesity, suggest novel linkages with specific pathways/genes, and further support the therapeutic targeting of ME1 for obesity, diabetes, and fatty liver disease. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic and immune-mediated skin condition characterized by pro-inflammatory cytokines and keratinocyte hyperproliferation. Dendritic cells, T lymphocytes, and keratinocytes represent the main cell subtypes involved in the pathogenesis of psoriasis, while the interleukin-23 (IL-23)/IL-17 pathway enhances the disease progression. Human adipose tissue is an endocrine organ, which secretes multiple proteins, known as adipokines, such as adiponectin, leptin, visfatin, or resistin. Current evidence highlights the immunomodulatory roles of adipokines, which may contribute to the progression or suppression of psoriasis. A better understanding of the complexity of psoriasis pathophysiology linked with adipokines could result in developing novel diagnostic or therapeutic strategies. This review aims to present the pathogenesis of psoriasis and the roles of adipokines in this process. [ABSTRACT FROM AUTHOR]

Maca root extract on insulin, insulin receptor substrate-1 (IRS1), leptin, and NAD-dependent deacetylase sirtuin-1 (SIRT1), as well as body weight changes evaluated in this study for a 60 days model of normal and high-fat diet (HFD) fed rats. 28 male rats allocated to four groups: (i) Control, (ii) Maca (40 mg/kg/day), (iii) HFD, and (iv) HFD + Maca. After the 60 days of study, fat tissue and liver insulin levels decreased in the HFD and HFD + Maca groups in comparison to Control and Maca groups (p <.001). Maca group showed a significant IRS1 increase in the fat tissue (p <.0001). Leptin levels were the highest in the Maca group and the lowest in the HFD group in the fat tissue (p <.01). SIRT1 levels were found the highest in the Maca groups (p <.01). These results show the protective and regulatory effectiveness of Maca when fed with a normal or HFD diet. [ABSTRACT FROM AUTHOR]

Background & Objective: Endometrial carcinoma is one of the most common malignancies in women in developed countries and the fourth malignancy in Iranian women. Therefore, the identification of its causative factors is essential for the prevention, diagnosis, and treatment. This study was aimed to compare the leptin receptor (Ob-R) expression in the endometrial carcinoma cases and non-carcinoma samples. Methods: In this case-control study, 89 samples (including 45 carcinoma and 44 noncarcinoma samples) were examined. The carcinomatous samples were selected by the census method and others were selected with random method. The data were obtained from histopathologic diagnosis, immunohistochemistry (negative, positive and intensity of immunoreactivity), age, history of diabetes, and hypertension. Ob-R expression was compared in the studied groups using Chi-square, Fisher tests and Multivariate logistic regression analysis. In all tests the level of significance was set at 0.05. The SPSS 26 was used for data analysis. Results: The frequency of high levels of leptin receptors in the patients with endometrial carcinoma was significantly higher compared to the control group (57.8% vs. 2.3%) (P<0.05). Adjusting the effects of age, history of diabetes mellitus (DM) and hypertension (HTN) revealed that the positive-receptor group had 37.75 (95% CI; 5.18-275.04) odds of having endometrial carcinoma (P<0.001). Conclusion: The leptin receptor may be a risk factor for the endometrial carcinoma among women tested in Kashan. Based on these results, leptin receptor might be considered as a potential biomarker for screening the endometrial carcinoma or targeting the therapeutic purposes. [ABSTRACT FROM AUTHOR]

