Elevated Leptin Research Articles

Cucumeropsis mannii seed oil ameliorates Bisphenol-A-induced adipokines dysfunctions and dyslipidemia.

This study demonstrated the therapeutic potentials of Cucumeropsis mannii seed oil (CMSO) capable of alleviating BPA-induced dyslipidemia and adipokine dysfunction. In this study, we evaluated the effects of CMSO on adipokine dysfunctions and dyslipidemia in bisphenol-A (BPA)-induced male Wistar rats. Six-week-old 36 albino rats of 100-200 g weight were assigned randomly to six groups, which received varied doses of BPA and/or CMSO. The administration of BPA and CMSO was done at the same time for 42 days by oral intubation. The adipokine levels and lipid profile were measured in adipose tissue and plasma using standard methods. BPA induced significant (p < .05) increases in triglycerides, cholesterol, leptin, LDL-C, and atherogenic and coronary risk indices in adipose tissue and plasma, as well as a decrease in adiponectin and HDL-C levels in Group II animals. BPA administration significantly (p < .05) elevated Leptin levels and reduced adiponectin levels. BPA plus CMSO reduced triglycerides, cholesterol, leptin, LDL-C, and atherogenic and coronary risk indices while increasing adiponectin levels and HDL-C in adipose tissue and plasma (p < .05). The results showed that BPA exposure increased adipose tissue as well as serum levels of the atherogenic index, triglycerides, cholesterol, coronary risk index, LDL-C, leptin, and body weight with decreased adiponectin levels and HDL-C. Treatment with CMSO reduced the toxicities caused by BPA in rats by modulating the body weight, adiponectin/leptin levels, and lipid profiles in serum and adipose tissue. This study has shown that CMSO ameliorates BPA-induced dyslipidemia and adipokine dysfunctions. We suggest for further clinical trial to establish the clinical applications.

Mathematical Modelling of Leptin-Induced Effects on Electrophysiological Properties of Rat Cardiomyocytes and Cardiac Arrhythmias

Elevated plasma leptin levels, or hyperleptinemia, have been demonstrated to correlate with metabolic syndrome markers, including obesity, and may be an independent risk factor for the development of cardiovascular disease. In this paper, we use cardiac models to study possible effects of hyperleptinemia on the electrophysiological properties of cardiomyocytes and cardiac arrhythmias. We modified the parameters of an improved Gattoni 2016 model of rat ventricular cardiomyocytes to simulate experimental data for the leptin effects on ionic currents. We used four model variants to investigate the effects of leptin-induced parameter modification at the cellular level and in 2D tissue. In all models, leptin was found to increase the duration of the action potential. In some cases, we observed a dramatic change in the shape of the action potential from triangular, characteristic of rat cardiomyocytes, to a spike-and-dome, indicating predisposition to arrhythmias. In all 2D tissue models, leptin increased the period of cardiac arrhythmia caused by a spiral wave and enhanced dynamic instability, manifesting as increased meandering, onset of hypermeandering, and even spiral wave breakup. The leptin-modified cellular models developed can be used in subsequent research in rat heart anatomy models.

Sex-specific effects of calving season on joint health and biomarkers in Montana ranchers

BackgroundAgricultural workers have a higher incidence of osteoarthritis (OA), but the etiology behind this phenomenon is unclear. Calving season, which occurs in mid- to late-winter for ranchers, includes physical conditions that may elevate OA risk. Our primary aim was to determine whether OA biomarkers are elevated at the peak of calving season compared to pre-season, and to compare these data with joint health survey information from the subjects. Our secondary aim was to detect biomarker differences between male and female ranchers.MethodsDuring collection periods before and during calving season, male (n = 28) and female (n = 10) ranchers completed joint health surveys and provided samples of blood, urine, and saliva for biomarker analysis. Statistical analyses examined associations between mean biomarker levels and survey predictors. Ensemble cluster analysis identified groups having unique biomarker profiles.ResultsThe number of calvings performed by each rancher positively correlated with plasma IL-6, serum hyaluronic acid (HA) and urinary CTX-I. Thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress, was significantly higher during calving season than pre-season and was also correlated with ranchers having more months per year of joint pain. We found evidence of sexual dimorphism in the biomarkers among the ranchers, with leptin being elevated and matrix metalloproteinase-3 diminished in female ranchers. The opposite was detected in males. WOMAC score was positively associated with multiple biomarkers: IL-6, IL-2, HA, leptin, C2C, asymmetric dimethylarginine, and CTX-I. These biomarkers represent enzymatic degradation, inflammation, products of joint destruction, and OA severity.ConclusionsThe positive association between number of calvings performed by each rancher (workload) and both inflammatory and joint tissue catabolism biomarkers establishes that calving season is a risk factor for OA in Montana ranchers. Consistent with the literature, we found important sex differences in OA biomarkers, with female ranchers showing elevated leptin, whereas males showed elevated MMP-3.

