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AbstractCardiovascular diseases (CVD) are a global health concern that accounts for a large share of annual mortality. Endothelial dysfunction is the main underlying factor that eventually leads to cardiovascular events. Recent studies have underscored the critical function of Protein Tyrosine Phosphatase 1B (PTP1B) in the onset of endothelial dysfunction, chiefly through its involvement in metabolic diseases such as diabetes, obesity, and leptin resistance. PTP1B attenuates insulin and leptin signaling by dephosphorylating their respective receptors at key tyrosine residues, resulting in resistance—both of which are significant mechanisms underpinning the development of endothelial dysfunction. PTP1B also contributes to the disruption of the endoplasmic reticulum, causing endoplasmic reticulum stress, another molecular driver of endothelial dysfunction. Efforts to inhibit PTP1B activity hold the promise of advancing the prevention and management of CVD and metabolic disorders, as these conditions share common risk factors and underlying cellular mechanisms. Numerous small molecules have been reported as PTP1B inhibitors; however, their progression to advanced clinical trials has been hindered by major challenges such as low selectivity and undesirable side effects. This review provides an in-depth analysis of PTP1B's involvement in metabolic diseases and its interaction with CVD and examines the strategies and challenges related to inhibiting this enzyme. [ABSTRACT FROM AUTHOR]

The modulation of leptin sensitivity in hypothalamic neurons plays a crucial role in metabolic regulation and the development of obesity. Three distinct approaches, exposure to leptin (LEPA), administration of leptin antagonist (LANTA), and treatment with palmitate (PA), were explored in this study to assess their effects on adult-derived mHypoA-2/12 neurons and the resulting transcriptomic signatures. To this end, 3' mRNA-Seq transcriptome analysis was employed, unexpectedly revealing downregulation of key genes associated with the NOD-like receptor signaling pathway (Irf9 , Mapk3 , Stat2 , Nfkbia , Ikbkg , Rela , Cxcl1 , and Traf5), the C-type lectin receptor signaling pathway (Nfkb2 , Irf9 , Mapk3 , Stat2 , Nfkbia , Ikbkg , Rela , and Ptgs2), the NF kappa B signaling pathway (Nfkbia , Ikbkg , Nfkb2 , Rela , Traf5 , Cxcl1 , and Ptgs2), and the IL 17 signaling pathway (Nfkbia , Ikbkg , Mapk3 , Rela , Traf5 , Cxcl1 , and Ptgs2). These findings help elucidate the molecular mechanisms through which these factors influence leptin sensitivity and provide insights into the pathways implicated in the development of leptin resistance in hypothalamic neurons. The surprising downregulation of these pathways suggests a complex interplay between leptin signaling and the cellular stress response in hypothalamic neurons. This alteration may reflect adaptive mechanisms in response to prolonged leptin or fatty acid exposure. Understanding these dynamics is essential for elucidating the role of hypothalamic inflammation in the progression of leptin resistance and associated metabolic disorders. [ABSTRACT FROM AUTHOR]

Obesity presents a significant challenge in managing patients with craniopharyngioma (CP). Cyst fluid (CF), rich in inflammatory mediators, is implicated in CP‐related obesity, though the precise mechanism remains unclear. This study investigated the impact of CF or C‐X‐C motif chemokine ligand‐1 (CXCL1) injections on body weight, Lee index, plasma lipid profiles, hepatic lipid accumulation, leptin levels, NF‐κB pathway, the suppressor of cytokine signaling 3 (SOCS3) expression, and leptin sensitivity in rats. Bioinformatics was employed to identify differentially expressed genes (DEGs) between CF/CXCL1‐treated and control SY5Y cells, as well as to confirm enriched pathways. Western blotting was used for experimental validation, including the effects of sodium salicylate (SS) on leptin sensitivity in SY5Y cells. Injecting CF or CXCL1 into the brain, without hypothalamic damage, led to increased body weight, Lee index, and hepatic lipid accumulation in rats, alongside elevated fasting blood glucose, triglycerides, and total cholesterol, while high‐density lipoprotein cholesterol levels decreased. Additionally, CF and CXCL1 could induce elevated leptin levels, a higher leptin‐to‐body weight ratio, and resistance to exogenous leptin by activating the NF‐κB pathway and upregulating the expression of SOCS3 in rats. Further validation confirmed that CF and CXCL1 suppress leptin signaling by activating the NF‐κB pathway and upregulating SOCS3. Moreover, SS mitigated the inhibitory effects of CF or CXCL1 on leptin signaling, preserving leptin sensitivity in SY5Y cells. These results highlight the obesogenic role of CF and CXCL1, offering insights into the development of morbid obesity through inflammatory factor‐mediated leptin resistance, independent of hypothalamic damage. SS may serve as a promising therapeutic approach for CP‐associated obesity, though additional clinical studies are necessary to confirm its efficacy. [ABSTRACT FROM AUTHOR]

Uterine physiology encompasses the intricate processes governing the structure, function, and regulation of the uterus, a pivotal organ within the female reproductive system. The escalating prevalence of obesity has emerged as a significant global health issue, profoundly impacting various facets of well-being, including female reproductive health. These effects extend to uterine structure and function, influencing reproductive health outcomes in women. They encompass alterations in uterine morphology, disruptions in hormonal signaling, and inflammatory processes. Insulin and leptin, pivotal hormones regulating metabolism, energy balance, and reproductive function, play crucial roles in this context. Insulin chiefly governs glucose metabolism and storage, while leptin regulates appetite and energy expenditure. However, in obesity, resistance to both insulin and leptin can develop, impacting uterine function. Inflammation and oxidative stress further exacerbate the development of uterine dysfunction in obesity. Chronic low-grade inflammation and heightened oxidative stress, characteristic of obesity, contribute to metabolic disruptions and tissue damage, including within the uterus. Obesity significantly disrupts menstrual cycles, fertility, and pregnancy outcomes in women. The accumulation of excess adipose tissue disrupts hormonal equilibrium, disturbs ovarian function, and fosters metabolic irregularities, all of which detrimentally impact reproductive health. [ABSTRACT FROM AUTHOR]

Background: Leptin, an adipokine essential for regulating energy balance, exerts important effects on brain function, notably within the hippocampus, a region integral to learning and memory. Leptin resistance, characterized by diminished responsiveness to elevated leptin levels, disrupts hippocampal function and exacerbates both obesity and cognitive impairments. Scope: This review critically examines how leptin resistance impairs hippocampal synaptic plasticity processes, specifically affecting long-term potentiation (LTP) and long-term depression (LTD), which are crucial for cognitive performance. Findings: Recent research highlights that leptin resistance disrupts N-methyl-D-aspartate (NMDA) receptor dynamics and hippocampal structure, leading to deficits in spatial learning and memory. Additionally, high-fat diets (HFDs), which contribute to leptin resistance, further deteriorate hippocampal function. Potential therapeutic strategies, including leptin sensitizers, show promise in mitigating brain disorders associated with leptin resistance. Complementary interventions such as caloric restriction and physical exercise also enhance leptin sensitivity and offer potential benefits to alleviating cognitive impairments. Aims of the review: This review synthesizes recent findings on the molecular pathways underlying leptin resistance and its impact on synaptic transmission and plasticity in the hippocampus. By identifying potential therapeutic targets, this work aims to provide an integrated approach for addressing cognitive deficits in obesity, ultimately improving the quality of life for affected individuals. [ABSTRACT FROM AUTHOR]