Accumulated evidence shows that melatonin possesses the potential to improve lipid metabolism by modifying gut microbiota and glucose metabolism via regulating the melatonin receptor signaling pathway. However, the contribution of melatonin consumption on glucose homeostasis by affecting gut microbiota has not been investigated in diabetes. In the current work, we investigated the effect of melatonin administration on gut microbiota and glucose homeostasis in db/db mice, a type 2 diabetes model with leptin receptor deficiency. Administration of melatonin through drinking water (at 0.25% and 0.50%) for 12 weeks decreased diabetic polydipsia and polyuria, increased insulin sensitivity and impeded glycemia. The accumulated fecal levels of total short‐chain fatty acids (SCFAs) and acetic acid are positively correlated with diabetes‐related parameters—homeostasis model assessment of insulin resistance (HOMA‐IR) index and fasting blood glucose (FBG) level. The reprogramming of gut microbiota structure and abundance and the reduction of fecal levels of SCFAs, including acetic acid, butyric acid, isovaleric acid, caproic acid, and isobutyric acid, by melatonin may be beneficial for enhancing insulin sensitivity and lowering FBG, which were verified by the results of correlation analysis between acetic acid or total SCFAs and HOMA‐IR and FBG. In addition, the melatonin downregulated hepatic genes, including fructose‐1,6‐bisphosphatase 1, forkhead box O1 alpha, thioredoxin‐interacting protein, phosphoenolpyruvate carboxy‐kinase (PEPCK), PEPCK1 and a glucose‐6‐phosphatase catalytic subunit, that responsible for gluconeogenesis support the result that melatonin improved glucose metabolism. Overall, results showed that the melatonin supplementation reduced fecal SCFAs level via reprogramming of gut microbiota, and the reduction of fecal SCFAs level is associated with improved glucose homeostasis in db/db mice. [ABSTRACT FROM AUTHOR]

Background: Maternal obesity (MO) is associated with a higher risk of immune‐mediated diseases in the offspring and higher leptin levels in cord blood (CB). This study evaluates the number and function of lymphocyte subtypes in CB related to MO and its relationship with leptin concentration and leptin receptor expression. Methods: Pregnant women with (n = 32) or without obesity (n = 41) were enrolled at delivery. Cord blood mononuclear cells were separated with Ficoll‐Hypaque. B and CD4+, regulatory and effector T cells were quantified by Flow Cytometry. Cord blood leptin concentration was measured by ELISA, and the leptin receptor (sLepR) on Treg cells was determined by Flow Cytometry. Results: MO was associated with higher numbers of CD4+, Treg and effector T cells in the CB of their offspring, without differences in the suppressive function of Tregs. Female offspring had a higher number of these cells and a higher cord leptin concentration. Tregs expressed higher levels of sLepR than effector T cells, without differences between groups. Conclusions: MO is associated with changes in the newborn's immune profile, more evident in female newborns with higher leptin concentrations. More studies are needed to identify the mechanisms by which the high levels of cord leptin in the newborn of women with obesity could affect the offspring's immune system. [ABSTRACT FROM AUTHOR]

Monogenic obesity can be caused by a mutation in one of the single genes involved in hunger and satiety. The most common mutations affect melanocortin 4 (MC4) followed by the leptin gene and its receptor. Leptin receptor (LEPR) gene mutation is an extremely rare endocrine disease characterized by early-onset obesity, hyperphagia in addition to pituitary hormone deficiency, and metabolic abnormalities. We report the case of a 12-month-old male infant born of a non-consanguineous marriage. He presented to us with rapid weight gain from 2 months of age along with hyperphagia. Biochemistry revealed a deranged lipid profile, elevated transaminases, and markedly raised serum leptin levels. On genetic analysis, a novel mutation was detected, which was a homozygous variation In exon 12 of the LEPR gene (chr1:g.65608901G>A) that resulted in the synonymous amino acid change of lysine at codon 584 proximal to donor splice site (p.Lys584). The in silico prediction of the variant was 'damaging' by MutationTaster2. The mutation was classified as a 'variant of uncertain significance' due to a lack of published literature and had to be correlated carefully with the clinical symptoms. It was recommended to do Sanger sequencing of the parents and other family members. However, due to financial constraints, the family could not afford the same. At the time of writing, funds were being arranged for procuring setmelanotide, which is a novel and effective therapy for monogenic obesity due to LepR mutation. [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with increased mortality among ovarian cancer and is a poor prognostic factor. There are significant links between the leptin hormone, a product of the obesity gene, and the development of ovarian cancer. Leptin is a vital hormone-like cytokine secreted from adipose tissue and is mainly involved in the maintenance of energy homeostasis. It regulates several intracellular signaling pathways and also interacts with various hormones and energy regulators. It acts as a growth factor by stimulating cell proliferation and differentiation and in this way contributes to cancer cell development. The aim of the study was to investigate the effects of leptin on human ovarian cancer cells. Methods: In this study, the effects of increasing the concentration of leptin were investigated on the cell viability of OVCAR-3 and MDAH-2774 ovarian cancer lines by MTT assay. Moreover, to elucidate the molecular mechanisms of leptin in ovarian cancer cells, changes in the expression levels of 80 cytokines were evaluated after leptin treatment via a human cytokine antibody array. Results: Leptin increases the proliferation of both ovarian cancer cell lines. IL-1 level was increased in OVCAR-3 cells and TGF-α level was increased in MDAH-2774 cells after leptin treatment. A decrease in IL-2, MCP-2/CCL8 and MCP-3/CCL7 levels was detected in both ovarian cancer cell lines with leptin administration. An increase in IL-3 and IL-10 expressions, insulin-like growth factor binding proteins (IGFBP) IGFBP-1, IGFBP-2 and IGFBP-3 levels were detected in both ovarian cancer cell lines with leptin administration. In conclusion; leptin has a proliferative effect on human ovarian cancer cell lines and affects different cytokines in different types of ovarian cancer cells. [ABSTRACT FROM AUTHOR]

Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)–STAT3 signaling axis in a subset of hypothalamic neurons. Leptin signaling is dysregulated in obesity, however, where appetite remains elevated despite high levels of circulating leptin. To gain insight into the mechanism of leptin receptor activation, here we determine the structure of a stabilized leptin-bound LepR signaling complex using single particle cryo-EM. The structure reveals an asymmetric architecture in which a single leptin induces LepR dimerization via two distinct receptor-binding sites. Analysis of the leptin–LepR binding interfaces reveals the molecular basis for human obesity-associated mutations. Structure-based design of leptin variants that destabilize the asymmetric LepR dimer yield both partial and biased agonists that partially suppress STAT3 activation in the presence of wild-type leptin and decouple activation of STAT3 from LepR negative regulators. Together, these results reveal the structural basis for LepR activation and provide insights into the differential plasticity of signaling pathways downstream of LepR. Leptin is a master regulator of body weight and energy homeostasis that is dysregulated in obesity. Here, authors determined the cryo-EM structure of the activated Leptin receptor complex, revealing insights into the mechanism of Leptin signaling [ABSTRACT FROM AUTHOR]

The pancreatic islet β-cell's preference for release of newly synthesized insulin requires careful coordination of insulin exocytosis with sufficient insulin granule production to ensure that insulin stores exceed peripheral demands for glucose homeostasis. Thus, the cellular mechanisms regulating insulin granule production are critical to maintaining β-cell function. In this report, we utilized the synchronous protein trafficking system, RUSH, in primary β-cells to evaluate proinsulin transit through the secretory pathway leading to insulin granule formation. We demonstrate that the trafficking, processing, and secretion of the proinsulin RUSH reporter, proCpepRUSH, are consistent with current models of insulin maturation and release. Using both a rodent dietary and genetic model of hyperglycemia and β-cell dysfunction, we show that proinsulin trafficking is impeded at the Golgi and coincides with the decreased appearance of nascent insulin granules at the plasma membrane. Ultrastructural analysis of β-cells from diabetic leptin receptor deficient mice revealed gross morphological changes in Golgi structure, including shortened and swollen cisternae, and partial Golgi vesiculation, which are consistent with defects in secretory protein export. Collectively, this work highlights the utility of the proCpepRUSH reporter in studying proinsulin trafficking dynamics and suggests that altered Golgi export function contributes to β-cell secretory defects in the pathogenesis of Type 2 diabetes. [ABSTRACT FROM AUTHOR]

Obesity has been associated with cognitive impairments, increasing the probability of developing dementia. Recently, zinc (Zn) supplementation has attracted an increasing attention as a therapeutic agent for cognitive disorders. Here, we investigated the potential effects of low and high doses of Zn supplementation on cognitive biomarkers and leptin signaling pathway in the hippocampus of high fat diet (HFD)-fed rats. We also explored the impact of sex difference on the response to treatment. Our results revealed a significant increase in body weight, glucose, triglycerides (TG), total cholesterol (TC), total lipids and leptin levels in obese rats as compared to controls. HFD feeding also reduced brain-derived neurotrophic factor (BDNF) levels and increased acetylcholinesterase (AChE) activity in the hippocampus of both sexes. The low and high doses of Zn supplementation improved glucose, TG, leptin, BDNF levels and AChE activity in both male and female obese rats compared to untreated ones. Additionally, downregulated expression of leptin receptor (LepR) gene and increased levels of activated signal transducer and activator of transcription 3 (p-STAT3) that observed in hippocampal tissues of obese rats were successfully normalized by both doses of Zn. In this study, the male rats were more vulnerable to HFD-induced weight gain, most of the metabolic alterations and cognition deficits than females, whereas the female obese rats were more responsive to Zn treatment. In conclusion, we suggest that Zn treatment may be effective in ameliorating obesity-related metabolic dysfunction, central leptin resistance and cognitive deficits. In addition, our findings provide evidence that males and females might differ in their response to Zn treatment. [ABSTRACT FROM AUTHOR]

