Reduction In Leptin Research Articles

Ethanolic Extract Clove-loaded Chitosan Nanoparticles Reduce Dyslipidemia, Enhance Liver and Kidney Functions, and Improve the Antioxidant System in Obese Rats

Background: Obesity, a chronic low-grade inflammatory disease characterized by multiple metabolic dysfunctions, poses a considerable worldwide health risk to adults and children. Clove has also shown that it possesses anti-inflammatory, anti-fungal, antibacterial, antioxidant, antiglycation, and anti-aging properties. Aim: The current study aimed to investigate the antiobesity effect of clove-loaded chitosan nanoparticles in obese rats. objective: The current study investigated the antiobesity effect of clove-loaded chitosan nanoparticles in obese rats. Method: Obesity is induced in rats by the administration of a High-Fat Diet (HFD) for 4 weeks. 24 rats were divided into 4 groups; Control group, in which rats were fed normal; HDF group, in which rats were HFD along with distilled water; HFD + empty nanoparticles (ENPs), in which rats were HFD along with ENPs (45 mg/kg); and HFD + clove nanoparticles (CNPs), in which rats were HFD along with CNPs (45 mg/kg) for four weeks. Results: Administration of ENPs and CNPs led to a notable reduction in glucose, aminotransferases, alkaline phosphatase, cholesterol, triglycerides, low-density lipoproteins, malondialdehyde, nitric oxide, caspase-3, PCNA, leptin, and DNA fragmentation. Additionally, it promoted an increase in total proteins, albumin, high-density lipoprotein, glutathione, catalase, and adiponectin. Also, the histopathological investigation of the liver and kidney showed the protective effect of ENPs and CNPs on the tissues of obese rats. Conclusion: The present investigation elucidated the preventive effects of chitosan nanoparticles loaded with clove on dyslipidemia in obese rats. Clove nanoparticles exhibited hypolipidemia, antioxidant, hypoglycemia, and hepatoprotective activities.

Impact of Combined Aerobic Training and Magnesium Supplementation on Serum Biomarkers and microRNA-155 and microRNA-21 Expression in Adipose Tissue of Type 2 Diabetic Rats: An Eight-Week Interventional Study.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance and chronic inflammation. Aerobic training (AT) and magnesium supplementation (Mg) have both been independently shown to have beneficial effects on glucose control and insulin sensitivity in individuals with T2DM. However, the potential synergistic effects of combining AT and Mg supplementation have not been extensively studied. This study aimed to investigate the effects of an 8-week AT and Mg supplementation on serum levels of insulin, glucose, leptin, adiponectin, TNF-α, IL-1β, IL-6, NF-κB, as well as the expression of mir-155 and mir-21 in the visceral adipose tissue (VAT) of rats with T2DM. For this experimental study, 32 male Wistar rats were induced with T2DM by a high-fat diet combined with a low-dose streptozotocin injection. The rats were randomly assigned to four groups: AT and Mg supplementation (AT + Mg), AT (5 days/week for 8 weeks), Mg supplementation (received daily supplementation of Mg chloride), and diabetic control (C). An 8-week AT program was implemented, with gradually increasing the intensity and duration to reach 25m/min and 60min in the 8th week, respectively. The training intensity was set at 50-60% of VO2max. The Mg groups were provided with rat diets containing 1000mg/kg of Mg. The AT + Mg group received both interventions, while the C group served as the untreated control. Serum biomarkers were measured using enzyme-linked immunosorbent assay (ELISA), and VAT samples were collected for gene expression analysis using real-time polymerase chain reaction (PCR). Serum biomarker analysis revealed that the AT + Mg group had a significant decrease in fasting insulin (p = 0.001) and serum glucose (p = 0.001), as well as an increase in adiponectin levels compared to the C group (p = 0.002). Additionally, the AT + Mg group showed a significant reduction in serum leptin, TNF-α, IL-6, IL-1β, and NF-κB, as well as downregulation of mir-155 and mir-21 in the VAT compared to the other groups. The AT group also showed improvements in several parameters, while the Mg group had fewer significant differences compared to the C group. The combination of AT and Mg supplementation provides a synergistic effect that improves serum biomarkers and downregulates pro-inflammatory microRNAs in the VAT of T2DM rats. Meanwhile, Mg supplementation alone does not have a significant effect on pro-inflammatory microRNAs in the VAT. These findings suggest that such combined interventions could be a promising strategy for managing T2DM, potentially ameliorating inflammatory states and improving metabolic health.

