miRNA and leptin signaling in metabolic diseases and at extreme environments.

The burden of growing concern about the dysregulation of metabolic processes arises due to complex interplay between environment and nutrition that has great impact on genetics and epigenetics of an individual. Thereby, any abnormality at the level of food intake regulating hormones may contribute to the development of metabolic diseases in any age group due to malnutrition, overweight, changing lifestyle, and exposure to extreme environments such as heat stress (HS), cold stress, or high altitude (HA). Hormones such as leptin, adiponectin, ghrelin, and cholecystokinin regulate appetite and satiety to maintain energy homeostasis. Leptin, an adipokine and a pleiotropic hormone, play major role in regulating the food intake, energy gain and energy expenditure. Using in silico approach, we have identified the major genes (LEP, LEPR, JAK2, STAT3, NPY, POMC, IRS1, SOCS3) that play crucial role in leptin signaling pathway. Further, eight miRNAs (hsa-miR-204-5p, hsa-miR-211-5p, hsa-miR-30, hsa-miR-3163, hsa-miR-33a-3p, hsa-miR-548, hsa-miR-561-3p, hsa-miR-7856-5p) from TargetScan 8.0 database were screened out that commonly target these genes. The role of these miRNAs should be explored as they might play vital role in regulating the appetite, energy metabolism, metabolic diseases (obesity, type 2 diabetes, cardiovascular diseases, inflammation), and to combat extreme environments. The miRNAs regulating leptin signaling and appetite may be useful for developing novel therapeutics for metabolic diseases.

A gut microbial metabolite cocktail fights against obesity through modulating the gut microbiota and hepatic leptin signaling.

BACKGROUND: Excessive body weight and obesity elevate the risk of chronic non-communicable diseases. The judicious application of the gut microbiome, encompassing both microorganisms and their derived compounds, holds considerable promise in the treatment of obesity. RESULTS: In this study, we showed that a cocktail of gut microbiota-derived metabolites, comprising indole 3-propionic acid (IPA), sodium butyrate (SB) and valeric acid (VA), alleviated various symptoms of obesity in both male and female mice subjected to a high-fat diet (HFD). The 16S ribosomal RNA (rRNA) sequencing revealed that administering the cocktail via oral gavage retained the gut microbiota composition in obese mice. Fecal microbiota transplantation using cocktail-treated mice as donors mitigated the obesity phenotype of HFD-fed mice. Transcriptomic sequencing analysis showed that the cocktail preserved the gene expression profile of hepatic tissues in obese mice, especially up-regulated the expression level of leptin receptor. Gene delivery via in vivo fluid dynamics further validated that the anti-obesity efficacy of the cocktail was dependent on leptin signaling at least partly. The cocktail also inhibited the expression of appetite stimulators in hypothalamus. Together, the metabolite cocktail combated adiposity by retaining the gut microbiota configuration and activating the hepatic leptin signaling pathway. CONCLUSIONS: Our findings provide a sophisticated regulatory network between the gut microbiome and host, and highlight a cocktail of gut microbiota-derived metabolites, including IPA, SB, and VA, might be a prospective intervention for anti-obesity in a preclinical setting. © 2024 Society of Chemical Industry.

Weight-loss maintenance is accompanied by interconnected alterations in circulating FGF21-adiponectin-leptin and bioactive sphingolipids.

Weight loss is often followed by weight regain. Characterizing endocrine alterations accompanying weight reduction and regain may disentangle the complex biology of weight-loss maintenance. Here, we profile energy-balance-regulating metabokines and sphingolipids in adults with obesity undergoing an initial low-calorie diet-induced weight loss and a subsequent weight-loss maintenance phase with exercise, glucagon-like peptide-1 (GLP-1) analog therapy, both combined, or placebo. We show that circulating growth differentiation factor 15 (GDF15) and C16:0-C18:0 ceramides transiently increase upon initial diet-induced weight loss. Conversely, circulating fibroblast growth factor 21 (FGF21) is downregulated following weight-loss maintenance with combined exercise and GLP-1 analog therapy, coinciding with increased adiponectin, decreased leptin, and overall decrements in ceramide and sphingosine-1-phosphate levels. Subgroup analyses reveal differential alterations in FGF21-adiponectin-leptin-sphingolipids between weight maintainers and regainers. Clinically, cardiometabolic health outcomes associate with selective metabokine-sphingolipid remodeling signatures. Collectively, our findings indicate distinct FGF21, GDF15, and ceramide responses to diverse phases of weight change and suggest that weight-loss maintenance involves alterations within the metabokine-sphingolipid axis.

