Effects of a Paleolithic diet compared to a diabetes diet on leptin binding inhibition in secondary analysis of a randomised cross-over study.

BACKGROUND: Beneficial effects from practising a Paleolithic diet as compared to a diabetes diet on weight, waist circumference, satiety, leptin, HbA1c and glucose control in randomised controlled trial participants with type 2 diabetes could be due to lower leptin resistance. Support for this hypothesis comes from an in vitro experiment that showed that digested wheat gluten, which is excluded from a Paleolithic diet, inhibits leptin from binding to its receptor, thus indicating a possible dietary cause of leptin resistance. However, the clinical relevance of the latter finding is unclear since removal of enzyme activity from the gluten digest by heat treatment also abolished leptin binding inhibition. Assessment of leptin binding inhibition in vivo is possible by comparison of total leptin levels with those of 'biologically active' leptin bound to its receptor (bioLep). OBJECTIVES: To assess the effects of a Paleolithic diet compared to a diabetes diet on leptin binding inhibition and to replicate our in vitro study. METHODS: BioLep and total leptin levels were measured in secondary analysis of fasting plasma samples from our open label random order three plus three-month long cross-over trial performed in 2005-2007, that compared a Paleolithic diet with a diabetes diet in participants with type 2 diabetes without insulin treatment (per protocol). BioLep was also measured in vitro for known recombinant leptin concentrations incubated with a series of concentrations of 10 kDa spin-filtered digested wheat gluten, with or without prior heat treatment, at 100ºC for 30 min and centrifugation. RESULTS: There was no difference between diets when comparing differences between bioLep and total leptin levels and their ratio in the 13 participants, three women and 10 men, aged 52-74 years with a mean BMI of 30 kg/m2 and a mean diabetes duration of eight years. We found no carry-over or period effect for bioLep and total leptin. In vitro, wheat gluten digest inhibited leptin binding in a dose-dependent manner but not after heat treatment. CONCLUSIONS: We found no leptin binding inhibition after the Paleolithic or diabetes diet, possibly due to its abolishment from cooking-related heat treatment of wheat gluten. TRIAL REGISTRATION: Registered on 14/02/2007 at ClinicalTrials.gov Identifier: NCT00435240.

The association between macrosomia and glucose, lipids and hormones levels in maternal and cord serum: a case-control study.

BACKGROUND: The formation of macrosomia is associated with excessive nutrition and/or unable to regulate effectively. This case-control study aims to explore the relationship between macrosomia and glucose, lipids and hormones levels in maternal and cord serum. METHODS: In the case-control study, 78 pairs of mothers and newborns were recruited who received care at one hospital of Hebei, China between 2016 and 2019. According to the birth weight (BW) of newborns, participants were divided into macrosomia group (BW ≥ 4000 g, n = 39) and control group (BW between 2500 g and 3999 g, n = 39). Maternal vein blood and cord vein blood were collected and assayed. All data were compared between the two groups. Unconditional logistics regression analysis was used to test the relationship between macrosomia and glucose, lipids and hormones in maternal and cord serum. RESULTS: In maternal and cord serum, the levels of leptin, leptin/adiponectin ratio (LAR), glucose and triglyceride (TG) in macrosomia group were higher than those in control group, and the levels of high-density lipoprotein cholesterol (HDL-C) were lower. The percentage of maternal glucose and lipids transfer to cord blood did not differ between the two groups. High levels of TG in maternal serum were positively correlated with macrosomia, and high levels of LAR, TG and glucose in cord serum were positively correlated with macrosomia. CONCLUSION: In conclusion, the results of the current study, suggest that the nutrients and metabolism-related hormones in maternal and umbilical cord are closely related to macrosomia. During pregnancy, the nutritional status of pregnant women should be paid attention to and to obtain a good birth outcome.

Appetite hormones, neuropsychological function and methylphenidate use in children with attention-deficit/hyperactivity disorder.