Calorie restriction-induced leptin reduction and T-lymphocyte activation in blood and adipose tissue in men with overweight and obesity

BackgroundT-Lymphocyte activation is modulated by the adipokine leptin and serum concentrations of this hormone can be reduced with short-term calorie restriction. The aim of this study was to understand whether leptin per se is important in determining levels of T-lymphocyte activation in humans, by investigating whether the reduction in leptin concentration following calorie restriction is associated with a decrease in T-Lymphocyte activation in blood and adipose tissue.MethodsTwelve men with overweight and obesity (age 35–55 years, waist circumference 95–115 cm) reduced their calorie intake by 50% for 3 consecutive days. Blood and subcutaneous adipose tissue were obtained for isolation of immune cells and cytokine analysis. CD4+ and CD8 + T-Lymphocytes were identified and characterised according to their expression of activation markers CD25 and CD69 by flow cytometry.ResultsSerum leptin was reduced by (mean ± SEM) 31 ± 16% (p < 0.001) following calorie restriction. The percentage of blood CD4 + CD25 + T-lymphocytes and level of CD25 expression on these lymphocytes were significantly reduced by 8 ± 10% (p = 0.016) and 8 ± 4% (p = 0.058), respectively. After calorie restriction, ex vivo leptin secretion from abdominal subcutaneous adipose tissue explants was not changed, and this corresponded with a lack of change in adipose tissue resident T-Lymphocyte activation.ConclusionsSerum leptin was reduced after calorie restriction and this was temporally associated with a reduction in activation of blood CD4 + CD25 + T-Lymphocytes. In abdominal subcutaneous adipose tissue, however, leptin secretion was unaltered, and there were no observed changes in adipose resident T-Lymphocyte activation.

Comparative analysis of anti-obesity effects of green, fermented, and γ-aminobutyric acid teas in a high-fat diet-induced mouse model

Obesity, a prevalent disease associated with numerous chronic conditions, including hyperlipidemia, hyperglycemia, diabetes, and metabolic syndrome, remains a major global health challenge. This study investigated the potential of green tea (GT), fermented tea (FT), and γ-aminobutyric acid (GABA) tea (GBT), which are rich in phytonutrients and polyphenols, for the management of obesity. Using a high-fat diet-induced obese mouse model (C57BL/6N), we explored the effect of these teas on various obesity-related parameters. The mice were categorized into five groups: normal diet with water, high-fat diet with water, and high-fat diet supplemented with GT, FT, or GBT. Over 13 weeks, we monitored body weight, perirenal and liver fat, adipocyte lipid accumulation, and key metabolic indicators, such as serum cholesterol, leptin, insulin, and fasting blood glucose. These teas contain beneficial phytochemicals such as GABA, theanine, and caffeine, and have demonstrated an enhanced antioxidant capacity, which increases the scavenging of free radicals and may reduce oxidative stress. The animal study indicated a decrease in feeding efficiency and significant reductions in body weight liver fat, epididymal fat, and perirenal fat, as well as in adipocyte lipid accumulation. Additionally, notable improvements were observed in metabolic health indicators, including reductions in serum cholesterol, leptin, insulin, and fasting blood glucose levels. Our findings revealed that GT, FT, or GBT significantly counteracted the negative effects of a high-fat diet, suggesting their potential in combating obesity and related metabolic disorders.

Conditional Deletion of β-Catenin in the Mediobasal Hypothalamus Impairs Adaptive Energy Expenditure in Response to High-Fat Diet and Exacerbates Diet-Induced Obesity.

β-Catenin is a bifunctional molecule that is an effector of the wingless-related integration site (Wnt) signaling to control gene expression and contributes to the regulation of cytoskeleton and neurotransmitter vesicle trafficking. In its former role, β-catenin binds transcription factor 7-like 2 (TCF7L2), which shows strong genetic associations with the pathogenesis of obesity and type-2 diabetes. Here, we sought to determine whether β-catenin plays a role in the neuroendocrine regulation of body weight and glucose homeostasis. Bilateral injections of adeno-associated virus type-2 (AAV2)-mCherry-Cre were placed into the arcuate nucleus of adult male and female β-catenin flox mice, to specifically delete β-catenin expression in the mediobasal hypothalamus (MBH-β-cat KO). Metabolic parameters were then monitored under conditions of low-fat (LFD) and high-fat diet (HFD). On LFD, MBH-β-cat KO mice showed minimal metabolic disturbances, but on HFD, despite having only a small difference in weekly caloric intake, the MBH-β-cat KO mice were significantly heavier than the control mice in both sexes (p < 0.05). This deficit seemed to be due to a failure to show an adaptive increase in energy expenditure seen in controls, which served to offset the increased calories by HFD. Both male and female MBH-β-cat KO mice were highly glucose intolerant when on HFD and displayed a significant reduction in both leptin and insulin sensitivity compared with controls. This study highlights a critical role for β-catenin in the hypothalamic circuits regulating body weight and glucose homeostasis and reveals potential mechanisms by which genetic variation in this pathway could impact on development of metabolic disease.