Overexpression of the receptor for resolvin E1 (ERV1) prevents early alveolar bone loss in leptin receptor deficiency-induced diabetes.

BACKGROUND: This study was designed to test the hypothesis that the leptin receptor (LepR) regulates changes in periodontal tissues and that the overexpression of the receptor for resolvin E1 (ERV1) prevents age- and diabetes-associated alveolar bone loss. METHODS: LepR-deficient transgenic (TG) mice were cross-bred with those overexpressing ERV1 (TG) to generate double-TG mice. In total, 95 mice were divided into four experimental groups: wild type (WT), TG, LepR deficient (db/db), and double transgenic (db/db TG). The groups were followed from 4 weeks up to 16 weeks of age. The natural progression of periodontal disease without any additional method of periodontitis induction was assessed by macroscopic and histomorphometric analyses. Osteoclastic activity was measured by tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: At 4 weeks, ERV1 overexpression prevented weight gain. From Week 8 onward, there was a significant increase in the weight of db/db mice with or without ERV1 overexpression compared to the WT mice, accompanied by an increase in glucose levels. By 8 weeks of age, the percentage of bone loss in the LepR deficiency groups was significantly greater compared to WT mice. ERV1 overexpression in the db/db TG mice prevented early alveolar bone loss; however, it did not impact the development of diabetic bone loss in aging mice after the onset of weight gain and diabetes. CONCLUSIONS: The findings suggest that the overexpression of ERV1 prevents LepR-associated alveolar bone loss during the early phases of periodontal disease by delaying weight gain, diabetes onset, and associated inflammation; however, LepR deficiency increases susceptibility to naturally occurring inflammatory alveolar bone loss as the animal ages, associated with excess weight gain, onset of diabetes, and excess inflammation.

Clinical and molecular characterisation of children with monogenic obesity: a case series.

INTRODUCTION: To study the clinical profile and molecular diagnosis of children with severe early-onset non-syndromic monogenic obesity. METHODS: The clinical and molecular data (performed using whole exome sequencing) of 7 children with early-onset (< 5 years) non-syndromic monogenic obesity were extracted from the Obesity Clinic files and analysed retrospectively. RESULTS: The median (IQR) age at presentation was 18 (10.5-27) months. Of the 7 patients, 5 were boys, 3 had a history of parental consanguinity, and 4 had a family history of severe early-onset obesity. All patients exhibited hyperphagia and showed signs of insulin resistance. Dyslipidaemia and fatty liver were observed in 4. The variants identified in 6 patients included 2 in leptin receptor, and one each in melanocortin 4 receptor, pro-opiomelanocortin, leptin, and neurotrophic tyrosine kinase receptor type 2 genes. Notably, 4 of these variants were novel. CONCLUSIONS: This case series provides valuable insights into the spectrum of genetic mutations associated with non-syndromic monogenic obesity in North Indian children. The findings underscore the significance of next-generation sequencing in identifying the aetiology of severe early-onset obesity.

[Exogenous leptin improves cerebral ischemia-reperfusion-induced glutamate excitotoxic injury in mice by up-regulating GLT-1 and GLAST expression in astrocytes].