Appetite hormones may play a significant role in neuronal excitability and synaptic plasticity and may also affect brain function development. This study aimed to explore the role of appetite hormones in attention deficit/hyperactivity disorder (ADHD), including aspects of pathophysiology, pharmacotherapy, and side effects. We recruited 119 patients with ADHD who were undergoing methylphenidate treatment (ADHD+MPH), 77 unmedicated ADHD patients (ADHD-MPH), and 87 healthy controls. Blood samples were collected from all participants to examine serum levels of orexin A, ghrelin, leptin, and adiponectin. Behavioral symptoms were assessed using the Swanson, Nolan, and Pelham Rating Scale, and visual and auditory attention were evaluated using computerized neuropsychological tests. The side effects of methylphenidate treatment were measured using Barkley's Side Effects Rating Scale. Orexin levels in the control group were significantly higher than in the ADHD-MPH (p=0.037) and ADHD+MPH (p<0.001) groups; additionally, orexin levels in the ADHD-MPH group were significantly higher than in the ADHD+MPH group (p=0.032). Leptin levels in both the ADHD+MPH (p=0.011) and ADHD-MPH (p=0.011) groups were significantly lower than in the control group. Ghrelin levels were positively associated with auditory attention across all ADHD groups (p=0.015). Furthermore, ghrelin levels were positively correlated with methylphenidate dosage (p=0.024), and negatively correlated with methylphenidate side effects (p=0.044) in the ADHD+MPH group. These findings provide further insight into the relationships between appetite hormones, pharmacotherapy, and ADHD. Orexin A and leptin are associated with the etiology of ADHD, while orexin A and ghrelin play important roles in attention deficits and methylphenidate usage in ADHD.

Unraveling the impact of hyperleptinemia on female reproduction: insights from transgenic pig model.

BACKGROUND: Infertility is a growing global health concern affecting millions of couples worldwide. Among several factors, an extreme body weight adversely affects reproductive functions. Leptin is a well-known adipokine that serves as an endocrine signal between adiposity and fertility. However, the exact mechanisms underlying the effects of high leptin level on female reproduction remain unclear. METHODS: Transgenic pigs overexpressing leptin (♀) were produced by backcrossing and screened for leptin overexpression. The growth curve, fat deposition, reproductive performance, apoptosis, serum hormones and cholesterol production, RNA sequencing, and single-nucleus RNA sequencing (snRNA-seq) of the leptin-overexpressing pigs and wild-type group were evaluated. RESULTS: Transgenic pigs overexpressing leptin (♀) were obtained, which exhibited significantly reduced body weight, body size, and back fat thickness. These pigs manifested a late onset of puberty (330 ± 54.3 vs. 155 ± 14.7 days), irregular estrous behavior characterized by increased inter-estrous interval (29.2 ± 0 vs. 21.3 ± 0.7 days), and more number of matings until pregnancy (at least 3 times). This reproductive impairment in leptin pigs was related to hormonal imbalances characterized by increased levels of FSH, LH, prolactin, E2, P4, and TSH, altered steroidogenesis such as increased levels of serum cholesterol esters along with steroidogenic markers (StAR, CYP19A), and ovarian dysfunctions manifested by neutrophilic infiltration and low expression of caspase-3 positive cells in the ovaries. Moreover, bulk RNA sequencing of the ovaries also revealed neutrophilic infiltration followed by upregulation of inflammation-related genes. Furthermore, snRNA-seq reflected that leptin overexpression triggered immune response, suppressed follicle development and luteinization, resulting in metabolic dysfunction and hormone imbalance in the ovary. CONCLUSIONS: Low body weight in leptin overexpressing pigs adversely affects the reproductive performance, causing delayed puberty, irregular estrous cycles, and reduced breeding efficiency. This is linked to metabolic imbalances, an increased immune response, and altered ovarian functions. This study provides a theoretical basis for the complex mechanisms underlying leptin, and infertility by employing leptin-overexpressing female pigs.

Novel perspectives on leptin in osteoarthritis: Focus on aging.

Osteoarthritis (OA) is a common chronic joint disease characterized by articular cartilage degeneration, subchondral sclerosis, synovitis, and osteophyte formation. OA is associated with disability and impaired quality of life, particularly among the elderly. Leptin, a 16-kD non-glycosylated protein encoded by the obese gene, is produced on a systemic and local basis in adipose tissue and the infrapatellar fat pad located in the knee. The metabolic mechanisms employed by leptin in OA development have been widely studied, with attention being paid to aging as a corroborative risk factor for OA. Hence, in this review, we have attempted to establish a potential link between leptin and OA, by focusing on aging-associated mechanisms and proposing leptin as a potential diagnostic and therapeutic target in aging-related mechanisms of OA that may provide fruitful guidance and emphasis for future research.

Redox Homeostasis and Non-Invasive Assessment of Significant Liver Fibrosis by Shear Wave Elastography.