Glucose‐dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone secreted by K cells in the small intestine and is considered an obesity‐promoting factor. In this study, we systematically investigated the anti‐obesity effects of intragastric safflower yellow (SY)/hydroxysafflor yellow A (HSYA) and the underlying mechanism for the first time. Our results showed that intragastric SY/HSYA, rather than an intraperitoneal injection, notably decreased serum GIP levels and GIP staining in the small intestine in diet‐induced obese (DIO) mice. Moreover, intragastric SY/HSYA was also first found to significantly suppress GIP receptor (GIPR) signaling in both the hypothalamus and subcutaneous White adipose tissue. Our study is the first to show that intragastric SY/HSYA obviously reduced food intake and body weight gain in leptin sensitivity experiments and decreased serum leptin levels in DIO mice. Further experiments demonstrated that SY treatment also significantly reduced leptin levels, whereas the inhibitory effect of SY on leptin levels was reversed by activating GIPR in 3 T3‐L1 adipocytes. In addition, intragastric SY/HSYA had already significantly reduced serum GIP levels and GIPR expression before the serum leptin levels were notably changed in high‐fat‐diet‐fed mice. These findings suggested that intragastric SY/HSYA may alleviate diet‐induced obesity in mice by ameliorating hyperleptinemia via dual inhibition of the GIP‐GIPR axis. [ABSTRACT FROM AUTHOR]

IntroductionThe leading cause of death in type 2 diabetes mellitus (T2DM) patients is cardiovascular-related events, including myocardial infraction-induced ventricular arrhythmia. Previous studies have shown that T2DM-induced functional remodeling of cardiac vagal postganglionic (CVP) neurons contributes to ventricular arrhythmogenesis. As leptin resistance is common in T2DM patients, and CVP neurons are located in epicardial adipose pads, a tissue that secretes leptin, in this study we aimed to elucidate a correlation between leptin resistance and CVP neuronal dysfunction in T2DM.MethodsA high fat-diet/low dose streptozotocin-induced T2DM rat model was used in this study to characterize T2DM-induced alterations in cardiac parasympathetic tone, determined by changes in baroreflex sensitivity and CVP neuronal excitability. The impact of leptin resistance on CVP neurons was also studied by examining the expression of leptin in epicardial adipose pads, and leptin receptors and uncoupling protein 2 (UCP2) in CVP neurons.ResultsT2DM rats exhibited diminished baroreflex sensitivity, and decreased CVP neuronal excitability, demonstrated by a reduced frequency of action potentials, diminished nAChR currents, and an attenuated response to nicotine stimulation. Additionally, compared to sham animals, the expression of leptin receptors and UCP2 in CVP neurons was reduced as early as 4 weeks post-T2DM although the leptin levels in epicardial adipose pads was increased during the progression of T2DM, which demonstrated the occurrence of leptin resistance in T2DM CVP neurons.ConclusionCardiac parasympathetic dysfunction in T2DM rats is due, in part, to functional remodeling of CVP neurons. As leptin resistance develops as early as 4 weeks post-T2DM induction, diminished leptin receptors-UCP2 signaling may contribute to CVP neuronal dysregulation.

The modulation of leptin sensitivity in hypothalamic neurons plays a crucial role in metabolic regulation and the development of obesity. Three distinct approaches, exposure to leptin (LEPA), administration of leptin antagonist (LANTA), and treatment with palmitate (PA), were explored in this study to assess their effects on adult-derived mHypoA-2/12 neurons and the resulting transcriptomic signatures. To this end, 3’ mRNA-Seq transcriptome analysis was employed, unexpectedly revealing downregulation of key genes associated with the NOD-like receptor signaling pathway (Irf9, Mapk3, Stat2, Nfkbia, Ikbkg, Rela, Cxcl1, and Traf5), the C-type lectin receptor signaling pathway (Nfkb2, Irf9, Mapk3, Stat2, Nfkbia, Ikbkg, Rela, and Ptgs2), the NF kappa B signaling pathway (Nfkbia, Ikbkg, Nfkb2, Rela, Traf5, Cxcl1, and Ptgs2), and the IL 17 signaling pathway (Nfkbia, Ikbkg, Mapk3, Rela, Traf5, Cxcl1, and Ptgs2). These findings help elucidate the molecular mechanisms through which these factors influence leptin sensitivity and provide insights into the pathways implicated in the development of leptin resistance in hypothalamic neurons. The surprising downregulation of these pathways suggests a complex interplay between leptin signaling and the cellular stress response in hypothalamic neurons. This alteration may reflect adaptive mechanisms in response to prolonged leptin or fatty acid exposure. Understanding these dynamics is essential for elucidating the role of hypothalamic inflammation in the progression of leptin resistance and associated metabolic disorders.

Abstract 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.

Aim. To optimise the curation of patients with a comorbid course of nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) to explore pathogenetically-based targets of high cardiovascular risk (CVR) formation. Materials and methods. An open comparative study was conducted with the formation of a cohort of 126 patients with comorbid course of NAFLD and CVD with different stages of liver fibrosis, who were divided into comparison groups according to SCORE-2 and SCORE-2-OR. Collection of complaints, medical and life history, examination, general laboratory investigations and examination of hormonal status, abdominal ultrasound, EchoCG and liver elastometry to assess the severity of fibrosis were performed. Work with the study data and graphical analysis was performed using Microsoft Office 2019 software package statistical analysis using STATISTICA 12.0. Results. SCORE-2 risk increased with increasing age of patients (z=-5.29; p0.01). The most common non-cardiovascular co-morbidities in the study sample were cholelithiasis in 35 (66.78%) patients. Soluble leptin receptor levels were lower (z=-8.60; p0.01) and leptin resistance index was higher (z=-5.95; p0.01) in the higher cardiovascular group. Corresponding data were also obtained when the changes in insulin resistance index were calculated and analysed (z=-2.15; p0.01). Fibrosis stage was higher, in patients with higher CVR (z=-3.488; p0.01), while no statistically significant difference in steatosis level was recorded. According to transient elastometry, patients taking statins had lower levels of fibrosis (z=-3.747; p0.01) and hepatic steatosis (z=-3.379; p0.01). Conclusions. The most common pathology is arterial hypertension. Gallstone disease and type 2 diabetes mellitus are often found in patients with a comorbid course. The risk of comorbid pathology and CVD increases with age. Formation of advanced stages of liver fibrosis, hyperinsulinaemia and leptin resistance phenomenon are associated with higher CVR according to SCORE-2 and SCORE-2-OR. The syndrome of increased intestinal permeability is a possible mechanism of increased CVD in patients with NAFLD.