OBJECTIVE: To investigate the protective effect of exogenous leptin against focal cerebral ischemia-reperfusion (I/R) injury in mice and explore the underlying mechanism. METHODS: A total of 100 C57BL/6 mice were randomly divided into 5 groups, including a sham-operated group, cerebral I/R model group, and 3 leptin treatment groups with intraperitoneal injections of 0.5, 1.0 or 2.0 leptin immediately after occlusion of the internal carotid artery. At 24 h after reperfusion, neurological function scores of the mice were assessed, and TTC staining was used to determine the area of cerebral infarction. The pathological changes in the cortical brain tissue of the mice were observed using HE staining, and degenerative damage of the cortical neurons were assessed with Fluoro-Jade C staining. The expression of glial fibrillary acidic protein in cortical brain tissues was detected using immunohistochemistry and Western blotting. In another 45 C57BL/6 mice with sham operation, I/R modeling, or leptin (1 mg/kg) treatment, glutamic acid in the cortical brain tissue was detected using glutamate assay, and cortical glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) protein expressions were detected using immunohistochemistry. RESULTS: Compared with the I/R model mice, the leptin-treated mice had significantly lower neurological deficit scores, smaller cerebral infarct area, milder pathologies in the cortical brain tissue, and lessened cortical neuronal damage with normal morphology and less excessive proliferation of the astrocytes. Leptin treatment significantly up-regulated the expressions of GLT-1 and GLAST and lowered the content of glutamic acid in the brain tissue of the I/R mice. CONCLUSION: Exogenous leptin has obvious neuroprotective effect against cerebral I/R injury in mice, mediated probably by controlling excessive astrocyte proliferation and up-regulating cortical GLT-1 and GLAST expressions to reduce glutamate-mediated excitotoxic injury of the astrocytes.

Total Gestational Weight Gain Is Explained by Leptin and Body Fat, Regardless of Pre-Pregnancy Body Mass Index and Other Adipokines, in Mexican Adolescents.

Pre-pregnancy body mass index (pBMI) is a predictor of gestational weight gain (GWG). However, other factors, such as adipokines and inflammation markers, may also be associated with GWG. The aim of the study was to determine the association of leptin, adiponectin, irisin, and C-reactive protein, with GWG in adolescents. A longitudinal study was conducted from 2018 to 2023 in adolescents with a clinically healthy pregnancy. The assessments included sociodemographic and clinical data, pBMI, percent of body fat, serum concentrations of leptin, adiponectin, irisin, and high-sensitivity C-reactive protein (hsCRP), and total GWG adequacy. Cox regression models were performed, the outcome variables were inadequate and excessive GWG. In 198 participants, being overweight/obesity was marginally associated with a protective effect against inadequate GWG (HR = 0.44, 95%CI = 0.18-1.06), regardless of maternal characteristics and adipokines. Leptin (HR = 1.014, 95%CI = 1.008-1.021), and body fat percent (HR = 1.11, 95%CI = 1.05-1.17) were associated with a higher risk of excessive GWG, independent of other maternal variables such as pBMI, while adiponectin was associated with a lower risk. These findings suggest that, in Mexican adolescents, adipose tissue and its adipokines during pregnancy may play a more significant role in the final GWG than body weight.

Association of serum trefoil factor 3 and leptin levels with obesity: A case-control study.

BACKGROUND: Obesity has a detrimental impact on individuals, communities, and healthcare systems. Trefoil factor 3 is a secretory protein involved in metabolic processes related to weight regulation. However, its relation with obesity is not fully understood. OBJECTIVE: We aimed to assess the serum trefoil factor 3 level and to immunohistochemical detect the leptin in obese patients to evaluate their relation to obesity pathogenesis. METHODS: As a case-control study, we enrolled 83 non-obese persons as a control group with a BMI (18.5-24.9) and 83 obese persons as a patient group with a BMI > 30. All the study volunteers are subjected to anthropometric measurements, glucose, and lipid profile analysis by colorimetric methods. Serum trefoil factor 3 level was estimated by ELISA and leptin hormone was detected immunohistochemically in the blood using cell block technique. RESULTS: ROC curve analysis for TFF3 showed a good relation with obesity with an AUC of 0.891 and a cut-off value of > 96 ng/ml. There was a significant positive correlation between TFF3 and fasting blood sugar, total cholesterol, and triglycerides. The logistic regression analysis showed that TFF3 is a good risk factor for obesity incidence [p = 0.008; OR = 1.117; (95 % CI): 1.029-1.213]. This was confirmed by multiple linear regression that gave an equation for the possibility of predicting BMI using several factors including TFF3 [BMI = 0.821 + 0.051 × TFF3 + 0.044 × FBS + 0.85 × TC]. The more surprising was the ability of the immunohistochemistry cell block technique to detect leptin antigens associated with an obese person blood not only adipose tissue or serum. CONCLUSION: Leptin hormone and TFF3 could be good indicators for obesity incidence. Further research with a larger sample size and in different populations could completely approve our results.