Hepatic fibrosis with various origins can be estimated non-invasively by using certain biomarkers and imaging-based measurements. The aim of our study was to examine redox homeostasis biomarkers and liver stiffness measurements for the assessment of significant liver fibrosis in different etiologies of chronic liver diseases. A cohort study consisting of 88 chronic liver disease patients of both sexes (age 49.1 ± 14.7 years) was performed. Cytokine profiles as well as redox homeostasis characteristics were determined. Liver fibrosis stages were assessed with shear wave elastography. The plasma levels of four cytokines showed no significant alteration between the four fibrotic stages; however, higher values were measured in the F2-4 stages. Free sulfhydryl group concentration, the marker of redox homeostasis, was lower in significant fibrosis (F0-F1: 0.36 ± 0.06 vs. F2-4: 0.29 ± 0.08 mmol/L, p < 0.05). Higher chemiluminescence values, as free radical-antioxidant parameters, were detected in advanced fibrosis stages in erythrocytes (F0-F1: 36.00 ± 37.13 vs. F2-4: 51.47 ± 44.34 RLU%). These data suggest that oxidative stress markers can predict significant fibrosis, with the aim of reducing the number of protocol liver biopsies in patients unlikely to have significant disease; however, their role in distinguishing between the certain fibrosis groups needs further studies.

The Impact of the Endocrine and Immunological Function of Adipose Tissue on Reproduction in Women with Obesity.

Obesity, which leads to metabolic dysregulation and body function impairment, emerges as one of the pressing health challenges worldwide. Excessive body fat deposits comprise a dynamic and biologically active organ possessing its own endocrine function. One of the mechanisms underlying the pathophysiology of obesity is low-grade systemic inflammation mediated by pro-inflammatory factors such as free fatty acids, lipopolysaccharides, adipokines (including leptin, resistin and visfatin) and cytokines (TNF-α, IL-1ß, Il-6), which are secreted by adipose tissue. Together with obesity-induced insulin resistance and hyperandrogenism, the exacerbated immune response has a negative impact on the hypothalamic-pituitary-gonadal axis at all levels and directly affects reproduction. In women, it results in disrupted ovarian function, irregular menstrual cycles and anovulation, contributing to infertility. This review focuses on the abnormal intracellular communication, altered gene expression and signaling pathways activated in obesity, underscoring its multifactorial character and consequences at a molecular level. Extensive presentation of the complex interplay between adipokines, cytokines, immune cells and neurons may serve as a foundation for future studies in search of potential sites for more targeted treatment of reproductive disorders related to obesity.

Clinical and biochemical responses to treatment of uncomplicated severe acute malnutrition: a multicenter observational cohort from the OptiDiag study.

BACKGROUND: Severe acute malnutrition (SAM) can be diagnosed using weight-for-height Z-score (WHZ) and/or mid-upper arm circumference (MUAC). Although some favor using MUAC alone, valuing its presumed ability to identify children at greatest need for nutritional care, the functional severity and physiological responses to treatment in children with varying deficits in WHZ and MUAC remain inadequately characterized. OBJECTIVE: We aimed to compare clinical and biochemical responses to treatment in children with 1) both low MUAC and low WHZ, 2) low MUAC-only, and 3) low WHZ-only. METHODS: A multicenter, observational cohort study was conducted in children aged 6-59 mo with nonedematous, uncomplicated SAM in Bangladesh, Burkina Faso, and Liberia. Anthropometric measurements and critical indicators were collected 3 times during treatment; metrics included clinical status, nutritional status, viability, and serum leptin, a biomarker of mortality risk in SAM. RESULTS: Children with combined MUAC and WHZ deficits had greater increases in leptin levels during treatment than those with low MUAC alone, showing a 34.4% greater increase on the second visit (95% confidence interval [CI]: 7.6%, 43.6%; P = 0.02) and a 34.3% greater increase on the third visit (95% CI: 13.2%, 50.3%; P = 0.01). Similarly, weight gain velocity was higher by 1.56 g/kg/d in the combined deficit group (95% CI: 0.38, 2.75; P = 0.03) compared with children with low MUAC-only. Children with combined deficits had higher rates of iron deficiency and wasting while those with low WHZ alone and combined deficits had higher rates of tachypnea and pneumonia during treatment. CONCLUSIONS: Given the comparable treatment responses of children with low WHZ alone and those with low MUAC alone, and the greater vulnerability at admission and during treatment in those with combined deficits, our findings support retaining WHZ as an independent diagnostic and admission criterion of SAM, alongside MUAC. This trial was registered at www. CLINICALTRIALS: gov/study/NCT03400930 as NCT03400930.