Lingling Wang,1 Huiguo Liu,1 Ling Zhou,1 Pengdou Zheng,1 Hai Li,2,3 Huojun Zhang,4,* Wei Liu2,3,* 1Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huojun Zhang, Email hjzhang@whu.edu.cn; Wei Liu, Email 404793938@tjh.tjmu.edu.cnAbstract: 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.Keywords: intermittent hypoxia, hypoxia-inducible factor 1 alpha, nonalcoholic fatty liver disease, oxidative stress, dyslipidemia, leptin resistance

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. [ABSTRACT FROM AUTHOR]

Objectives: Elevated circulating branched-chain amino acids (BCAAs) have been associated with obesity, insulin resistance, and MASLD. Nonetheless, BCAA supplementation has been shown to provide protective outcomes towards the intervention of MASLD. Currently, there is a lack of study towards the contribution of the BCAA: valine on MASLD. Herein, the effect of low-dose valine supplementation was investigated for its role in the progression of MASLD. Methods: C57BL/6J mice were fed a high-fat/high-cholesterol diet (HFD) to induce MASLD. Upon the establishment of MASLD, valine was supplemented via voluntary oral administration. Clinical and biochemical parameters associated with MASLD were measured, and molecular mechanism and gut microbiota modulation from the effect of valine were investigated. Results: Low-dose valine was found to attenuate the progression of MASLD, significantly reducing the gain in body weight, liver weight, and epididymal white adipose tissue (eWAT) weight, while also attenuating hyperglycemia and hyperleptinemia, and improving serum lipid profiles. Mechanistically, in the liver, genes related to hepatic lipogenesis and cholesterol biosynthesis were downregulated, while those associated with fatty acid oxidation, autophagy, and antioxidant capacity were upregulated, and AMPK pathway activity was enhanced. Liver and hypothalamic leptin resistance and inflammation were also attenuated, allowing better appetite control in mice fed a HFD and leading to reduced food intake. Additionally, metabolic flexibility in the eWAT was improved, and the gut microbiome was modulated by low-dose valine supplementation. Conclusion: Low-dose valine supplementation attenuates MASLD by enhancing systemic leptin sensitivity and modulating the gut microbiome.

Uterine physiology encompasses the intricate processes governing the structure, function, and regulation of the uterus, a pivotal organ within the female reproductive system. The escalating prevalence of obesity has emerged as a significant global health issue, profoundly impacting various facets of well-being, including female reproductive health. These effects extend to uterine structure and function, influencing reproductive health outcomes in women. They encompass alterations in uterine morphology, disruptions in hormonal signaling, and inflammatory processes. Insulin and leptin, pivotal hormones regulating metabolism, energy balance, and reproductive function, play crucial roles in this context. Insulin chiefly governs glucose metabolism and storage, while leptin regulates appetite and energy expenditure. However, in obesity, resistance to both insulin and leptin can develop, impacting uterine function. Inflammation and oxidative stress further exacerbate the development of uterine dysfunction in obesity. Chronic low-grade inflammation and heightened oxidative stress, characteristic of obesity, contribute to metabolic disruptions and tissue damage, including within the uterus. Obesity significantly disrupts menstrual cycles, fertility, and pregnancy outcomes in women. The accumulation of excess adipose tissue disrupts hormonal equilibrium, disturbs ovarian function, and fosters metabolic irregularities, all of which detrimentally impact reproductive health.

Background: Leptin, an adipokine essential for regulating energy balance, exerts important effects on brain function, notably within the hippocampus, a region integral to learning and memory. Leptin resistance, characterized by diminished responsiveness to elevated leptin levels, disrupts hippocampal function and exacerbates both obesity and cognitive impairments. Scope: This review critically examines how leptin resistance impairs hippocampal synaptic plasticity processes, specifically affecting long-term potentiation (LTP) and long-term depression (LTD), which are crucial for cognitive performance. Findings: Recent research highlights that leptin resistance disrupts N-methyl-D-aspartate (NMDA) receptor dynamics and hippocampal structure, leading to deficits in spatial learning and memory. Additionally, high-fat diets (HFDs), which contribute to leptin resistance, further deteriorate hippocampal function. Potential therapeutic strategies, including leptin sensitizers, show promise in mitigating brain disorders associated with leptin resistance. Complementary interventions such as caloric restriction and physical exercise also enhance leptin sensitivity and offer potential benefits to alleviating cognitive impairments. Aims of the review: This review synthesizes recent findings on the molecular pathways underlying leptin resistance and its impact on synaptic transmission and plasticity in the hippocampus. By identifying potential therapeutic targets, this work aims to provide an integrated approach for addressing cognitive deficits in obesity, ultimately improving the quality of life for affected individuals.

Background. Leptin influences energy metabolism, as it is able to inform the central nervous system about adipose tissue reserves, and is also an important neuroendocrine regulator. Therefore, an increase in leptin stimulates thyrotropin-releasing hormone secretion, which leads to an increase of thyroid-stimula­ting hormone with normal or slightly elevated levels of thyroxine and triiodothyronine. Leptin imbalance leads to leptin resistance, which develops as a result of impaired sensitivity of hypothalamic receptors to leptin, its penetration through the blood-brain barrier, damage or dysfunction of these receptors, dysfunction of transport proteins accompanied by an increased content of inflammatory mediators that affect leptin receptors and, in turn, damage them. The purpose of the study was to reveal the relationship between hyperleptinemia and leptin resistance in people with different body weight and thyroid nodules. Materials and methods. One hundred and twenty-three patients were examined, who were divided into four groups depen­ding on the body mass index to determine the le­vels of leptin, insulin, and degree of insulin resistance: group 1 — excess body weight (n = 22); group 2 — class 1 obesity (n = 28); group 3 — class 2 obesity (n = 32); group 4 — class 3 obesity (n = 21). The control group consisted of persons with normal body weight (n = 20). Results. It was found that all examined patients had hyperleptinemia (34.5 ng/ml) simultaneously with hyperinsulinemia and insulin resistance (HOMA-IR was 8.3 units). Patients with thyroid neoplasia compared to individuals with normal body weight had significantly higher (by 1.3 times) serum leptin concentrations (p