Transgenerational epigenetic self-memory of Dio3 dosage is associated with Meg3 methylation and altered growth trajectories and neonatal hormones.

Intergenerational and transgenerational epigenetic effects resulting from conditions in previous generations can contribute to environmental adaptation as well as disease susceptibility. Previous studies in rodent and human models have shown that abnormal developmental exposure to thyroid hormone affects endocrine function and thyroid hormone sensitivity in later generations. Since the imprinted type 3 deiodinase gene (Dio3) regulates sensitivity to thyroid hormones, we hypothesize its epigenetic regulation is altered in descendants of thyroid hormone overexposed individuals. Using DIO3-deficient mice as a model of developmental thyrotoxicosis, we investigated Dio3 total and allelic expression and growth and endocrine phenotypes in descendants. We observed that male and female developmental overexposure to thyroid hormone altered total and allelic Dio3 expression in genetically intact descendants in a tissue-specific manner. This was associated with abnormal growth and neonatal levels of thyroid hormone and leptin. Descendant mice also exhibited molecular abnormalities in the Dlk1-Dio3 imprinted domain, including increased methylation in Meg3 and altered foetal brain expression of other genes of the Dlk1-Dio3 imprinted domain. These molecular abnormalities were also observed in the tissues and germ line of DIO3-deficient ancestors originally overexposed to thyroid hormone in utero. Our results provide a novel paradigm of epigenetic self-memory by which Dio3 gene dosage in a given individual, and its dependent developmental exposure to thyroid hormone, influences its own expression in future generations. This mechanism of epigenetic self-correction of Dio3 expression in each generation may be instrumental in descendants for their adaptive programming of developmental growth and adult endocrine function.

Novel Leptin-Based Therapeutic Strategies to Limit Synaptic Dysfunction in Alzheimer's Disease.

Accumulation of hyper-phosphorylated tau and amyloid beta (Aß) are key pathological hallmarks of Alzheimer's disease (AD). Increasing evidence indicates that in the early pre-clinical stages of AD, phosphorylation and build-up of tau drives impairments in hippocampal excitatory synaptic function, which ultimately leads to cognitive deficits. Consequently, limiting tau-related synaptic abnormalities may have beneficial effects in AD. There is now significant evidence that the hippocampus is an important brain target for the endocrine hormone leptin and that leptin has pro-cognitive properties, as activation of synaptic leptin receptors markedly influences higher cognitive processes including learning and memory. Clinical studies have identified a link between the circulating leptin levels and the risk of AD, such that AD risk is elevated when leptin levels fall outwith the physiological range. This has fuelled interest in targeting the leptin system therapeutically. Accumulating evidence supports this possibility, as numerous studies have shown that leptin has protective effects in a variety of models of AD. Recent findings have demonstrated that leptin has beneficial effects in the preclinical stages of AD, as leptin prevents the early synaptic impairments driven by tau protein and amyloid ß. Here we review recent findings that implicate the leptin system as a potential novel therapeutic target in AD.

Leptin gene expression in the brain is associated with the physiological onset of estivation in western sand lance Ammodytes japonicus.