Serum Adiponectin and Leptin Among Ghanaian Migrants in Amsterdam and Their Compatriots in Rural and Urban Ghana: The RODAM Study.

The rapidly rising cardiometabolic disease (CMD) burden in urbanizing sub-Saharan African populations and among sub-Saharan African migrants in Europe likely affects serum adiponectin and leptin levels, but this has not yet been quantified. To compare the serum levels of adiponectin and leptin among migrant, and non-migrant (urban and rural) populations of Ghanaian descent. Cross-sectional analysis of serum leptin and adiponectin in the multi-centre Research on Obesity and Diabetes among African Migrants (RODAM) study. Logistic-regression models were used to examine the association between these adipocyte-derived hormones after stratification (sex, geographic area) and adjustments for potential confounders. A total of 2518 Ghanaians were included. Rural participants had the highest serum adiponectin and lowest leptin levels compared to Amsterdam and urban Ghanaians (P < .001). In fully adjusted models, participants living in urban Ghana had significantly higher odds of hyperleptinemia compared to rural participants (women-odds ratio 2.88; 95% CI, 1.12-7.38, P = .028 and men 43.52, 95% CI, 4.84-391.25, P < .001). Urban Ghanaian men also had higher odds of elevated leptin: adiponectin ratio (6.29, 95% CI, 1.43-27.62, P = .015). The odds of hyperleptinemia were only higher in Amsterdam Ghanaian men (10.56; 95% CI, 1.11-100.85, P = .041), but not in women (0.85; 95% CI, 0.30-2.41, P = .759). There was no significant association between hypoadiponectinemia and geographical location in both sexes. Urbanization is associated with serum adiponectin and leptin levels after adjusting for confounding covariates in sub-Saharan Africans. These findings serve as a backdrop for further research on the role adipokines play in CMD epidemiology among Africans.

Elevated serum leptin levels are associated with lower renal function among middle-aged and elderly adults in Taiwan, a community-based, cross-sectional study.

Plasma leptin is considered a risk factor for obesity and cardio-metabolic disease, but the link between serum leptin and renal function is still under evaluation. In our study, we focused on the relationship between serum leptin and renal function, and we investigated the relationship in more detail. The 396 middle-aged and elderly Taiwanese adults recruited for our health survey were the subject of our research. All participants agreed to participate and signed a consent form before they joined and completed our study. We divided the participants into three groups according to eGFR tertiles and analyzed the parameters between each group. Then, we used Pearson's correlation test to investigate the relationship between eGFR levels and cardio-metabolic risk factors with adjustment for age. The scatter plot indicates the trend between serum leptin levels and eGFR levels. Participants were reclassified into three subgroups according to their leptin levels and the bar chart reveals the prevalence of chronic kidney disease (CKD) in each group. Finally, we used multivariate linear regression to evaluate the relationship between serum leptin and eGFR levels with adjustment for age, sex, smoking status, drinking status, body mass index (BMI), uric acid levels, hypertension (HTN), diabetes mellitus (DM), and dyslipidemia. In our study, we analyzed the data from 396 eligible participants. A total of 41.4% of the participants were male, and the average age of all participants was 64.81 years ( ± 8.78). The participants in the high eGFR group were more likely to have lower serum leptin levels. Furthermore, eGFR values were negatively correlated with serum leptin levels even after adjustment for age. The prevalence of CKD in the high serum leptin group was higher than that in the low serum leptin group. Serum leptin levels showed significant negative correlations with eGFR levels (β=-0.14, p<0.01) in the multivariate linear regression after adjusting for age, sex, smoking status, drinking status, BMI, uric acid levels, HTN, DM, and dyslipidemia. According to our study, serum leptin levels show a negative relationship with eGFR levels in middle-aged and elderly people in Taiwan. In addition, high serum leptin levels could be an novel marker to survey kidney failure in clinical practices.

Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population

Type 2 diabetes (T2D) has a heterogeneous etiology influencing its progression, treatment, and complications. A data driven cluster analysis in European individuals with T2D previously identified four subtypes: severe insulin deficient (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) diabetes. Here, the clustering approach was applied to individuals with T2D from the Qatar Biobank and validated in an independent set. Cluster-specific signatures of circulating metabolites and proteins were established, revealing subtype-specific molecular mechanisms, including activation of the complement system with features of autoimmune diabetes and reduced 1,5-anhydroglucitol in SIDD, impaired insulin signaling in SIRD, and elevated leptin and fatty acid binding protein levels in MOD. The MARD cluster was the healthiest with metabolomic and proteomic profiles most similar to the controls. We have translated the T2D subtypes to an Arab population and identified distinct molecular signatures to further our understanding of the etiology of these subtypes.

A comparative study of Western, high-carbohydrate, and standard lab diet consumption throughout adolescence on metabolic and anxiety-related outcomes in young adult male and female Long-Evans rats

Anxiety and obesity are prevalent health concerns that are affected by diet in rodents and humans. How diet influences the development and maintenance of anxiety and obesity has been challenging to characterize, in part, due to methodological differences in chosen experimental and control diets. Within the same experiment, anxiety- and obesity-related effects were characterized in rats fed a Western diet (WD) relative to two control diets. Sixty Long-Evans rats split equally by sex were given standard diet (SD), control (i.e., high-carbohydrate) diet (HCD), or WD from weaning until sacrifice in early adulthood. Anxiety-related behavior was characterized in a modified open field test (mOFT) that allowed for the measurement of defensive behaviors (e.g., hiding within a refuge area), in addition to traditional OF measures (e.g., time in center). Both anxiety-related behaviors and hippocampal CA3 BDNF revealed specific sex differences. Neither adolescent weight gain of male and female rats, nor total body weight in early adulthood, were dependent on administration of HCD or WD, although the WD group consumed the most calories. In males only, administration of either WD or HCD resulted in elevated leptin levels relative to administration of the SD. Results indicate that SDs and HCDs are two distinct types of control diets that can affect comparability of studies and that using an SD might reveal more subtle metabolic changes. Control diet choice should be strongly considered during study design and interpretation, depending on specific research goals. Such studies should include both males and females as these effects are sex-specific.

Proteomic Profiling of Extracellular Vesicles Released by Leptin-Treated Breast Cancer Cells: A Potential Role in Cancer Metabolism.