AbstractThe high prevalence of metabolic syndrome is threatening the health of populations all over the world. Contemporary work demonstrates that high leptin concentration is directly related to the development of metabolic syndrome such as obesity, fatty liver diseases, type 2 diabetes mellitus and cardiovascular diseases. Anthocyanins are a widespread group of dietary polyphenols, which can ameliorate chronic diseases related to metabolic syndrome. In addition, anthocyanins can regulate the leptin pathway in chronic metabolic diseases, however the potential mechanism between anthocyanin and leptin is complex and elusive. In this review paper, we have evaluated the bioactivity of anthocyanins on the mediation of leptin level and the upstream and downstream pathways in chronic metabolic diseases. Anthocyanins could regulate the hypertrophy of adipose tissue, and the expression of leptin level via mediating TNF-α, C/EBP, PPAR, CREB and SREBP-1. Anthocyanins promoted the leptin sensitivity by increasing the level of leptin receptor, phosphorylation of JAK2/STAT3, PI3K/AKT, and additionally ameliorated metabolic disorder related outcome, including oxidative stress, inflammation, lipid accumulation, insulin resistance and the balance of gut microbiota. However, direct evidence of anthocyanins treatment on leptin signal transduction is still limited which calls for future molecular binding and gene regulation test. [ABSTRACT FROM AUTHOR]

Patients with obesity and type 2 diabetes (T2D) have shown alterations in the affinity of IgG anti-leptin antibodies which are possibly related to metabolic alterations. In the present exploratory study, we analyzed serum samples from adults with T2D classified by body mass index (BMI) and evaluated the relationship of IgG anti-leptin antibodies with body composition, metabolic and cardiovascular risk parameters. Serum IgG anti-leptin antibodies (total, free and immune complexes fractions) were measured by in-house ELISA. Body composition, metabolic biomarkers (glucose, glycated hemoglobin, lipid profile, insulin, leptin) and cardiometabolic risk indexes (AIP, HOMA-IR, HOMA-ß) were evaluated in one hundred T2D patients. Patients with T2D and obesity presented a decrease in the percentage of IgG anti-leptin immune complexes compared to patients with T2D and overweight (p < 0.0053). Negative correlations of IgG anti-leptin immune complexes with triglycerides (TG) (r=-0.412, p = 0.023) and VLDL-C (r=-0.611, p = 0.017) were found in normal weight T2D patients. Free IgG anti-leptin antibodies correlated positively with TC (r = 0.390, p = 0.032) and LDL-C (r = 0.458, p = 0.011) in overweight individuals with T2D. Finally, total IgG anti-leptin antibodies correlated positively with leptin hormone levels (r = 0.409, p = 0.024) and negatively with HOMA-IR (r =-0.459, p = 0.012) in T2D patients with obesity. The decrease of IgG anti-leptin immune complexes observed in patients with T2D and obesity suggests a reduction in antibody affinity to the hormone that may impact its transport and signaling, lipid, lipoprotein and insulin metabolism. [ABSTRACT FROM AUTHOR]

Context The impact of obesity on glucose homeostasis has high interindividual variability, which may be partially explained by different adipokine concentrations. Leptin regulates energy balance and metabolism, and although its plasma levels are proportional to fat mass, they vary significantly across individuals with the same level of adiposity. Objective We tested whether glucose homeostasis differs in subjects with similar degrees of adiposity but different leptin levels. Methods We analyzed 1290 healthy adults from the Relationship Between Insulin Sensitivity and Cardiovascular Disease study cohort (30-60 years; male/female, 577/713; body mass index [BMI], 25 ± 3 kg/m2) characterized for body composition and metabolic variables with a 75-g oral glucose tolerance test, euglycemic-hyperinsulinemic clamp, β-cell function, and lipidomics. Results Individuals were divided into relatively high and low leptin (RHL and RLL) if they were above or below the sex-specific leptin-fat mass (%) regression. Despite similar glucose tolerance, RHL showed markedly higher fasting and oral glucose tolerance test insulin concentration (+30% and +29%, respectively; P <.0001) and secretion (+17% and +11%, respectively; P <.0001). Regardless of BMI, RHL individuals had lower whole-body (−17-23%, P <.0001) and adipose tissue insulin sensitivity (−24%, P <.0001) compared with RLL. Notably, lean RHL individuals showed similar insulin sensitivity and β-cell function to RLL individuals with overweight/obesity. Conclusion Subjects with leptin levels that are inappropriately elevated for their fat mass show whole-body/adipose tissue insulin resistance and hyperinsulinemia, regardless of BMI. [ABSTRACT FROM AUTHOR]

We studied the production of short-chain fatty acids (SCFA) by the intestinal microbiota in mice with obesity caused by a diet and a genetic defect in the leptin receptor gene. In mice, intestinal contents were examined and SCFA were quantitatively assayed by gas chromatography. SCFA concentration in the intestinal contents of mice with alimentary obesity model was significantly lower in the first phase of the experiment (day 14), and the change in their production in dynamics was fundamentally different from this process in the control group (standard diet). The dynamics of the concentration of these metabolites in the model of genetic obesity was similar to that in the control, but the production of SCFA was significantly reduced in mice with leptin resistance in the middle phase (day 60) of the experiment. These findings indicate that the production of SCFA is more influenced by the diet than by leptin resistance. [ABSTRACT FROM AUTHOR]

Ceramide-induced mitochondrial fission drives high-fat diet (HFD)-induced obesity. However, molecules targeting mitochondrial dynamics have shown limited benefits in murine obesity models. Here, we reveal that these compounds are either unable to block ceramide-induced mitochondrial fission or require extended incubation periods to be effective. In contrast, targeting endolysosomal trafficking events important for mitochondrial fission rapidly and robustly prevented ceramide-induced disruptions in mitochondrial form and function. By simultaneously inhibiting ARF6- and PIKfyve-dependent trafficking events, the synthetic sphingolipid SH-BC-893 blocked palmitate- and ceramide-induced mitochondrial fission, preserved mitochondrial function, and prevented ER stress in vitro. Similar benefits were observed in the tissues of HFD-fed mice. Within 4 h of oral administration, SH-BC-893 normalized mitochondrial morphology in the livers and brains of HFD-fed mice, improved mitochondrial function in white adipose tissue, and corrected aberrant plasma leptin and adiponectin levels. As an interventional agent, SH-BC-893 restored normal body weight, glucose disposal, and hepatic lipid levels in mice consuming a HFD. In sum, the sphingolipid analog SH-BC-893 robustly and acutely blocks ceramide-induced mitochondrial dysfunction, correcting diet-induced obesity and its metabolic sequelae.