Background: Previous observational studies have suggested that circulating adipokine concentrations are related to a greater risk of venous thromboembolism (VTE). However, it remained unclear whether these observations reflect causality. Objective: This study aimed to investigate the causal relationship between circulating adipokine concentrations (including adiponectin, leptin, PAI-1, MCP-1, leptin receptor, and RETN) and the risk of VTE and its subtypes (DVT and PE) and to determine whether circulating adipokine concentrations are a mediator of venous thromboembolic events in obese patients. Methods: We used Mendelian randomization (MR) analyses to determine the effects of the body mass index (BMI), adiponectin, leptin, PAI-1, MCP-1, leptin receptor, and RETN levels on VTE, DVT, and PE in a cohort of 11,288 VTE cases, 5,632 DVT cases, 5,130 PE cases, and 254,771 controls. We then assessed the proportion of the effect of obesity on VTE, DVT, and PE explained by circulating leptin levels. Result: Genetically predicted higher BMI was related to increased VTE (OR = 1.45, p < 0.001), DVT (OR = 1.63, p < 0.001), and PE (OR = 1.37, p < 0.001) risk, and higher circulating leptin levels increase odds of VTE (OR = 1.96, q < 0.001), DVT (OR = 2.52, q < 0.001), and PE (OR = 2.26, q = 0.005). In addition, we found that the causal effect between elevated serum adiponectin and the decreased risk of VTE (OR = 0.85, p = 0.013, q = 0.053) and PE (OR = 0.81, p = 0.032, q = 0.083) and between MCP-1 and the reduced risk of VTE (OR = 0.88, p = 0.048, q = 0.143) is no longer significant after FDR adjustment. In MR mediation analysis, the mediation effect of circulating leptin levels in the causal pathway from BMI to PE was estimated to be 1.28 (0.95-1.71, p = 0.10), accounting for 39.14% of the total effect. Conclusion: The circulating leptin level is a risk factor for VTE, DVT, and PE, but it might be a potential mediator of BMI on the risk of PE, and thus, interventions on the circulating leptin level in obesity might reduce the risk of PE. Adiponectin is a potential protective factor for both VTE and PE. [ABSTRACT FROM AUTHOR]

Background: Effective screening and treatment have reduced the number of women dying from breast cancer (BC). However, the long-term sequelae of BC treatment and psychosocial factors seriously affect the life quality of BC patients and survivors. Therefore, the discovery and application of targeted biomarkers to improve the functional outcome and life quality of BC patients is necessary. Aims: To explore the impact of leptin (LEP)/ leptin receptor (LEPR) expression on occurrence and survival of BC. Methods: Totally 132 primary BC and 66 non-BC patients who underwent surgery in department of breast surgery in Shanxi Cancer Hospital from January to October in 2009 were enrolled in this retrospective study. LEP and LEPR were examined in BC tissues, benign breast tissues, para-carcinoma tissues using immunohistochemical staining. Kaplan–Meier curve was generated to test survival time. Results: The high level expression of LEP and LEPR in BC tissues were significantly higher than that in benign breast tissues and in para-carcinoma tissues (all P < 0.05). The LEP expression in patients with lymph node metastases was significantly higher than that in patients without lymph nodes metastases (P = 0.002). LEPR expression was correlated with higher Ki-67 rate (P = 0.002). LEP and LEPR both had no impact on survival (all P > 0.05). Conclusions: High LEP/LEPR expression were risk factors for occurrence of BC, but without impact on survival. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease mainly mediated by IgG autoantibody. While follicular helper T (Tfh) cells are crucial for supporting IgG autoantibody generation in human SLE, underlying mechanisms for Tfh cell mal-differentiation remain unclear. Methods: In total, 129 SLE patients and 37 healthy donors were recruited for this study. Circulating leptin was determined by ELISA from patients with SLE and healthy individuals. CD4 T cells isolated from SLE patients and healthy donors were activated with anti-CD3/CD28 beads under cytokine-unbiased conditions in the presence or absence of recombinant leptin protein, followed by detection for Tfh cell differentiation by quantifying intracellular transcription factor Bcl-6 and cytokine IL-21. AMPK activation was assessed by analyzing phosphor-AMPK using phosflow cytometry and immunoblots. Leptin receptor expression was determined using flow cytometry and its overexpression was achieved by transfection with an expression vector. Humanized SLE chimeras were induced by injecting patients' immune cells into immune-deficient NSG mice and used for translational studies. Results: Circulating leptin was elevated in patients with SLE, inversely associated with disease activity. In healthy individuals, leptin efficiently inhibited Tfh cell differentiation through inducing AMPK activation. Meanwhile, leptin receptor deficiency was a feature of CD4 T cells in SLE patients, impairing the inhibitory effect of leptin on the differentiation of Tfh cells. As a result, we observed the coexistence of high circulating leptin and increased Tfh cell frequencies in SLE patients. Accordingly, overexpression of leptin receptor in SLE CD4 T cells abrogated Tfh cell mal-differentiation and IgG anti-dsDNA generation in humanized lupus chimeras. Conclusion: Leptin receptor deficiency blocks the inhibitory effect of leptin on SLE Tfh cell differentiation, serving as a promising therapeutic target for lupus management. [ABSTRACT FROM AUTHOR]