Tumor extracellular vesicles (EVs), as endocytic vesicles able to transport nucleic acids, proteins, and metabolites in recipient cells, have been recognized fundamental mediators of cell-to-cell communication in breast cancer. The biogenesis and release of EVs are highly regulated processes and both the quantity of EVs and their molecular cargo might reflect the metabolic state of the producing cells. We recently demonstrated that the adipokine leptin, whose circulating levels correlate with adipose tissue expansion, is an inducer of EV release from breast cancer cells. Here, we show a specific proteomic signature of EVs released by MCF-7 breast cancer cells grown in the presence of leptin (Lep-EVs), in attempt to find additional molecular effectors linking obesity to breast cancer biology. An analysis of the proteomic profile of Lep-EVs by LC-MS/MS revealed a significant enrichment in biological processes, molecular functions, and cellular components mainly related to mitochondrial machineries and activity, compared to protein content of EVs from untreated breast cancer cells. Metabolic investigations, carried out to assess the autocrine effects of these vesicles on breast cancer cells, revealed that Lep-EVs were able to increase ATP levels in breast cancer cells. This result is associated with increased mitochondrial respiration evaluated by Seahorse analyzer, supporting the concept that Lep-EVs can modulate MCF-7 breast cancer cell oxidative metabolism. Moreover, taking into account the relevance of tumor immune cell crosstalk in the tumor microenvironment (TME), we analyzed the impact of these vesicles on macrophage polarization, the most abundant immune component in the breast TME. We found that tumor-derived Lep-EVs sustain the polarization of M0 macrophages, derived from the human THP-1 monocytic cells, into M2-like tumor-associated macrophages, in terms of metabolic features, phagocytic activity, and increased expression of CD206-positive population. Overall, our results indicate that leptin by inducing the release of EV-enriched in mitochondrial proteins may control the metabolism of MCF-7 breast cancer cells as well as that of macrophages. Characterization of tumor-derived EV protein cargo in an obesity-associated milieu, such as in the presence of elevated leptin levels, might allow identifying unique features and specific metabolic mechanisms useful to develop novel therapeutic approaches for treatment of breast cancer, especially in obese patients.

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.

Are we approaching a holistic view of leptin's role in arthritis?

Adipokines—in particular, leptin, the forerunner of this superfamily—are receiving increasing attention for their role in exerting both beneficial and harmful actions in musculoskeletal inflammatory diseases. Leptin has been extensively associated with cartilage metabolism and OA. OA human chondrocytes have been shown to produce higher levels of leptin than normal cartilage1, with the pattern of leptin expression related to the level of cartilage destruction2,3. Moreover, elevated leptin levels have been found in serum, IPFP, synovial tissues, and cartilage of OA patients compared with healthy controls4,5.

Serum leptin level as a cardiovascular risk factor in type 2 diabetic patients

Type 2 diabetes mellitus ( T2DM ) is a metabolic disease that is associated with an increased risk for atherosclerosis. Leptin is a hormone – like cytokine that is derived mainly from adipose tissue and has multiple functions. Recently, many vascular and atherogenic effects for leptin have been demonstrated. The aim was to study serum leptin level and its relationship with some cardiovascular risk factors in T2DM patients. Forty diabetic males with ischemic heart disease (IHD group), aged ≥ 40 years old, were compared with 40 diabetic males of similar ages who had no clinical history of IHD (DM group). Each main study group was divided into two subgroups according to the presence or absence of metabolic syndrome. The IHD group was also subdivided according to their clinical endpoints into stable angina pectoris (angina group), significant coronary artery disease on angiography (angiography group ) and myocardial infarction (MI group ). In addition to anthropometric measurements; serum lipid profile, thiobarbituric acid -reactive substances (TBARS) and leptin levels as well as plasma fibrinogen level were quantified .A highly significant increase of mean serum leptin level was observed in IHD group iin comparriison wiitth tthatt off DM grroup (11.56  10.27 vs. 7.39  3.54 ng /3ml, p&lt;0.01). IIHD pattiientts showed a hiighlly siigniiffiicantt iincrrease iin serrum llevell offTBARS iin comparriison wiitth tthatt off DM grroup ((9.00  3.61vs. 6.65  2.41 mol (MDA)/L, P&lt;0.001). The mean plasma level of fibrinogen is significantly higher in IHD group than in DM group (3.30  0.65 vs. 2.99  0.63 g/dl, p &lt; 0.05). Serum leptin level was significantly higher in (angiography group) but not in (angina group) while the level was even lower in (MI group) when compared with that of DM group. A significant increase of mean serum leptin level was observed in IHD subgroup with non-metabolic syndrome in comparison with the D.M subgroup with non-metabolic syndrome (13.06  11.01 vs. 7.06  3.08 ng/ml, P&lt;0.05). In IHD group, serum leptin level showed a positive correlation with BMI ,W/h ratio, serum TBARS, and plasma fibrinogen. In DM group, serum leptin level showed a positive correlation with BMI, W/h ratio, and plasma fibrinogen, while insignificantly correlated with TBARS. In conclusion, T2DM patients with IHD have an elevated serum leptin level that is associated with oxidative stress, inflammation and active or worsening ischemic heart disease independent of metabolic syndrome. Thus, serum leptin level could be an additional factor to assess cardiovascular risk

Paeoniflorin Ameliorates Colonic Fibrosis in Rats with Postinfectious Irritable Bowel Syndrome by Inhibiting the Leptin/LepRb Pathway.