Investigating the effect of radiofrequency electromagnetic field exposure on molecular pathways related to insulin resistance and adipogenesis in zebrafish embryos - A pilot study without quantitative exposure metrics.

In recent years, obesity has become a global problem in children and adolescents, in parallel with the rapid increase in the use of information and communication technology. Recognizing the embryonic causes of obesity may help prevent adverse adult health outcomes. In our study, we hypothesized that radiofrequency-electromagnetic field (RF-EMF) exposure during embryogenesis would affect the molecular mechanisms related to adipogenesis and insulin resistance in zebrafish. To achieve this, we set up a system that emits RF-EMF in the 900 MHz band and subjected zebrafish embryos to its RF-EMF. We created two groups in which we exposed 30 min (EMF-30) and 60 min (EMF-60) per day, and a control group that was not exposed to RF-EMF. We ended the exposure at 96 hpf and analyzed the expression of lepa, ins, and pparg that are involved in the regulation of glucose and lipid metabolism. In addition, we analyzed oxidative stress parameters, embryonic development, and locomotor activity. We found decreased mRNA transcript abundance of lepa, ins, pparg, and activities of superoxide dismutase and acetylcholine esterase, along with increased lipid peroxidation (LPO), nitric oxide (NO), and glutathione S-transferase (GST). Locomotor activity increased in the EMF-30 group and decreased in the EMF-60 group. Our results showed that exposure to RF-EMF during the embryonic period disrupted the molecular pathways related to insulin resistance and adipogenesis in zebrafish. However, due to limited available resources, we were not able to appropriately quantify the actual RF exposure strength of the samples. Hence the results reported here should only be seen as preliminary, and further studies employing high quality exposure apparatus and dosimetry should be carried out in future.

History and future of leptin: Discovery, regulation and signaling.

The cloning of leptin 30 years ago in 1994 was an important milestone in obesity research. Prior to the discovery of leptin, obesity was stigmatized as a condition caused by lack of character and self-control. Mutations in either leptin or its receptor were the first single gene mutations found to cause severe obesity, and it is now recognized that obesity is caused mostly by a dysregulation of central neuronal circuits. Since the discovery of the leptin-deficient obese mouse (ob/ob) the cloning of leptin (ob aka lep) and leptin receptor (db aka lepr) genes, we have learned much about leptin and its action in the central nervous system. The first hope that leptin would cure obesity was quickly dampened because humans with obesity have increased leptin levels and develop leptin resistance. Nevertheless, leptin target sites in the brain represent an excellent blueprint to understand how neuronal circuits control energy homeostasis. Our expanding understanding of leptin function, interconnection of leptin signaling with other systems and impact on distinct physiological functions continues to guide and improve the development of safe and effective interventions to treat metabolic illnesses. This review highlights past concepts and current emerging concepts of the hormone leptin, leptin receptor signaling pathways and central targets to mediate distinct physiological functions.

Is there any concern of insulin resistance and metabolic dysfunctions with antiseizure medications? A prospective comparative study of valproate vs. levetiracetam.

PURPOSE: To evaluate the incidence of insulin resistance and its association with change in serum anti-seizure medication (ASM) level and their pharmacokinetic, body composition and metabolic hormones after six months of levetiracetam (LEV) exposure in persons with epilepsy (PWE) in comparison to valproate (VPA). METHODS: This prospective-longitudinal study included clinically diagnosed PWE on VPA or LEV monotherapy (for<3 months). At enrolment, body weight/composition, BMI were measured and blood samples were collected for assessing metabolic dysfunctions by estimation of serum insulin, insulin resistance [in terms of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], leptin, adiponectin, lipid profile along with ASMs level. Subjects were followed up for six months and all the above parameters were reassessed. RESULTS: A total of 150 PWE were screened based on inclusion and exclusion criteria, and 105 number of subjects were enrolled (n = 35 in VPA and n = 70 in LEV group). Out of them, 92 subjects (n = 32 in VPA; n = 60 in LEV) completed six months follow-up. After six months, serum insulin level increased significantly in VPA group compared to baseline p < 0.001). Insulin resistance (HOMA-IR>2.5) was observed in 14.28 % of PWE in VPA group. Significantly higher percentage-change in body-weight (p = 0.003), leptin and decreased adiponectin were found in VPA-group compared to baseline ((p = 0.003, 0.02, 0.001, <0.001, respectively). These changes were independent of serum level or pharmacokinetic of VPA. On the other hand, no such changes were observed in LEV-group despite increased serum LEV level and altered pharmacokinetic parameters after six months. CONCLUSION: Six months treatment with VPA resulted in insulin resistance and metabolic dysfunctions in PWE. These alterations were not correlated with change in VPA serum level. These changes were not observed in LEV therapy suggesting its better safety profile. This may be considered while prescribing the ASM like VPA and LEV in adult patients with obesity or insulin resistance and diabetes.