For survival, it is crucial for eating behaviours to be sequenced through two distinct seeking and consummatory phases. Heterogeneous lateral hypothalamus (LH) neurons are known to regulate motivated behaviours, yet which subpopulation drives food seeking and consummatory behaviours have not been fully addressed. Here, in male mice, fibre photometry recordings demonstrated that LH leptin receptor (LepR) neurons are correlated explicitly in both voluntary seeking and consummatory behaviours. Further, micro-endoscope recording of the LHLepR neurons demonstrated that one subpopulation is time-locked to seeking behaviours and the other subpopulation time-locked to consummatory behaviours. Seeking or consummatory phase specific paradigm revealed that activation of LHLepR neurons promotes seeking or consummatory behaviours and inhibition of LHLepR neurons reduces consummatory behaviours. The activity of LHLepR neurons was increased via Neuropeptide Y (NPY) which acted as a tonic permissive gate signal. Our results identify neural populations that mediate seeking and consummatory behaviours and may lead to therapeutic targets for maladaptive food seeking and consummatory behaviours. Eating behviours consist of seeking and consummatory phases. Here, authors show that two distinct lateral hypothalamic leptin receptor neurons orchestrate seeking and consummatory phases of eating behaviour via hunger signal, Neuropeptide Y. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a clinically highly heterogeneous disease with a survival rate ranging from months to decades. Evidence suggests that a systemic deregulation of immune response may play a role and affect disease progression. Here, we measured 62 different immune/metabolic mediators in plasma of sporadic ALS (sALS) patients. We show that, at the protein level, the majority of immune mediators including a metabolic sensor, leptin, were significantly decreased in the plasma of sALS patients and in two animal models of the disease. Next, we found that a subset of patients with rapidly progressing ALS develop a distinct plasma assess immune–metabolic molecular signature characterized by a differential increase in soluble tumor necrosis factor receptor II (sTNF-RII) and chemokine (C-C motif) ligand 16 (CCL16) and further decrease in the levels of leptin, mostly dysregulated in male patients. Consistent with in vivo findings, exposure of human adipocytes to sALS plasma and/or sTNF-RII alone, induced a significant deregulation in leptin production/homeostasis and was associated with a robust increase in AMP-activated protein kinase (AMPK) phosphorylation. Conversely, treatment with an AMPK inhibitor restored leptin production in human adipocytes. Together, this study provides evidence of a distinct plasma immune profile in sALS which affects adipocyte function and leptin signaling. Furthermore, our results suggest that targeting the sTNF-RII/AMPK/leptin pathway in adipocytes may help restore assess immune–metabolic homeostasis in ALS. [ABSTRACT FROM AUTHOR]