Abstract Background Weight re-gain (which is also known as re-obesity) is an overwhelming challenge many dieters face in their pursuit to maintain consistent results following successful weight loss. This frustrating pattern of weight cycling can have various mental and physical implications, which further puts another roadblock in any weight reduction program. Main body of the abstract A comprehensive analysis of the causes behind the phenomenon of re-obesity has been widely conducted in literature, exploring the importance of creating the right mindset for weight loss maintenance and identifying the hormonal role, specifically of insulin–leptin resistance and ghrelin enhanced affinity, on appetite and food intake regulation. Insulin–Leptin resistance, due to circulating prostaglandins and prostaglandin metabolites, along with a decline in leptin-producing adipocytes following body mass reduction, cuts off leptin’s satiety signals to the brain. The persistence of this hormonal dysregulation after weight loss is collectively called obesogenic memory, and it seems to be largely mediated by dysbiosis. Short conclusion In conclusion, understanding of the influence of hormonal dysbiosis on re-obesity is fundamental in targeting the culprits behind ineffective attempts at weight loss sustenance, optimization of diet duration, use of synbiotics. Fecal and oral microbial transplantation hold high potential in improving long-term management interventions in obesity patients.

Obesity is associated with dysfunctions in hypothalamic neurons that regulate metabolism, including agouti-related protein (AgRP)-expressing neurons. In a recent article, Zhang et al. demonstrated that either diet- or genetically induced obesity promoted iron accumulation specifically in AgRP neurons. Preventing iron overload in AgRP neurons mitigated diet-induced obesity and related comorbidities in male mice. [ABSTRACT FROM AUTHOR]

Age-related obesity significantly increases the risk of chronic diseases such as type 2 diabetes, cardiovascular diseases, hypertension, and certain cancers. The insulin–leptin axis is crucial in understanding metabolic disturbances associated with age-related obesity. Rho GTPase Cdc42 is a member of the Rho family of GTPases that participates in many cellular processes including, but not limited to, regulation of actin cytoskeleton, vesicle trafficking, cell polarity, morphology, proliferation, motility, and migration. Cdc42 functions as an integral part of regulating insulin secretion and aging. Some novel roles for Cdc42 have also been recently identified in maintaining glucose metabolism, where Cdc42 is involved in controlling blood glucose levels in metabolically active tissues, including skeletal muscle, adipose tissue, pancreas, etc., which puts this protein in line with other critical regulators of glucose metabolism. Importantly, Cdc42 plays a vital role in cellular processes associated with the insulin and leptin signaling pathways, which are integral elements involved in obesity development if misregulated. Additionally, a change in Cdc42 activity may affect senescence, thus contributing to disorders associated with aging. This review explores the complex relationships among age-associated obesity, the insulin–leptin axis, and the Cdc42 signaling pathway. This article sheds light on the vast molecular web that supports metabolic dysregulation in aging people. In addition, it also discusses the potential therapeutic implications of the Cdc42 pathway to mitigate obesity since some new data suggest that inhibition of Cdc42 using antidiabetic drugs or antioxidants may promote weight loss in overweight or obese patients. [ABSTRACT FROM AUTHOR]

Disruption of leptin (LEP) signaling in the hypothalamus caused by type 2 diabetes (T2D) can impair appetite regulation. The aim of this study was to investigate whether the improvement in appetite regulation induced by high-intensity interval training (HIIT) in rats with T2D can be mediated by LEP signaling. In this study, 20 male Wister rats were randomly assigned to one of four groups: CO (non-type 2 diabetes control), T2D (type 2 diabetes), EX (non-type 2 diabetes exercise), and T2D + EX (type 2 diabetes + exercise).To induce T2D, a combination of a high-fat diet for 2 months and a single dose of streptozotocin (35 mg/kg) was administered. Rats in the EX and T2D + EX groups performed 4–10 intervals of treadmill running at 80–100% of their maximum velocity (Vmax). Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), serum levels of insulin (INS) and LEP (LEPS) as well as hypothalamic expression of LEP receptors (LEP-R), Janus kinase 2 (JAK-2), signal transducer and activator of transcription 3 (STAT-3), neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin cocaine (POMC), amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1) were assessed. ANOVA and Tukey post hoc tests were used to compare the results between the groups. The levels of LEPS and INS, as well as the levels of LEP-R, JAK-2, STAT-3, POMC, and CART in the hypothalamus were found to be higher in the T2D + EX group compared to the T2D group. On the other hand, the levels of HOMA-IR, NPY, AGRP, SOCS3, and FOXO1 were lower in the T2D + EX group compared to the T2D group (P < 0.0001). The findings of this study suggest that HIIT may improve appetite regulation in rats with T2D, and LEP signaling may play a crucial role in this improvement. Graphical abstract (leptin signaling in the hypothalamus), Leptin (LEP), Leptin receptor (LEP-R), Janus kinase 2 (JAK2), Signal transducer and activator of transcription 3 (STAT3), expressing Neuropeptide Y (NPY), Agouti-related protein (AGRP), anorexigenic neurons (expressing pro-opiomelanocortin cocaine (POMC), Amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1). [ABSTRACT FROM AUTHOR]

The prevalence of obesity has reached pandemic dimensions. It is associated with multiple comorbidities and is becoming a clinical and public health threat. Obesity is a multifactorial disease with a complex pathophysiology and interplay of various systems. A strong interplay exists between the neuro-endocrine system, the immune system with systemic chronic low-grade inflammation, and microbiome dysbiosis that can lead to the development of obesity, which in turn can exacerbate each of these factors, hence creating a vicious cycle. The conventional treatment with lifestyle modifications such as diet, physical exercise, pharmacotherapy, and bariatric surgery does not always result in sufficient weight control thus paving the way for other strategies. As one such strategy, acupuncture is increasingly used worldwide to treat obesity. This narrative review outlines the evidence for this neuro-endocrine-immune interplay in the pathophysiology of obesity. Furthermore, the existing experimental and clinical evidence of acupuncture as a multi-targeted therapy for obesity is explained and future research perspectives are discussed. [ABSTRACT FROM AUTHOR]

Leptin (LEP) can cross the blood–brain barrier and facilitate cross-talk between the adipose tissue and central nerve system (CNS). This study aimed to investigate the effect of 8-week high-intensity interval training (HIIT) on the LEP signaling in the hippocampus of rats with type 2 diabetes. 20 rats were randomly divided into four groups: (i) control (Con), (ii) type 2 diabetes (T2D), (iii) exercise (EX), and (iv) type 2 diabetes + exercise (T2D + EX). The rats in the T2D and T2D + EX were fed a high-fat diet for two months, then a single dose of STZ (35 mg/kg) was injected to induce diabetes. The EX and T2D + EX groups performed 4–10 intervals of treadmill running at 80–100% of Vmax. Serum and hippocampal levels of LEP as well as hippocampal levels of LEP receptors (LEP-R), Janus kinase 2 (JAK-2), signal transducer and activator of transcription 3 (STAT-3), activated protein kinase (AMP-K), proxy zoster receptor α (PGC-1α), beta-secretase 1 (BACE1), Beta-Amyloid (Aβ), Phosphoinositide 3-kinases (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), Glycogen Synthase Kinase 3 Beta (GSK3β), and hyperphosphorylated tau proteins (TAU) were measured. One-way ONOVA and Tukey post-hoc tests were used to analyze the data. Serum and hippocampal levels of LEP as well as hippocampal levels of LEP-R, JAK-2, STAT-3, AMP-K, PGC1α, PI3K, AKT, and mTOR were increased while hippocampal levels of BACE1, GSK3B, TAU, and Aβ were decreased in T2D + EX compared with T2D group. Serum LEP and hippocampal levels of LEP, LEP-R, JAK-2, STAT-3, AMP-K, PGC1α, PI3K, AKT, and mTOR were decreased. Conversely hippocampal levels of BACE1, GSK3B, TAU, and Aβ were increased in T2D group compared with CON group. HIIT could improve LEP signaling in the hippocampus of rats with type 2 diabetes and decrease the accumulation of Tau and Aβ, which may reduce the risk of memory impairments. [ABSTRACT FROM AUTHOR]