Synergistic Activation of LEPR and ADRB2 Induced by Leptin Enhances ROS Generation in TNBC Cells.

Purpose: Leptin interacts not only with leptin receptor (LEPR) but also engages with other receptors. While the pro-oncogenic effects of the adrenergic receptor ß2 (ADRB2) are well-established, the role of leptin in activating ADRB2 in triple-negative breast cancer (TNBC) remains unclear. Materials and Methods: The pro-carcinogenic effects of LEPR were investigated using murine TNBC cell lines, 4T1 and EMT6, and a tumor-bearing mouse model. Expression levels of LEPR, NOX4, and ADRB2 in TNBC cells and tumor tissues were analyzed via Western blot and qPCR. Changes in reactive oxygen species (ROS) levels were assessed using flow cytometry and MitoSox staining, while immunofluorescence double-staining confirmed the co-localization of LEPR and ADRB2. Results: LEPR activation promoted NOX4-derived ROS and mitochondrial ROS production, facilitating TNBC cell proliferation and migration, effects which were mitigated by the LEPR inhibitor Allo-aca. Co-expression of LEPR and ADRB2 was observed on cell membranes, and bioinformatics data revealed a positive correlation between the two receptors. Leptin activated both LEPR and ADRB2, enhancing intracellular ROS generation and promoting tumor progression, which was effectively countered by a specific ADRB2 inhibitor ICI118551. In vivo, leptin injection accelerated tumor growth and lung metastases without affecting appetite, while treatments with Allo-aca or ICI118551 mitigated these effects. Conclusion: This study demonstrates that leptin stimulates the growth and metastasis of TNBC through the activation of both LEPR and ADRB2, resulting in increased ROS production. These findings highlight LEPR and ADRB2 as potential biomarkers and therapeutic targets in TNBC.

Negative feedback control of hypothalamic feeding circuits by the taste of food.

The rewarding taste of food is critical for motivating animals to eat, but whether taste has a parallel function in promoting meal termination is not well understood. Here, we show that hunger-promoting agouti-related peptide (AgRP) neurons are rapidly inhibited during each bout of ingestion by a signal linked to the taste of food. Blocking these transient dips in activity via closed-loop optogenetic stimulation increases food intake by selectively delaying the onset of satiety. We show that upstream leptin-receptor-expressing neurons in the dorsomedial hypothalamus (DMHLepR) are tuned to respond to sweet or fatty tastes and exhibit time-locked activation during feeding that is the mirror image of downstream AgRP cells. These findings reveal an unexpected role for taste in the negative feedback control of ingestion. They also reveal a mechanism by which AgRP neurons, which are the primary cells that drive hunger, are able to influence the moment-by-moment dynamics of food consumption.

Predictors of weight and waist gain in US South Asians: Findings from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study.

Background: Weight and waist gain are significant concerns in adulthood. Both weight and waist gain are particularly important among South Asians, known to have an increased risk of developing chronic cardiometabolic complications at any body mass index compared to other racial and ethnic groups. The aim of this study was to investigate factors predicting weight and waist gain in a longitudinal cohort of South Asians living in the US (United States). Methods: This was a prospective analysis using data from exam 1 (2010-2013) and exam 2 (2015-2018) of the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study, a prospective cohort study of South Asians (recruited from San Francisco and Chicago), with a mean 4.8 years of follow-up. Results: Of 634 participants studied (42.7 % women, mean age 55 years, BMI 25.7 kg/m2, weight 70.4 kg at exam 1), 34.7 % had gained ≥5 % weight and 32.3 % gained ≥5 % waist at exam 2. In the adjusted models, older age, higher number of years of US residence, and having diabetes were associated with lower odds of weight gain; being female and having higher adiponectin were associated with higher odds of weight gain. Being female and being employed full/part time or being retired predicted lower likelihood of waist gain. Being single, separated/divorced, having a higher leptin and a higher C-reactive protein level predicted higher likelihood of waist gain. Conclusions: The current study identified several social, demographic, and clinical factors that can serve as targets for obesity interventions among US South Asians. In addition, this study also raises hypotheses about associations of adipokine levels with weight and waist gain.