Background: Leptin (LEP) acts as a proinflammatory cytokine and may play an important role in the pathophysiology of cystic fibrosis (CF). This review aimed to assess the quantitative difference in leptin status between CF patients and non-CF controls. Methods: In this study, the researchers conducted systematic searches of various databases, such as PubMed, Excerpta Medica Database, Google Scholar, Web of Science, and the China National Knowledge Infrastructure. The data collected from the above databases were assessed using the Stata 11.0 and R 4.1.3 software. The correlation coefficients and the Standardized Mean Differences (SMD) were employed to assess the effect size. A combination analysis was also carried out with the help of either a fixed-effects or randomeffects model. In addition, the single-cell sequencing GSE193782 dataset was obtained to determine the mRNA expression levels of LEP and leptin receptor (LEPR) in the bronchoalveolar lavage fluid, to verify the different leptin expression between the CF patients and healthy controls. Results: A total of 919 CF patients and 397 controls from 14 articles were included in this study. CF patients and non-CF controls showed similar serum/plasma leptin levels. Gender, specimen testing, age, and study design were all taken into account for carrying out subgroup analyses. The results revealed no variations in serum/plasma leptin levels between the controls and CF patients in the various subgroups. Female CF patients exhibited higher leptin concentrations compared to male CF patients, and male healthy individuals showed lower leptin levels than female healthy participants. Aside from the fact that serum/plasma leptin appeared to be favorably linked to fat mass and BMI, the findings in this study also indicated that serum/plasma concentrations were not associated with Forced Expiratory Volume in the first second (FEV1). No statistically significant differences were observed in the leptin and leptin receptor mRNA expression levels between the healthy controls and CF patients. The leptin receptor and leptin expression levels in alveolar lavage fluid were low in various cells, without any distinctive distribution patterns. Conclusions: The current meta-analysis indicated the absence of significant differences in leptin levels between CF patients and healthy individuals. Gender, fat mass, and BMI may all be correlated with leptin concentrations. [ABSTRACT FROM AUTHOR]

Objectives: to study the relationships of leptin and leptin SR with adiposity indices, and glycemic indices in patients with type 2 diabetes mellitus (T2DM) compared to healthy subjects. Methods: This cross-sectional study involved 65 patients with T2DM and 63 healthy controls. Fasting plasma levels of leptin, leptin SR, insulin and lipid profile were measured by enzyme linked immunosorbent essay, basal insulin resistance and beta-cell function were assessed using the homeostasis model assessment. Results: leptin SR level was significantly higher in T2DM patients than in controls (5.8 ± 1.6 and 4.8 ± 1.3 respectively; p= 0.001). In patients with T2DM, leptin SR was negatively correlated with homeostasis model of b-cell function and body fat mass while it has a significant positive correlation with glycosylated hemoglobin (HbA1c). The independent predictors for leptin SR in patients with T2DM were triglycerides (TG) and HbA1c. Conclusions: elevated serum leptin SR level in patients with T2DM was positively correlated with TG and abnormal glucose metabolism which indicate that it plays a role in pathophysiology of T2DM. The association of elevated leptin SR level with high TG and deterioration of β-cell function indicate that in some individuals, particularly non-obese, dyslipidemia might be a cause rather than a complication of diabetes. [ABSTRACT FROM AUTHOR]

The lineage of periodontal ligament (PDL) stem cells contributes to alveolar bone (AB) and cementum formation, which are essential for tooth-jawbone attachment. Leptin receptor (LepR), a skeletal stem cell marker, is expressed in PDL; however, the stem cell capacity of LepR+ PDL cells remains unclear. We used a Cre/LoxP-based approach and detected LepR-cre-labeled cells in the perivascular around the root apex; their number increased with age. In the juvenile stage, LepR+ PDL cells differentiated into AB-embedded osteocytes rather than cementocytes, but their contribution to both increased with age. The frequency of LepR+ PDL cell-derived lineages in hard tissue was < 20% per total cells at 1-year-old. Similarly, LepR+ PDL cells differentiated into osteocytes following tooth extraction, but their frequency was < 9%. Additionally, both LepR+ and LepR− PDL cells demonstrated spheroid-forming capacity, which is an indicator of self-renewal. These results indicate that both LepR+ and LepR− PDL populations contributed to hard tissue formation. LepR− PDL cells increased the expression of LepR during spheroid formation, suggesting that the LepR− PDL cells may hierarchically sit upstream of LepR+ PDL cells. Collectively, the origin of hard tissue-forming cells in the PDL is heterogeneous, some of which express LepR. [ABSTRACT FROM AUTHOR]