Introduction. Leptin resistance (LR) is characterized by a weakening of the positive metabolic effect of leptin, despite its elevated level, while maintaining some of the pleiotropic effects, including those on the cardiovascular system. However, since most of the data have been obtained in cellular and animal models, the role of LR in cardiovascular diseases remains unclear. The lack of precise diagnostic criteria for assessing LR limits the study of this phenomenon. As a result, data on the incidence and contribution of LR in MI are critically scarce today, in addition, they are extremely contradictory.Purpose: to evaluate the prevalence of LR and its clinical and prognostic significance in conjunction with metabolic disorders in the hospital period of myocardial infarction (MI).Materials and methods. The study included 114 men with an established diagnosis of ST elevation MI. Patients on the 1st and 12th day of MI measured the concentration of leptin, the leptin receptor. The free leptin index (FLI) was calculated as the ratio of leptin concentration (ng/mL) to the concentration of soluble leptin receptor (ng/mL) multiplied by 100. LR was recorded at leptin > 6.45 ng/mL and LL >25. Assessment of glucose, lipid spectrum (total cholesterol, TAG, LDL-C, VLDL-C, HDL-C, FFA) in blood serum was performed using standard test systems from Thermo Fisher Sientific on an automatic biochemical analyzer Konelab 30i (Finland) , the content of C-peptide and insulin were determined using enzyme immunoassay (Monobind, USA) according to the protocol established by the manufacturer. To determine insulin resistance (IR), the QUICKI index was calculated, the severity of IR was assessed according to A. Katz et al. A comparative analysis of clinical and anamnestic characteristics and cardiovascular prognosis between patients with and without PR was carried out. Data analyzed using Statistica 10.0.Results. In patients with MI in the whole group in the hospital period, there was an increased content of leptin relative to the reference interval of 2.0-5.6 ng/ml. On the 1st and 12th days of the disease, the leptin concentration in patients with MI was 11.6 [6.6;20.5] ng/ml and 11.5 [5.4;13.9] ng/ml, respectively. . The content of the leptin receptor did not go beyond the established reference interval. LSI on the 1st day of the disease was 32.7 [14.3; 70.5], on the 12th day - 31.9 [16.2; 64.5]. The prevalence of LR in the hospital period for MI was 64%. LR was associated with CVD risk factors - hereditary burden for cardiovascular pathology (p=0.02), arterial hypertension (p=0.01), dyslipidemia (p=0.001), obesity (p=0.001). When assessing the metabolic profile, a statistically significant increase in the content of glucose (p=0.02), insulin (p=0.02) and C-peptide (p=0.03) on the 1st day of MI, insulin (p=0 .01) and C-peptide (p=0.03) on the 12th day of the disease, a decrease in the QUICKI index (p=0.03) throughout the hospital period in patients with PR compared with patients without PR. In the group of patients with PR, 45 people (61.8%) had a moderate and severe degree of IR, in patients without PR - in 12 patients (29.2%). When conducting a correlation analysis, a significantly significant direct relationship was found between the level of insulin on the 12th day of MI and LSI (r=0.509, p=0.02), as well as an inverse correlation between the QUICKI index on the 12th day and LSI (r= -0.367, p=0.01). Among the studied parameters of lipid metabolism, only the content of FFA on the 1st day of the disease in the group of patients with LR was higher than in the group without LR (p=0.03). Patients with LR were more often prone to early postinfarction angina (p=0.03), recurrent MI (p=0.001), rhythm and conduction disturbances (p=0.03) during the hospital period of MI. Prognostic significance in relation to the risk of adverse cardiovascular events in the hospital period of MI, according to logistic regression analysis, had LSI both on the 1st and 12th days of the disease, as well as FFA levels on the 1st day of the disease.Conclusion. Patients with MI are characterized by a high prevalence of LR in the hospital period. LR is associated with CVD risk factors, metabolic disorders, and IR formation. The identified features in the presence of LR can probably contribute to the development of adverse cardiovascular events in the hospital period of MI.

Background. Leptin influences energy metabolism, as it is able to inform the central nervous system about adipose tissue reserves, and is also an important neuroendocrine regulator. Therefore, an increase in leptin stimulates thyrotropin-releasing hormone secretion, which leads to an increase of thyroid-stimulating hormone with normal or slightly elevated levels of thyroxine and triiodothyronine. Leptin imbalance leads to leptin resistance, which develops as a result of impaired sensitivity of hypothalamic receptors to leptin, its penetration through the blood-brain barrier, damage or dysfunction of these receptors, dysfunction of transport proteins accompanied by an increased content of inflammatory mediators that affect leptin receptors and, in turn, damage them. The purpose of the study was to reveal the relationship between hyperleptinemia and leptin resistance in people with different body weight and thyroid nodules. Materials and methods. One hundred and twenty-three patients were examined, who were divided into four groups depending on the body mass index to determine the levels of leptin, insulin, and degree of insulin resistance: group 1 -excess body weight (n = 22); group 2 -class 1 obesity (n = 28); group 3 -class 2 obesity (n = 32); group 4 -class 3 obesity (n = 21). The control group consisted of persons with normal body weight (n = 20). Results. It was found that all examined patients had hyperleptinemia (34.5 ng/ml) simultaneously with hyperinsulinemia and insulin resistance (HOMA-IR was 8.3 units). Patients with thyroid neoplasia compared to individuals with normal body weight had significantly higher (by 1.3 times) serum leptin concentrations (p < 0.05; p < 0.001). The research proved that the level of leptinemia is directly related to the body mass index, waist circumference (r = 0.54; p < 0.001) and hip circumference (r = 0.51; p < 0.001). Conclusions. Among patients with leptin resistance and insulin resistance against the background of obesity of various classes, thyroid neoplasms occur in 28 % of cases. Leptin resistance along with insulin resistance can be considered as independent risk factor for neoplasia. People with abdominal obesity need a mandatory examination of the structural and functional state of the thyroid gland for early detection of nodular neoplasms. [ABSTRACT FROM AUTHOR]