Comparison of the effects of three sourdough postbiotics on high-fat diet-induced intestinal damage.

There is significant interest in using postbiotics as an intervention strategy to address obesity. This study assesses the efficacy of postbiotics derived from different sourdough strains (Lactiplantibacillus plantarum LP1, LP25, and Pediococcus pentosaceus PP18) in mitigating intestinal injury in zebrafish fed on a high-fat diet. We screened postbiotics for their anti-colon cancer cell effects and compared various preparation methods applied to live bacterial strains, including heat-killing at different temperatures, pH adjustments, and ultraviolet radiation exposure. Heat-killing at 120 °C proved to be the most effective preparation method. A marked variation in health effects was observed in the heat-killed microbial cells, as evidenced by their hydrophobicity and self-aggregation ability. A five-week high-fat dietary intervention study in zebrafish demonstrated that diets supplemented with 108 CFU g-1 K-LP25 significantly attenuated weight gain and body fat, along with reductions in FASN, Leptin, and SREBF1 mRNA expression. However, diets supplemented with 107 CFU g-1 K-PP18 only reduced Leptin and SREBF1 mRNA expression. K-PP18 was more effective at mitigating gut barrier damage, promoting colonic Occludin, ZO-1, and Claudin-1 levels. Additionally, K-LP25 supplementation markedly downregulated the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, reducing intestinal inflammation. Supplementation with K-LP1 and K-PP18 increased the abundance of Acinetobacter spp., whereas K-LP25 increased the abundance of Cetobacterium and Plesiomonas. Collectively, these findings suggest that inactivated strains confer protective effects against high-fat diet-induced intestinal damage in zebrafish, with variation observed across different species. Studying the effects of sourdough-derived postbiotics on gut health may open new avenues for dietary interventions to manage gut-related diseases.

Effect of Interval Resistance Training with Different Intensities on Some Selected Adipokines in Obese Men

Objective: Adipose tissue-derived adipokines affect cardiometabolic health. This study aimed to evaluate the effect of interval resistance training with different intensities on leptin, adiponectin, and acrosin levels in obese males.&#x0D; Materials and Methods: Fourty-four obese males (27.70± 3.02 years) were randomly allocated into four groups: high intensity (HI), moderate intensity (MI), low intensity (LI), and control (C). Subjects of the HI, MI, and LI groups implemented the training program for 12 weeks, three sessions a week with intensities corresponding 80% 1RM, 60% 1RM, and 40% 1RM,, respectively. Body composition and plasma levels of leptin, adiponectin, and asprosin were evaluated before and after interval resistance training at different intensities.&#x0D; Results: Following exercise, serum levels of leptin and asporin were significantly reduced in all groups (P&lt; 0.01). The greatest reduction of leptin and asporin levels was recorded in the HI group (P= 0.001, P= 0.01) for leptin and asporsin levels, respectively. The level of adiponectin significantly decreased after exercise in all groups (P&lt; 0.001, F= 12.44). The greatest reduction was observed in the HI group compared with the MI and UI group (P= 0.001).&#x0D; Conclusion: Interval resistance training with different intensities can cause significant changes in leptin, asprosin, and adiponectin levels in obese men, and this improvement was better at high intensities.

Reduction of leptin levels during acute exercise is dependent on fasting but not on caloric restriction during chronic exercise: A systematic review and meta-analysis.