Leptin (LEP) gene produces hormone leptin which is secreted by adipose tissue, and plays an important role in energy balance, regulating feed intake, regulating endocrine function, and immune functions. This study aims to identify molecular markers of LEP gene and its association with growth traits based on SNP in Bali cattle. The blood samples were collected from 16 male and 30 female Bali cattle. The growth data were recorded from 2018 to 2020, consist of body weight and body size. Amplification of leptin gene with polymerase chain reaction (PCR) using pair of primers, Leptin_ 3Forward: 5'- AGCTTGGAAACATGGTGGTC-3' and Leptin_3Reverse: 5'- CATGATGCTCCCTGGATTCT-3' with DNA target 898 bp. The SNPs were identified by the direct sequencing technique. Genotypes of the SNPs were identified using sequencing method. Association of LEP genotypes with growth traits was performed using oneway ANOVA. Three DNA polymorphisms of the LEP gene were found, namely g.2913C/T, g.3260T/C, and g.3549G/A. SNP g.2913C/T was significantly associated (P<0,05) with weaning shoulder height (WSH), weaning body length (WBL), weaning chest circumference (WCC), yearling shoulder height (YSH), yearling body length (YBL), and yearling chest circumference (YCC). Meanwhile, SNPs g.3260T/C and g.3549G/A were not associated with the body weight and body size in Bali cattle. In conclusion, the SNP g.2913C/T can be used as molecular marker for body size in weaning and yearling of Bali Cattle. [ABSTRACT FROM AUTHOR]

[Objectives] The aim of this study was to understand the effect of leptin(LEP) on the expression of SOCS3 and STAT3 proteins in yak mammary epithelial cells (YMEC) and the possible effects of prolactin on leptin function. [Methods]YMEC were used as carriers, with different dosage of LEP(0,50,100,200,400 and 800 ng·mL-1)applied for 48 h and JAK2/JAK3 signal pathway blocker AG490 applied for 48 hours. The relative expression of SOCS3 and STAT3 at protein and STAT3 protein phosphorylation were detected by Western blot. [Results]In the absence of prolactin,all concentrations except 50 ng·mL-1 LEP inhibited the protein expression of SOCS3, while all concentrations of LEP inhibited the expression of STAT3 protein, and the phosphorylation level of STAT3 protein was higher than that of protein. In the presence of prolactin,SOCS3 protein was inhibited at the dosage of 100 ng·mL-1 LEP,and the other dosage promoted it; 800 ng·mL-1 LEP significantly inhibited the expression of STAT3 protein, and the expression of STAT3 phosphorylation increased except 100 ng·mL-1 group. After adding AG490, it was found that SOCS3 and STAT3 were mainly induced by JAK2 activation,and the upstream factors of SOCS3 and STAT3 protein phosphorylation might not be just JAK2. [Conclusions] High dosage of leptin inhibits the expression of SOCS3 and STAT3 protein. Leptin exerted its physiological effects through the JAK2/STAT3 pathway, While SOCS3 is a negative feedback regulator of JAK2/STAT3 pathway; PRL can relieve leptin resistance caused by high LEP concentrations and can promote the expression of SOCS3 and STAT3 proteins. [ABSTRACT FROM AUTHOR]

Dual inhibitors of protein phosphotyrosine phosphatase 1B (PTP1B)/T-cell protein phosphotyrosine phosphatase (TC-PTP) based on the 3-(hydroxymethyl)-4-oxo-1,4-dihydrocinnoline scaffold have been identified. Their dual affinity to both enzymes has been thoroughly corroborated by in silico modeling experiments. The compounds have been profiled in vivo for their effects on body weight and food intake in obese rats. Likewise, the effects of the compounds on glucose tolerance, insulin resistance, as well as insulin and leptin levels, have been evaluated. In addition, the effects on PTP1B, TC-PTP, and Src homology region 2 domain-containing phosphatase-1 (SHP1), as well as the insulin and leptin receptors gene expressions, have been assessed. In obese male Wistar rats, a five-day administration of all studied compounds led to a decrease in body weight and food intake, improved glucose tolerance, attenuated hyperinsulinemia, hyperleptinemia and insulin resistance, and also compensatory increased expression of the PTP1B and TC-PTP genes in the liver. The highest activity was demonstrated by 6-Chloro-3-(hydroxymethyl)cinnolin-4(1H)-one (compound 3) and 6-Bromo-3-(hydroxymethyl)cinnolin-4(1H)-one (compound 4) with mixed PTP1B/TC-PTP inhibitory activity. Taken together, these data shed light on the pharmacological implications of PTP1B/TC-PTP dual inhibition, and on the promise of using mixed PTP1B/TC-PTP inhibitors to correct metabolic disorders. [ABSTRACT FROM AUTHOR]