Background: Weight re-gain (which is also known as re-obesity) is an overwhelming challenge many dieters face in their pursuit to maintain consistent results following successful weight loss. This frustrating pattern of weight cycling can have various mental and physical implications, which further puts another roadblock in any weight reduction program. A comprehensive analysis of the causes behind the phenomenon of re-obesity has been widely conducted in literature, exploring the importance of creating the right mindset for weight loss maintenance and identifying the hormonal role, specifically of insulin–leptin resistance and ghrelin enhanced affinity, on appetite and food intake regulation. Insulin–Leptin resistance, due to circulating prostaglandins and prostaglandin metabolites, along with a decline in leptin-producing adipocytes following body mass reduction, cuts off leptin's satiety signals to the brain. The persistence of this hormonal dysregulation after weight loss is collectively called obesogenic memory, and it seems to be largely mediated by dysbiosis. Short conclusion: In conclusion, understanding of the influence of hormonal dysbiosis on re-obesity is fundamental in targeting the culprits behind ineffective attempts at weight loss sustenance, optimization of diet duration, use of synbiotics. Fecal and oral microbial transplantation hold high potential in improving long-term management interventions in obesity patients. [ABSTRACT FROM AUTHOR]

Craniopharyngioma (CP) is a benign tumor with a high rate of obesity and frequent recurrence. Moreover, the role of leptin/leptin receptors axis in obesity and the prognosis of CP is still unknown. Plasma leptin concentration and mRNA expression of leptin receptors were assessed in patients with CP. Moreover, the association between leptin/leptin receptors axis, weight-related outcomes, and progression-free survival (PFS) were explored in CP patients. Leptin receptors overexpressed in CP tumor tissue were compared to normal brain tissue (p < 0.05); compared to healthy controls, the concentration of leptin was elevated in CP with or without matched age, sex, and body mass index (BMI) (p < 0.05). The high plasma leptin level was an independent risk predictor for significant weight gain (adjusted odds ratio (aOR) = 2.29, and p = 0.030) and new-onset obesity (aOR = 6.64, and p = 0.016). High plasma leptin level (adjusted hazard ratio (aHR) = 3.74, and p = 0.011) and leptin receptor (LEPR) mRNA expression (aHR = 3.12, and p = 0.045) were independent risk factors for poor PFS in CP. Inappropriately elevated leptin relative to BMI and its failure to inhibit further weight gain indicate the existence of leptin resistance in patients with CP. Leptin and LEPR were independent predictors for PFS of patients with CP. The leptin/leptin receptors axis may be a potential therapeutic target for obesity in patients with CP. [ABSTRACT FROM AUTHOR]

High sodium intake is associated with obesity and insulin resistance, and high extracellular sodium content may induce systemic inflammation, leading to cardiovascular disease. In this study, we aim to investigate whether high tissue sodium accumulation relates with obesity-related insulin resistance and whether the pro-inflammatory effects of excess tissue sodium accumulation may contribute to such association. In a cross-sectional study of 30 obese and 53 non-obese subjects, we measured insulin sensitivity determined as glucose disposal rate (GDR) using hyperinsulinemic euglycemic clamp, and tissue sodium content using 23Na magnetic resonance imaging. Median age was 48 years, 68% were female and 41% were African American. Median (interquartile range) BMI was 33 (31.5, 36.3) and 25 (23.5, 27.2) kg/m2 in the obese and non-obese individuals, respectively. In obese individuals, insulin sensitivity negatively correlated with muscle (r = −0.45, p = 0.01) and skin sodium (r = −0.46, p = 0.01). In interaction analysis among obese individuals, tissue sodium had a greater effect on insulin sensitivity at higher levels of high-sensitivity C-reactive protein (p-interaction = 0.03 and 0.01 for muscle and skin Na+, respectively) and interleukin-6 (p-interaction = 0.024 and 0.003 for muscle and skin Na+, respectively). In interaction analysis of the entire cohort, the association between muscle sodium and insulin sensitivity was stronger with increasing levels of serum leptin (p-interaction = 0.01). Higher muscle and skin sodium are associated with insulin resistance in obese patients. Whether high tissue sodium accumulation has a mechanistic role in the development of obesity-related insulin resistance through systemic inflammation and leptin dysregulation remains to be examined in future studies. Clinicaltrials.gov registration: NCT02236520. • High tissue sodium associates with increased insulin resistance in obese individuals. • This association is stronger with increasing levels of serum inflammatory markers. • This association is stronger with increasing levels of leptin resistance. • Inflammation and leptin dysregulation may be implicated in the association between tissue sodium and insulin sensitivity. [ABSTRACT FROM AUTHOR]

Background: Weight loss is important to reduce the risk of metabolic complications in obese individuals, in whom dysregulated adipokines play a central role. This study aims to investigate whether dysregulated adipokines and postprandial triglycerides (TG) improve with a modest weight loss. Methods: Individuals with obesity (BMI ≥ 30 kg/m2) were recruited among patients at the University Hospital of North Norway and the Stamina Health weight loss rehabilitation program. We measured resting energy expenditure (REE), and calculated the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), leptin to adiponectin (L:A) ratio, indirect leptin sensitivity (REE:leptin ratio), postprandial TG clearance at 6 h, and TG response before and after weight loss. The goal of the weight loss intervention was a loss of ≥5 % of initial total body weight. Results: 28 participants completed the study, of which 13 lost ≥ 5 % body weight and 18 lost

Aim. To compare the incidence of leptin resistance (LR) in patients with acute and chronic coronary artery disease (CAD) and patients with acquired heart defects (AHD).Material and methods. The study included 234 patients: 114 patients with acute myocardial infarction (MI) and 120 patients with chronic CAD. The comparison group consisted of 48 patients with degenerative non-rheumatic AHD — aortic stenosis (AS). The control group consisted of 40 healthy volunteers. On the 1st day of hospitalization, the concentration of leptin and leptin receptor was measured, and the free leptin index (FLI) was assessed. LR was recorded at leptin >6,45 ng/ ml and FLI >25. Statistical data processing was carried out using the software package Statistica 10.0 and SPSS 17.0 for Windows.Results. Initially, LR in MI, chronic CAD and non-coronary disease was revealed in 64%, 56,2% and 25%, respectively. Significant differences in the incidence of LR were observed between patients with MI and chronic CAD relative to patients with AHD (p=0,02 and p=0,03, respectively), while no differences were found between patients with coronary pathology (p=0,82). Equation of patients for body mass index (BMI) did not affect the incidence of LR. High incidence of LR remained for patients with acute and chronic CAD, and amounted to 63% and 57,3%, respectively, while for patients with AS — 25%.Conclusion. Patients with acute and chronic CAD are characterized by a high LR incidence, in contrast to patients with AHD. The number of LR cases in patients with coronary pathology did not depend on BMI values, which indicates possible alternative leptin sources contributing the development of hyperleptinemia. In addition, studying the mechanisms underlying the leptin receptor decrease in CAD is necessary for adequate leptin effects and the prevention of LR.