The importance of leptin in controlling body mass has recently gained more attention. Its levels are directly associated with the amount of fat mass, but not necessarily dependent on it. Exercise has great potential in reducing leptin levels, however the response of exercise to this cytokine is still not well understood. The objective of the review was to analyze the effects of physical exercise on plasma leptin concentration, either acutely (post-exercise/training session) and/or after a training period (short- or long-term), as well as to investigate the existence of possible moderating variables. The studies included in this systematic review were published between 2005 and May 2023. Only peer-reviewed studies, available in English, performed with humans that evaluated the effects of any form of exercise on leptin levels were included. The search was conducted on May 03, 2023, in Embase (Elsevier), MEDLINE via PubMed®, and Web of Science (Core collection). The risk of bias in the included trials was assessed by the Physiotherapy Evidence Database tool, considering 11 questions regarding the methodology of each study with 10 questions being scored. The data (n, mean, and standard deviation) were extracted from included studies to perform random effects meta-analyses using standardized mean difference between the pre- and post-intervention effects. Twenty-five studies (acute effect: 262 subjects; short- and long-term effect: 377 subjects) were included in this systematic review and meta-analysis. Short- and long-term physical exercise and caloric restriction plus exercise reduce plasma leptin levels, presenting statistically significant differences (p<0.001); as well as acute effect (p = 0.035), however the latter result was influenced by the pre-exercise meal as shown in the subgroup analysis. In this meta-analysis the effect of moderating factors on leptin reduction, not addressed by past reviews, is verified, such as the relationship with caloric restriction, exercise intensity and pre-exercise meal on acute responses. Both acute and chronic exercise reduce leptin levels, yet the acute effect is dependent on the pre-exercise meal. In addition to having a long-term reduction in leptin levels, the minimum amount of weekly exercise to have a significant reduction in plasma leptin is 180 minutes of moderate-intensity exercise and 120 minutes of high-intensity exercise.

The effect of curcumin supplementation on circulating adiponectin and leptin concentration in adults: a GRADE-assessed systematic review and meta-analysis of randomised controlled trials.

Curcumin is a phytocompound found in the root of turmeric, a common herbal ingredient in many Asian cuisines. The compound contains anti-inflammatory activity, which is mediated through an upregulation of adiponectin and reduction of leptin. Results of randomised controlled trials (RCT) have shown that the effects of curcumin on adipokines are conflicting. Therefore, the current systematic review and meta-analysis of RCT were conducted with the aim of elucidating the role of curcumin supplementation on serum adiponectin and leptin. The search included PubMed, Embase, Cochrane Library, Scopus, Web of Science and Google Scholar from inception to August 2023. For net changes in adipokines, standardised mean differences (SMD) were calculated using random effects models. Thirteen RCT with fourteen treatment arms were eligible for inclusion in this meta-analysis. Curcumin supplementation was effective in increasing serum adiponectin (SMD = 0·86, 95 % CI (0·33, 1·39), P < 0·001; I2 = 93·1 %, P < 0·001) and reducing serum leptin (SMD = -1·42, 95 % CI (-2·29, -0·54), P < 0·001; I2 = 94·7 %, P < 0·001). In conclusion, curcumin supplementation significantly increased circulating adiponectin and decreased leptin levels in adults.

Leptin Reduction as a Required Component for Weight Loss.

Partial leptin reduction can induce significant weight loss, while weight loss contributes to partial leptin reduction. The cause-and-effect relationship between leptin reduction and weight loss remains to be further elucidated. Here, we show that FGF21 and the GLP1R agonist liraglutide rapidly induce a reduction in leptin. This leptin reduction contributes to the beneficial effects of GLP1R agonism in metabolic health, as transgenically maintaining leptin levels during treatment partially curtails the beneficial effects seen with these agonists. Moreover, a higher degree of leptin reduction during treatment, induced by including a leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induces greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, upon cessation of either liraglutide or FGF21 treatment, the expected immediate weight regain is observed, associated with a rapid increase in circulating leptin levels. Prevention of this leptin surge with leptin neutralizing antibodies slows down weight gain and preserves a better glucose tolerance. Mechanistically, a significant reduction in leptin induces a higher degree of leptin sensitivity in hypothalamic neurons. Our observations support a model that postulates that a reduction of leptin levels is a necessary prerequisite for substantial weight loss and partial leptin reduction is a viable strategy to treat obesity and its associated insulin resistance.

Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study.

This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

Beneficial Short-Term Effects of Bariatric Surgery on Nutritional Inflammatory Profile and Metabolic Biomarkers.