Dormancy is an essential ecological characteristic for the survival of organisms that experience harsh environments. Although factors that initiate dormancy vary, suppression or cessation of feeding activities are common among taxa. To distinguish between extrinsic and intrinsic causes of metabolic reduction, we focused on estivation, which occurs in summer when the feeding activity is generally enhanced. Sand lances (genus Ammodytes) are a unique marine fish with a long estivation period from early summer to late autumn. In the present study, we aimed to elucidate the control mechanisms of estivation in western sand lance (A. japonicus), and firstly examined behavioral changes in 8 months including a transition between active and dormant phases. We found that swimming/feeding behavior gradually decreased from June, and completely disappeared by late August, indicating all individuals had entered estivation. Next, we focused on leptin, known as a feeding suppression hormone in various organisms, and examined leptin-A gene (AjLepA) expression in the brain that may regulate the seasonal behavioral pattern. AjLepA expression decreased after 7 days of fasting, suggesting that leptin has a function to regulate feeding in this species. The monthly expression dynamics of AjLepA during the feeding (active) and non-feeding (estivation) periods showed that the levels gradually increased with the onset of estivation and reached its peak when all the experimental fish had estivated. The present study suggests that the suppression of feeding activity by leptin causes shift in the physiological modes of A. japonicus before estivation.

Role of leptin and adiponectin in the pathogenesis of post-transplant diabetes mellitus.

Solid organ transplantation is a life-saving treatment for patients with end-stage organ failure, but it poses unique challenges due to metabolic and immunological changes in recipients. One significant complication is post-transplant diabetes mellitus (PTDM), which affects a variety of solid organ recipients. Leptin, a hormone produced by adipose tissue, regulates appetite and affects glucose metabolism. High leptin levels are associated with the development of PTDM, especially in kidney transplant recipients. Adiponectin, another adipokine, increases insulin sensitivity and has anti-diabetic properties. Low adiponectin levels are associated with insulin resistance and increase the risk of PTDM. As the incidence of PTDM increases due to the increased life expectancy among transplant patients, understanding the role of adipokines such as leptin and adiponectin becomes crucial for early detection and treatment. Additional studies on other adipokines may also provide valuable information on the pathogenesis of PTDM.

Adipokine modulation in obesity: Evaluating the integrative impact of chlorella vulgaris supplementation and interval resistance training in obese males.

Aims: To evaluate the effects of 12-week chlorella vulgaris (CV) combined with interval resistance training (IRT) on plasma levels of leptin, adiponectin and neuregulin-4 (Nrg-4) in obese men. Methods: Obese men (n = 44, BMI of 32.1 ± 1.5 kg/m2) were randomly allocated to the following groups of 11 participants per group: Control Placebo group (CP), CV supplement group (CV), Interval Resistance Training group plus Placebo (IRT + P), and Interval Resistance Training plus CV supplement group (IRT + CV). IRT was performed three times a week for 12 weeks using three sets of 10 repetitions at 60 % 1RM, and integrating an active rest interval with 15 repetitions at 20 % 1RM. Participants consumed either CV (1800 mg daily) or a placebo. Pre- and post-intervention blood samples were obtained to assess adipokines which were measured by ELISA. Results: While CV or IRT separately did not alter plasma levels of leptin (p > 0.05), their combination reduced leptin levels (p = 0.007). IRT and IRT plus CV increased the plasma levels of adiponectin and Nrg-4 (p < 0.01). An intergroup comparison indicated significant elevations of adiponectin and Nrg-4 in the CV compared to the CP group (p < 0.05). Conclusion: The combination of IRT and CV modulates plasma levels of leptin, adiponectin and NRG4 more effectively than either IRT or CV separately in obese men.

An integrative exploration of environmental stressors on the microbiome-gut-brain axis and immune mechanisms promoting neurological disorders.