The consumption of saturated fatty acids (SFA), the main compound in coconut oil (CO), can promote insulin and leptin resistance and are associated with inflammation and obesity. We investigated the effects of CO supplementation on leptin signaling in healthy mice. Swiss male mice received oral supplementation for eight weeks with 300 μL of water for the control group (CV) or CO (100 or 300 μL). Sensitivity to leptin/insulin was evaluated after eight weeks of supplementation. The CO induced endoplasmic reticulum stress and leptin resistance in the hypothalamus, as demonstrated by reduced effect on the energy expenditure, hypothalamic pJAK2 and pSTAT3, and POMC expression. In the adipose tissue, lipogenesis was favored and STAT3 and JAK2 signaling was impaired after CO supplementation. Furthermore, the supplementation with CO reduced pAKT in the hypothalamus, liver and white adipose tissue. These results show that CO induces hypothalamic and peripheral resistance to leptin and insulin in healthy mice.

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]

Abstract Objective Obesity is related to increasing leptin and some inflammatory factors that are associated with low-grade inflammation. Moreover, several studies have shown Caveolin-1 (CAV1) genetic variations may be associated with dietary intake. The current study aimed to evaluate the interaction of CAV1 rs3807992 with types of the energy-adjusted dietary inflammatory index (EDII) in leptin, leptin resistance, and Galectin 3, as inflammatory factors. Methods This cross-sectional study was carried out on 363 overweight and obese females. Dietary intake and DII were obtained from a 147-item food frequency questionnaire (FFQ). The CAV-1 genotype was measured using the PCR-RFLP method. Anthropometric values and serum levels of leptin and Galectin 3 were measured by standard methods. Results Increased adherence to EDII in the interaction with CAV1 genotypes led to an increase in leptin level 79.15 (mg/l) (β = 79.15, CI = − 1.23,163.94, P = 0.04) in model 3, after controlling for further potential confounders. By contrast, adherence to EDII in the interaction with the genotype including risk alleles showed no significant interaction, even after adjustment in model 3 (β = 0.55, CI = − 0.99, 2.09, P = 0.48). Although, a marginal positive significant interaction was found between EDII and CAV1 genotypes on Galectin 3, after adjustment in model 3 (β = 31.35, CI = 0.13, 77.13, P = 0.05). Conclusions The present study indicates that a high adherence of EDII and CAV1 genotypes containing risk alleles may be a prognostic factor and increase both leptin and Galectin3. However, it seems that the presence of interaction was not on leptin resistance. Further functional studies are necessary to elucidate the exact mechanism.

With the prevalence of obesity and associated comorbidities, studies aimed at revealing mechanisms that regulate energy homeostasis have gained increasing interest. In 1994, the cloning of leptin was a milestone in metabolic research. As an adipocytokine, leptin governs food intake and energy homeostasis through leptin receptors (LepR) in the brain. The failure of increased leptin levels to suppress feeding and elevate energy expenditure is referred to as leptin resistance, which encompasses complex pathophysiological processes. Within the brain, LepR-expressing neurons are distributed in hypothalamus and other brain areas, and each population of the LepR-expressing neurons may mediate particular aspects of leptin effects. In LepR-expressing neurons, the binding of leptin to LepR initiates multiple signaling cascades including janus kinase (JAK)–signal transducers and activators of transcription (STAT) phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), extracellular regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK) signaling, etc., mediating leptin actions. These findings place leptin at the intersection of metabolic and neuroendocrine regulations, and render leptin a key target for treating obesity and associated comorbidities. This review highlights the main discoveries that shaped the field of leptin for better understanding of the mechanism governing metabolic homeostasis, and guides the development of safe and effective interventions to treat obesity and associated diseases.

Alzheimer's disease (AD) is the most common type of dementia characterized by the deposition of amyloid beta (Aβ) plaques and tau-neurofibrillary tangles in the brain. Visceral obesity (VO) is usually associated with low-grade inflammation due to higher expression of pro-inflammatory cytokines by adipose tissue. The objective of the present review was to evaluate the potential link between VO and the development of AD. Tissue hypoxia in obesity promotes tissue injury, production of adipocytokines, and release of pro-inflammatory cytokines leading to an oxidative-inflammatory loop with induction of insulin resistance. Importantly, brain insulin signaling is involved in the pathogenesis of AD and lower cognitive function. Obesity and enlargement of visceral adipose tissue are associated with the deposition of Aβ. All of this is consonant with VO increasing the risk of AD through the dysregulation of adipocytokines which affect the development of AD. The activated nuclear factor kappa B (NF-κB) pathway in VO might be a potential link in the development of AD. Likewise, the higher concentration of advanced glycation end-products in VO could be implicated in the pathogenesis of AD. Taken together, different inflammatory signaling pathways are activated in VO that all have a negative impact on the cognitive function and progression of AD except hypoxia-inducible factor 1 which has beneficial and neuroprotective effects in mitigating the progression of AD. In addition, VO-mediated hypoadiponectinemia and leptin resistance may promote the progression of Aβ formation and tau phosphorylation with the development of AD. In conclusion, VO-induced AD is mainly mediated through the induction of oxidative stress, inflammatory changes, leptin resistance, and hypoadiponectinemia that collectively trigger Aβ formation and neuroinflammation. Thus, early recognition of VO by visceral adiposity index with appropriate management could be a preventive measure against the development of AD in patients with VO. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is considered a metabolic disorder that has been steadily increasing globally and seems to parallel the increasing prevalence of obesity. It consists of a cluster of risk factors which traditionally includes obesity and hyperlipidemia, hyperinsulinemia, hypertension, and hyperglycemia. These four core risk factors are associated with insulin resistance (IR) and, importantly, the MetS is known to increase the risk for developing cerebrocardiovascular disease and type 2 diabetes mellitus. The MetS had its early origins in IR and syndrome X. It has undergone numerous name changes, with additional risk factors and variables being added over the years; however, it has remained as the MetS worldwide for the past three decades. This overview continues to add novel insights to the MetS and suggests that leptin resistance with hyperleptinemia, aberrant mitochondrial stress and reactive oxygen species (ROS), impaired folate-mediated one-carbon metabolism with hyperhomocysteinemia, vascular stiffening, microalbuminuria, and visceral adipose tissues extracellular vesicle exosomes be added to the list of associated variables. Notably, the role of a dysfunctional and activated endothelium and deficient nitric oxide bioavailability along with a dysfunctional and attenuated endothelial glycocalyx, vascular inflammation, systemic metainflammation, and the important role of ROS and reactive species interactome are discussed. With new insights and knowledge regarding the MetS comes the possibility of new findings through further research. [ABSTRACT FROM AUTHOR]