Bariatric surgery (BS) has several potential metabolic benefits. However, little is known about its impact on changes in the inflammatory potential of diet and its effect on inflammatory and metabolic markers. This study aimed to assess the short-term beneficial effects of BS on dietary inflammatory potential and inflammatory and metabolic markers. Participants (n = 20) were evaluated 3 months before and after BS. Body mass, body mass index, anthropometric measurements, fat mass, fat-free mass, visceral fat, skeletal muscle mass, basal metabolic rate, serum lipids, HOMA-IR, QUICKI and inflammatory markers, including leptin, adiponectin, adiponectin/leptin ratio and plasminogen activator inhibitor-1 (PAI-1), were evaluated. Diet data were collected using a 3-day diet record and the dietary inflammatory index (DII®) and energy-adjusted dietary inflammatory index (E-DIITM) scores were computed. There was a reduction in DII® (2.56 vs 2.13) and E-DIITM (2.18 vs 0.45) indicating an improvement in inflammatory nutritional profile. Moreover, there were increases in the adiponectin/leptin ratio (0.08 vs 0.21) and QUICKI scores (0.31 vs 0.37), and reductions in leptin (36.66 vs 11.41 ng/ml) and HOMA-IR scores (3.93 vs 1.50). There were also improvements in body composition and anthropometric parameters. BS promotes changes in metabolic profile, inflammatory state and food intake and these modifications appeared to be associated with improvements in diet-related inflammation, an increase in the adiponectin/leptin ratio and a reduction in leptin. These results contribute to knowledge on the contribution bariatric surgery can make to the treatment of obesity and the reduction of related comorbidities.

212-OR: Leptin Reduction as a Required Component for Weight Loss

A significant reduction in circulating leptin levels is well corelated with substantial weight loss. However, it is still not clear whether the observed leptin reduction is a cause or consequence of weight reduction. Here, we showed that FGF21 and liraglutide could rapidly induce leptin reduction, and this reduction contributes to the beneficial effects of FGF21 and liraglutide, as blocking the leptin reduction by a transgenic approach curtails the beneficial effects. Moreover, a higher degree of leptin reduction, induced by combination of leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induced greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, after removing liraglutide and FGF21, a significant weight gain is associated with rapid increase in circulating leptin levels and prevention of leptin surge by leptin neutralizing antibody slows down weight gain and preserves a better glucose tolerance. Mechanically, a significant reduction in leptin reduction induces a higher degree of leptin sensitivity in neurons, located in hypothalamic region, other than AP. In conclusion, this study supports a model that leptin reduction is required for substantial weight loss and partial leptin reduction may be a novel strategy to treat obesity and its associated metabolic syndromes. Disclosure S.Zhao: None. P.E.Scherer: None.

Estimation of Serum Leptin, Adiponectin, and Malondialdehyde Levels in Tobacco-Induced Oral Squamous Cell Carcinoma: ELISA-Based Study

Background Tobacco, a harmful, addictive chemical is responsible for occurrence of oral cancer by triggering inflammation and lipid peroxidation. The aim of the present study is to explore if there exists any difference in serum levels of inflammatory biomarkers such as leptin, adiponectin, and lipid peroxidation marker malondialdehyde (MDA) and also its correlation with oxidative stress in cases of tobacco-induced oral squamous cell carcinoma (OSCC) as compared with tobacco users having no lesion. Materials and Methods Enrolled participants in this study included a total of 84 subjects (all males and 28 in each group) inclusive of healthy individuals, tobacco users with no lesion, and oral cancer cases. Serum leptin, adiponectin, and MDA levels were measured via enzyme-linked immunosorbent assay method in all subjects. Results A significant reduction in serum leptin and adiponectin levels in patients with OSCC was observed when compared with tobacco users with no lesions and healthy persons (control). For serum MDA, findings were comparable in control and tobacco consumers with no lesions groups but significantly higher in OSCC cases. The correlation between serum adiponectin, leptin, and MDA levels with body mass index (BMI) was highly significant. In addition, comparison of BMI with serum markers and histopathological grades of OSCC showed significant difference. Conclusion These present study observations suggest that reduced adiponectin and leptin and elevated serum MDA could serve as valuable markers for both preventive and clinical intervention, and may deserve further investigation for the early diagnosis, treatment, and prognosis of OSCC.