The microbiome-gut-brain axis is altered by environmental stressors such as heat, diet, and pollutants as well as microbes in the air, water, and soil. These stressors might alter the host's microbiome and symbiotic relationship by modifying the microbial composition or location. Compartmentalized mutualistic microbes promote the beneficial interactions in the host leading to circulating metabolites and hormones such as insulin and leptin that affect inter-organ functions. Inflammation and oxidative stress induced by environmental stressors may alter the composition, distribution, and activities of the microbes in the microbiomes such that the resultant metabolite and hormone changes are no longer beneficial. The microbiome-gut-brain axis and immune adverse changes that may accompany environmental stressors are reviewed for effects on innate and adaptive immune cells, which may make host immunity less responsive to pathogens and more reactive to self-antigens. Cardiovascular and fluid exchanges to organs might adversely alter organ functionality. Organs, especially the brain, need a consistent supply of nutrients and clearance of debris; disruption of these exchanges by stressors, and involvement of gut microbiome are discussed regarding neural dysfunctions with Alzheimer's disease, autistic spectrum disorders, viral infections, and autoimmune diseases. The focus of this review includes the manner in which environmental stressors may disrupt gut microbiota leading to adverse immune and hormonal influences on development of neuropathology related to hyperhomocysteinemia, inflammation, and oxidative stress, and how certain therapeutics may be beneficial. Strategies are explored to lessen detrimental effects of environmental stressors on central and peripheral health navigated toward (1) understanding neurological disorders and (2) promoting environmental and public health and well-being.

Association of Obstructive Sleep Apnea with Nonalcoholic Fatty Liver Disease: Evidence, Mechanism, and Treatment.

Obstructive sleep apnea (OSA), a common sleep-disordered breathing condition, is characterized by intermittent hypoxia (IH) and sleep fragmentation and has been implicated in the pathogenesis and severity of nonalcoholic fatty liver disease (NAFLD). Abnormal molecular changes mediated by IH, such as high expression of hypoxia-inducible factors, are reportedly involved in abnormal pathophysiological states, including insulin resistance, abnormal lipid metabolism, cell death, and inflammation, which mediate the development of NAFLD. However, the relationship between IH and NAFLD remains to be fully elucidated. In this review, we discuss the clinical correlation between OSA and NAFLD, focusing on the molecular mechanisms of IH in NAFLD progression. We meticulously summarize clinical studies evaluating the therapeutic efficacy of continuous positive airway pressure treatment for NAFLD in OSA. Additionally, we compile potential molecular biomarkers for the co-occurrence of OSA and NAFLD. Finally, we discuss the current research progress and challenges in the field of OSA and NAFLD and propose future directions and prospects.

Adipokine receptor expression in mast cells is altered by specific ligands and proinflammatory cytokines.

Adipokines play essential roles in regulating a range of biological processes, but growing evidence indicates that they are also fundamental in immunological mechanisms and, primarily, inflammatory responses. Adipokines mediate their actions through specific receptors. However, although adipokine receptors are widely distributed in many cell and tissue types, limited data are available on their expression in mast cells (MCs) and, consequently, adipokine's significance in the modulation of MC activity within the tissues. In this study, we demonstrate that rat peritoneal MCs constitutively express the leptin receptor (i.e. LEPR), adiponectin receptors (i.e. ADIPOR1 and ADIPOR2) and the chemerin receptor (i.e. CMKLR1). We also found that LEPR, ADIPOR1, ADIPOR2 and CMKLR1 expression in MCs changes in response to stimulation by their specific ligands and some cytokines with potent proinflammatory properties. Furthermore, the involvement of intracellular signaling molecules in leptin-, adiponectin- and chemerin-induced MC response was analyzed. Overall, our findings suggest that adipokines leptin, adiponectin and chemerin can significantly affect the activity of MCs in various processes, especially during inflammation. These observations may contribute significantly to understanding the relationship between adipokines, immune mechanisms and diseases or conditions with an inflammatory component.

A quantitative pipeline to assess secretion of human leptin coding variants reveals mechanisms underlying leptin deficiencies.