Insulin and leptin acutely modulate the energy metabolism of primary hypothalamic and cortical astrocytes.

Astrocytes constitute a heterogeneous cell population within the brain, contributing crucially to brain homeostasis and playing an important role in overall brain function. Their function and metabolism are not only regulated by local signals, for example, from nearby neurons, but also by long-range signals such as hormones. Thus, two prominent hormones primarily known for regulating the energy balance of the whole organism, insulin, and leptin, have been reported to also impact astrocytes within the brain. In this study, we investigated the acute regulation of astrocytic metabolism by these hormones in cultured astrocytes prepared from the mouse cortex and hypothalamus, a pivotal region in the context of nutritional regulation. Utilizing genetically encoded, fluorescent nanosensors, the cytosolic concentrations of glucose, lactate, and ATP, along with glycolytic rate and the NADH/NAD+ redox state were measured. Under basal conditions, differences between the two populations of astrocytes were observed for glucose and lactate concentrations as well as the glycolytic rate. Additionally, astrocytic metabolism responded to insulin and leptin in both brain regions, with some unique characteristics for each cell population. Finally, both hormones influenced how cells responded to elevated extracellular levels of potassium ions, a common indicator of neuronal activity. In summary, our study provides evidence that insulin and leptin acutely regulate astrocytic metabolism within minutes. Additionally, while astrocytes from the hypothalamus and cortex share similarities in their metabolism, they also exhibit distinct properties, further underscoring the growing recognition of astrocyte heterogeneity.

Fetal growth restriction and placental defects in obese mice are associated with impaired decidualisation: the role of increased leptin signalling modulators SOCS3 and PTPN2.

Decidualisation of the endometrium is a key event in early pregnancy, which enables embryo implantation. Importantly, the molecular processes impairing decidualisation in obese mothers are yet to be characterised. We hypothesise that impaired decidualisation in obese mice is mediated by the upregulation of leptin modulators, the suppressor of cytokine signalling 3 (SOCS3) and the protein tyrosine phosphatase non-receptor type 2 (PTPN2), together with the disruption of progesterone (P4)-signal transducer and activator of transcription (STAT3) signalling. After feeding mice with chow diet (CD) or high-fat diet (HFD) for 16 weeks, we confirmed the downregulation of P4 and oestradiol (E2) steroid receptors in decidua from embryonic day (E) 6.5 and decreased proliferation of stromal cells from HFD. In vitro decidualised mouse endometrial stromal cells (MESCs) and E6.5 deciduas from the HFD showed decreased expression of decidualisation markers, followed by the upregulation of SOCS3 and PTPN2 and decreased phosphorylation of STAT3. In vivo and in vitro leptin treatment of mice and MESCs mimicked the results observed in the obese model. The downregulation of Socs3 and Ptpn2 after siRNA transfection of MESCs from HFD mice restored the expression level of decidualisation markers. Finally, DIO mice placentas from E18.5 showed decreased labyrinth development and vascularisation and fetal growth restricted embryos. The present study revealed major defects in decidualisation in obese mice, characterised by altered uterine response to E2 and P4 steroid signalling. Importantly, altered hormonal response was associated with increased expression of leptin signalling modulators SOCS3 and PTPN2. Elevated levels of SOCS3 and PTPN2 were shown to molecularly affect decidualisation in obese mice, potentially disrupting the STAT3-PR regulatory molecular hub.

Impact of Resistance and Endurance Training on Ghrelin and Plasma Leptin Levels in Overweight and Obese Subjects.

Exercise training is a valuable tool for improving body weight and composition in overweight or obese adults, which leads to a negative energy balance. It is relevant to consider whether exercise can help people lose weight or prevent weight gain because any energy expended in exercise increases the severity of hunger and promotes food consumption. Over the past decade, the identification of the circulating peptide ghrelin, which alerts the brain to the body's nutritional state, has significantly expanded our understanding of this homeostatic mechanism that controls appetite and body weight. To shed more light on this issue, we decided to investigate the effects of resistance and endurance training on plasma ghrelin and leptin levels. In addition, we sought to understand the mechanisms by which acute and chronic exercise can regulate hunger. This review analyzes studies published in the last fifteen years that focused on changes suffered by ghrelin, leptin, or both after physical exercise in overweight or obese individuals. Most studies have shown a decrease in leptin levels and an increase in ghrelin levels in these cases. Exercise regimens that support weight maintenance need further investigation.