"Decreased-Ghrelin Mechanism by Camellia Sinensis Product Mediated Appetite Suppression, Weight Modulation and Leptin Reduction"

"Decreased-Ghrelin Mechanism by Camellia Sinensis Product Mediated Appetite Suppression, Weight Modulation and Leptin Reduction"

0002 Impact of Acute, Isocaloric Time-Restricted Eating on Resting Metabolic Rate and Obesogenic Factors in Healthy Lean Adults

Abstract Introduction Time-restricted eating (TRE) is a dietary strategy in which energy is consumed over a 6-10h window during the day and is associated with reduced energy intake and subsequent weight loss in people with obesity. However, the impact of isocaloric TRE on obesogenic factors such as hormones related to hunger and appetite, as well as energy expenditure and metabolic rate is relatively unknown. We therefore investigated the impact of 1 week of isocaloric TRE on obesity-related outcomes including circulating leptin, ghrelin, and peptide YY (PYY) and resting metabolic rate (RMR). Methods Thirteen healthy adults (8F, 26.9±3.9y, 23.3±2.1kg/m2) participated in a 2-week protocol. During Week 1, energy was consumed over a 13h period with meals individually anchored to habitual wake time and consumed at +1h, +6h, +11h and +14h after wake. For Week 2, participants were instructed to match energy intake from Week 1 but restrict intake to an 8h period (meals at +1h, +5h, and +9h after wake). At the end of each week, participants were admitted to the laboratory for an overnight stay. Blood samples were collected hourly overnight and assayed for leptin, ghrelin, and PYY. RMR was assessed using hood calorimetry immediately after wake. Results TRE was associated with a significant reduction in circulating leptin levels (p&amp;lt; 0.001) without changes in body weight (p=0.536), PYY or ghrelin levels. The respiratory exchange ratio (RER) calculated from hood calorimetry was significantly lower during TRE (0.76 vs 0.81; p=0.04) despite no change in energy expenditure (p=0.478) suggesting a higher reliance on fat oxidation during TRE compared with habitual eating. Conclusion Reductions in leptin in conjunction with lower RER suggests that TRE promotes increased fat utilization as compared with habitual eating. Future studies should evaluate whether long-term isocaloric TRE is associated with reduced adipose tissue mass. Support (if any) This project was supported by R01DK125653.

Sex-Specific Effects of the Genetic Variant rs10487505 Upstream of leptin in the Development of Obesity.

The SNP rs10487505 in the promotor region of the leptin gene was reported to be associated with decreased circulating leptin and increased body mass index (BMI). However, the phenotypic outcomes affected by rs10487505 in the leptin regulatory pathway have not been systematically studied. Therefore, the aim of this study was to elucidate the influence of rs10487505 on leptin mRNA expression and obesity-related parameters. We genotyped rs10487505 in DNA samples from 1665 patients with obesity and lean controls and measured leptin gene expression in paired samples of adipose tissue (AT, N = 310), as well as circulating leptin levels. We confirm the leptin-lowering effect of rs10487505 in women. In contrast to the previously reported data from population-based studies, in this mainly obese cohort, we describe a lower mean BMI in women carrying the C allele of rs10487505. However, no association of rs10487505 with AT leptin mRNA expression was found. Our data suggest that reduced circulating leptin levels are not a result of the direct silencing of leptin mRNA expression. Furthermore, leptin reduction by rs10487505 does not associate with BMI in a linear manner. Instead, the decreasing effect on BMI might be dependent on the severity of obesity.

OR10-2 Hormonal and Cardiometabolic Changes Associated with Diazoxide Choline Extended-Release (DCCR) Tablets in Patients with Prader-Willi Syndrome