Obesity is a serious chronic condition that requires a comprehensive multidisciplinary approach. The main components of obesity treatment are education towards healthy eating habits, increased physical activity, decreased sedentarism and regular sleep pattern. Excess body weight is often associated with psychopathological behavior. Children often present with sadness, depression, low self-esteem, and therefore the role of psychotherapy or cognitive behavioral therapy is highly important in the complex approach to the treatment of childhood obesity. In recent years, the use of pharmacotherapy, both targeted for the treatment of certain genetic disorders and for the treatment of polygenic obesity, has significantly expanded. Three drugs are currently approved for use in children. These are metreleptin for genetically confirmed leptin deficiency, and setmelanotide, which is used in individuals with pathogenic variants of genes encoding leptin receptor, proopiomelanocortin or proprotein convertase genes, and in patients with Bardet-Biedl syndrome. Other types of obesity may benefit from treatment with liraglutide, which is a glucagon-like peptide 1 analogue. Obesity research is ongoing, and new molecules and their combinations that may be complementary in a comprehensive approach to obesity treatment can be expected. [ABSTRACT FROM AUTHOR]

Endotoxemia remains a critical clinical dilemma due to high mortality rate provoked by the systemic inflammatory response, which often leads to sever hepatic injury and immune dysregulation. This study aimed at delineating the modulatory effect of fucoxanthin (FX) and γ-radiation (IR) on LPS-induced spleen and liver injury. LPS sensitized mice showed enhanced splenic and hepatic TLR4/NF-κB- signaling, suppressed splenic α-7nAchR-expression, activated hepatic RIPK/HMGB-1, impaired hepatic leptin/STAT-3 signaling, extensive oxidative stress, and marked apoptosis with sever degenerative histopathological examination. FX and/or IR protected liver and spleen against detrimental effects evoked by LPS. Overall, FX and/or IR exhibited protective effect against endotoxemia. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in MFN2, encoding mitofusin 2. How the resulting selective form of mitochondrial dysfunction leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, Mfn2R707W/R707W knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation measured in isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation selectively perturbs mitochondrial morphology and activates the integrated stress response in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response. [ABSTRACT FROM AUTHOR]

Previously, we reported that a crude polyphenol-enriched fraction of Cyclopia intermedia (CPEF), a plant consumed as the herbal tea, commonly known as honeybush, reduced lipid content in 3T3-L1 adipocytes and inhibited body weight gain in obese, diabetic female leptin receptor-deficient (db/db) mice. In the current study, the mechanisms underlying decreased body weight gain in db/db mice were further elucidated using western blot analysis and in silico approaches. CPEF induced uncoupling protein 1 (UCP1, 3.4-fold, p < 0.05) and peroxisome proliferator-activated receptor alpha (PPARα, 2.6-fold, p < 0.05) expression in brown adipose tissue. In the liver, CPEF induced PPARα expression (2.2-fold, p < 0.05), which was accompanied by a 31.9% decrease in fat droplets in Hematoxylin and Eosin (H&E)-stained liver sections (p < 0.001). Molecular docking analysis revealed that the CPEF compounds, hesperidin and neoponcirin, had the highest binding affinities for UCP1 and PPARα, respectively. This was validated with stabilising intermolecular interactions within the active sites of UCP1 and PPARα when complexed with these compounds. This study suggests that CPEF may exert its anti-obesity effects by promoting thermogenesis and fatty acid oxidation via inducing UCP1 and PPARα expression, and that hesperidin and neoponcirin may be responsible for these effects. Findings from this study could pave the way for designing target-specific anti-obesity therapeutics from C. intermedia. [ABSTRACT FROM AUTHOR]