Leptin bioavailability and markers of brain atrophy and vascular injury in the middle age.

INTRODUCTION: We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle-aged adults. METHODS: We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB-R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme-linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. RESULTS: Higher sOB-R was associated with lower fractional anisotropy (FA, ß = -0.114 ± 0.02, p < 0.001), and higher free water (FW, ß = 0.091 ± 0.022, p < 0.001) and peak-width skeletonized mean diffusivity (PSMD, ß = 0.078 ± 0.021, p < 0.001). Correspondingly, higher FLI was associated with higher FA (ß = 0.115 ± 0.027, p < 0.001) and lower FW (ß = -0.096 ± 0.029, p = 0.001) and PSMD (ß = -0.085 ± 0.028, p = 0.002). DISCUSSION: Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle-aged adults, supporting the putative neuroprotective role of leptin in late-life dementia risk. HIGHLIGHTS: Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

LEP rs7799039 and LEPR rs1137101 gene variants are not associated with clinical features in patients with metabolic syndrome in the Turkish population.

OBJECTIVES: Genetic predisposition plays a role in the etiology of metabolic syndrome (MetS), an important health problem worldwide. Leptin (LEP), produced by adipose tissue, plays a crucial role in the development of MetS. In this study, we evaluated the effects of LEP and LEP receptor (LEPR) variants on clinical findings and risk of developing MetS in the Turkish population. METHODS: A total of 320 patients were included in the study, of whom 150 were patients with MetS and 170 were healthy controls. DNA was extracted from blood samples. LEP rs7799039 and LEPR rs1137101 variants were genotyped using the polymerase chain reaction-based restriction fragment length polymorphism method. The genotype distributions of these variants and clinical and laboratory findings were compared. RESULTS: The LEP rs7799039 GA and AA genotypes and A allele frequencies were higher in participants with MetS than in the control group. For LEP rs7799039, the genotype AA-GA was higher in males, and the GG genotype was higher in females. On analyzing the clinical outcomes associated with these variants, it was observed that individuals possessing LEP rs7799039 GA and AA genotypes displayed elevated levels of triglycerides. In addition, those with the AG-GG genotype of LEPR rs1137101 had lower mean hemoglobin levels. CONCLUSION: Our results showed that the LEP rs7799039 and LEPR rs1137101 variants may be associated with both the risk of MetS development and clinical findings. Among the various contributors to MetS, a genetic predisposition is commonly recognized as the primary cause.

Improved leptin sensitivity and increased soluble leptin receptor concentrations may underlie the additive effects of combining PYY [, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ] and exendin-4 on body weight lowering in diet-induced obese mice.

Objective: Co-treatment with long acting PYY and the GLP-1 receptor agonists has potential as an efficient obesity treatment. This study investigates whether the mechanisms behind additive reduction of food intake and weight loss depends on complementary effects in brain areas regulating food intake and if restoration of leptin sensitivity is involved. Methods: Diet-induced obese (DIO) mice were co-treated with PYY(3-36) and exendin-4 (Ex4, GLP-1R agonist) for 14 days using minipumps. Leptin responsiveness was evaluated by measuring food intake and body weight after leptin injection, and gene expression profile was investigated in various of brain regions and liver. Results: We show that weight loss associated with co-treatment of PYY(3-36) and Ex4 and Ex4 mono-treatment in DIO mice increased expression of several genes in area postrema (AP) known to be involved in appetite regulation and Cart, Pdyn, Bdnf and Klb were synergistically upregulated by the co-treatment. The upregulations were independent of weight loss, as shown by inclusion of a weight matched control. Moreover, PYY(3-36) and Ex4 co-treatment resulted in synergistically upregulated plasma concentrations of soluble leptin receptor (SLR) and improved sensitivity to exogenous leptin demonstrated by food intake lowering. Conclusion: The study results suggest that synergistic upregulation of appetite-regulating genes in AP and improved leptin sensitivity are important mediators for the additive weight loss resulting from PYY and Ex4 co-treatment.