Abstract Background Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental condition, characterized by hyperphagia, obesity, hormone deficiencies and behavioral/psychological manifestations. DCCR is under investigation as a treatment for hyperphagia in PWS through its actions on hypothalamic circuits involved in appetite regulation including NPY neurons and central inhibition of DMV neurons to improve insulin sensitivity. In addition to these effects, DCCR acts on pancreatic beta cells, to reduce glucose stimulated insulin secretion, which might have additional effects to reduce fat deposition in adipocytes, serum leptin concentrations and insulin resistance. Objectives and methods This analysis characterized changes in hormonal and cardiometabolic parameters in patients with PWS receiving oral daily DCCR. 125 participants with genetically-confirmed PWS ≥4 years old with hyperphagia were treated with DCCR in multi-center studies conducted at 29 sites in the US and the UK: a 13-week, Phase 3, double-blind, placebo-controlled study (DESTINY PWS) and its long-term, open-label extension study (analysis at 52 weeks). The target DCCR dose for these studies was ≥3.3 mg/kg with an optimal dose of 4.2 - 5.8 mg/kg. Overall, 103 patients received DCCR (100-525 mg/day) for 52 weeks. For all parameters, the baseline measurement was defined as (immediately prior to) start of DCCR treatment. Results Serum leptin, insulin, and HOMA-IR were significantly reduced following 52 weeks of DCCR administration. Results are expressed as Least square (LS) mean change from baseline [Standard Error (SE)]. There were significant decreases in: Leptin (ng/mL) = -11.08[1.26], p&amp;lt;0.001; Insulin (μIU/mL) = -2.5[0.69], p&amp;lt;0.001; and HOMA-IR = -0.5 [0.17], p=0.003. Serum adiponectin (µg/mL) was significantly increased: 1.82[0.41], p &amp;lt; 0.001. Fat mass measured by DXA was stable at 52 weeks. Conclusions The reductions in fasting leptin, insulin and HOMA-IR, and the increase in adiponectin with prolonged DCCR treatment in the absence of reductions in total body fat are consistent with improved insulin sensitivity that may also reflect improvement in leptin sensitivity and healthier body fat distribution, such as reduced visceral adiposity. This could result from both direct pancreatic and hypothalamus-to-periphery actions of DCCR. It remains to be determined if such beneficial metabolic changes also result in reduced systemic inflammation and cardiovascular health. DCCR administration was associated with significant reductions in leptin, insulin, and HOMA-IR, increases in adiponectin and stabilization of body fat. These and other changes in cardiometabolic parameters suggest that DCCR may have long term health benefit in patients with PWS. Presentation: Sunday, June 12, 2022 11:15 a.m. - 11:30 a.m.

PSUN48 Serum leptin levels among chronic kidney diseased subjects with hypertensive heart disease: An observational cross-sectional study

Abstract Background Chronic kidney disease (CKD) is one of the main health concerns in Sub-Saharan Africa. Leptin, a peptide hormone produced by the adipocytes have been observed to trigger complications such as cardiovascular diseases with significant mortality. The precise role of leptin in hypertension-mediated development of CKD is unknown. Research findings in this area have been inconsistent. The aim of the study was to evaluate serum leptin levels among CKD patients attending a tertiary referral hospital. Methodology An observational cross-sectional study. One hundred and eight (108) participants took part in the study. A structured questionnaire was used to gather their anthropometric and demographic characteristics. Blood samples were obtained and analyzed for leptin and other biochemical parameters. Results There were significant differences in the plasma levels of leptin, glucose (FBG), creatinine and triglyceride among CKD subjects compared with controls (p &amp;lt;0.05 respectively). An inverse correlation was found for leptin vs estimated GFR (r = -0.505, p= 0.0001) among CKD subjects. In the CKD group, being at stage 5 made the largest unique contribution (beta = 0.47, p &amp;lt; 0.0001) to the variance in serum leptin levels, followed by HDL, FBG, HHD diagnosis of more than 6 years, female gender and BMI respectively (p&amp;lt; 0.05). In the control group, female gender made the largest unique contribution to circulating leptin levels (beta = 0.709, p &amp;lt; 0.0001) followed by BMI (beta = 0.341, p &amp;lt; 0.0001), and eGFR (beta = -0.222, p = 0.011). Conclusion Serum leptin levels were significantly higher among CKD subjects co-burdened with hypertension heart disease in Accra. Stage 5 CKD was the most significant predictor of serum leptin levels. These findings underscore the role of leptin in the biochemical complexities observed in CKD subjects. Therapeutic strategies targeting leptin reduction are welcomed in the management of CKD. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

The rheumatoid arthritis drug auranofin lowers leptin levels and exerts antidiabetic effects in obese mice

Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and coincides with type 2 diabetes mellitus (T2DM). However, pharmacological targeting of inflammation lacks durable therapeutic effects in insulin-resistant conditions. Through a computational screen, we discovered that the FDA-approved rheumatoid arthritis drug auranofin improved insulin sensitivity and normalized obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia in mouse models of T2DM. We also discovered that auranofin accumulation in WAT depleted inflammatory responses to a high-fat diet without altering body composition in obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved by leptin receptor deletion abolished the antidiabetic effects of auranofin. These experiments also revealed that the metabolic benefits of leptin reduction were superior to immune impacts of auranofin in WAT. Our studies uncover important metabolic properties of anti-inflammatory treatments and contribute to the notion that leptin reduction in the periphery can be accomplished to treat obesity and T2DM.