The hormone leptin, primarily secreted by adipocytes, plays a crucial role in regulating whole-body energy homeostasis. Homozygous loss-of-function mutations in the leptin gene (LEP) cause hyperphagia and severe obesity, primarily through alterations in leptin's affinity for its receptor or changes in serum leptin concentrations. Although serum concentrations are influenced by various factors (e.g., gene expression, protein synthesis, stability in the serum), proper delivery of leptin from its site of synthesis in the endoplasmic reticulum via the secretory pathway to the extracellular serum is a critical step. However, the regulatory mechanisms and specific machinery involved in this trafficking route, particularly in the context of human LEP mutations, remain largely unexplored. We have employed the Retention Using Selective Hooks (RUSH) system to elucidate the secretory pathway of leptin. We have refined this system into a medium-throughput assay for examining the pathophysiology of a range of obesity-associated LEP variants. Our results reveal that leptin follows the default secretory pathway, with no additional regulatory steps identified prior to secretion. Through screening of leptin variants, we identified three mutations that lead to proteasomal degradation of leptin and one variant that significantly decreased leptin secretion, likely through aberrant disulfide bond formation. These observations have identified novel pathogenic effects of leptin variants, which can be informative for therapeutics and diagnostics. Finally, our novel quantitative screening platform can be adapted for other secreted proteins.

Weight Loss Improved Hypothalamic GH Deficiency but not Hypogonadotropic Hypogonadism in a Man With Down Syndrome.

Down syndrome (DS) is associated with several endocrine disorders, including diabetes, obesity, and primary hypogonadism. Here, we present a man with DS who manifested with atypical hypogonadotropic hypogonadism and in whom weight loss resulted in the improvement of hypothalamic GH deficiency. A 27-year-old man with DS and severe obesity was admitted for hypoxia resulting from obesity hypoventilation syndrome. Laboratory tests showed normal levels of LH and FSH despite low testosterone and free testosterone levels. Moreover, thyroid stimulating hormone and prolactin levels were slightly elevated, although a euthyroid function was observed, and GH and IGF-1 levels were low. Endocrinological stimulation tests revealed hypogonadotropic hypogonadism and hypothalamic GH deficiency. Reduction in body weight by 35.3% resulted in the improvement of the IGF-1, thyroid stimulating hormone, and prolactin levels to the reference range, whereas the LH and FSH levels remained low, despite slight elevation. Levels of leptin, which suppresses the hypothalamus-gonadotroph-gonadal axis and upregulates thyrotropin-releasing hormone expression, decreased with weight loss. Furthermore, ghrelin, whose levels increase with weight loss, stimulates GH secretion. Thus, leptin and ghrelin could have contributed to the observed changes in the pituitary hormone profile after weight loss.

Serum levels of leptin, ghrelin putative peptide YY-3 in patients with fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders (FASD) are a severe developmental condition resulting from exposure to alcohol during pregnancy. The aim of this study was to examine the concentrations of hormones involved in appetite regulation-ghrelin, leptin, and putative peptide YY-3 (PYY)-in the serum of individuals with FASD. Additionally, we investigated the relationship between these hormone levels and clinical indicators. We conducted an enzyme-linked immunosorbent assay on samples collected from 62 FASD patients and 23 individuals without the condition. Our results revealed a significant decrease in leptin levels among FASD patients compared to the control group (5.124 vs. 6.838 ng/mL, p = 0.002). We revealed no statistically significant differences in the levels of other hormones studied (ghrelin and PYY). Comparisons of hormone levels were also conducted in three subgroups: FAS, neurobehavioral disorders associated with prenatal alcohol exposure and FASD risk, as well as by sex. Assignment to FASD subgroups indicated changes only for leptin. Sex had no effect on the levels of hormones. Moreover, the levels of leptin showed a negative correlation with cortisol levels and a positive correlation with BMI and proopiomelanocortin. Alterations in appetite regulation can contribute to the improper development of children with FASD, which might be another factor that should be taken into consideration in the proper treatment of patients.

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.