Postinfectious irritable bowel syndrome (PI-IBS) is a highly prevalent gastrointestinal disorder associated with immune dysregulation and depression- and anxiety-like behaviors. Through traditional medicine, the active ingredient of Paeoniae Radix called paeoniflorin (PF) was previously found to prevent the symptoms of PI-IBS. However, there is limited information on the effects of PF on intestinal function and depression- and anxiety-like symptoms in PI-IBS animal models. Here, we aimed to determine the effects of PF treatment on the symptoms of PI-IBS in a rat model. The PI-IBS rat model was established via early postnatal sibling deprivation (EPSD), trinitrobenzenesulfonic acid (TNBS), and chronic unpredictable mild stress (CUMS) stimulation and then treated with different dosages of PF (10, 20, and 40 mg/kg) and leptin (1 and 10 mg/kg). The fecal water content and body weight were measured to evaluate the intestinal function, while the two-bottle test for sucrose intake, open field test (OFT), and elevated plus maze test (EMT) were performed to assess behavioral changes. The serum leptin levels were also measured using an enzyme-linked immunosorbent assay. Furthermore, the expressions of leptin and its receptor, LepRb, were detected in colonic mucosal tissues through an immunohistochemical assay. The activation of the PI3K/AKT signaling pathway and the expression of brain-derived neurotrophic factor (BDNF) were also detected via western blotting. After the experimental period, the PI-IBS rats presented decreased body weight and increased fecal water content, which coincided with elevated leptin levels and heightened depression- and anxiety-like behaviors (e.g., low sucrose intake, less frequency in the center areas during OFT, and fewer activities in the open arms during EMT). However, the PF treatment ameliorated these observed symptoms. Furthermore, PF not only inhibited leptin/LepRb expression but also reduced the PI3K/AKT phosphorylation and BDNF expression in PI-IBS rats. Notably, cotreatment with leptin (10 mg/kg) reduced the effects of PF (20 mg/kg) on colonic fibrosis, leptin/LepRb expression, and PI3K/AKT activation. Therefore, our findings suggest that leptin is targeted by PF via the leptin/LepRb pathway, consequently ameliorating the symptoms of PI-IBS. Our study also contributes novel insights for elucidating the pharmacological action of PF on gastrointestinal disorders and may be used for the clinical treatment of PI-IBS in the future.

Developmental exposure to indoor flame retardants and hypothalamic molecular signatures: Sex-dependent reprogramming of lipid homeostasis.

Polybrominated diphenyl ethers (PBDEs) are a class of flame-retardant organohalogen pollutants that act as endocrine/neuroendocrine disrupting chemicals (EDCs). In humans, exposure to brominated flame retardants (BFR) or other environmentally persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and novel organophosphate flame retardants has been associated with increasing trends of diabetes and metabolic disease. However, the effects of PBDEs on metabolic processes and their associated sex-dependent features are poorly understood. The metabolic-disrupting effects of perinatal exposure to industrial penta-PBDE mixture, DE-71, on male and female progeny of C57BL/6N mouse dams were examined in adulthood. Dams were exposed to environmentally relevant doses of PBDEs daily for 10 weeks (p.o.): 0.1 (L-DE-71) and 0.4 mg/kg/d (H-DE-71) and offspring parameters were compared to corn oil vehicle controls (VEH/CON). The following lipid metabolism indices were measured: plasma cholesterol, triglycerides, adiponectin, leptin, and liver lipids. L-DE-71 female offspring were particularly affected, showing hypercholesterolemia, elevated liver lipids and fasting plasma leptin as compared to same-sex VEH/CON, while L- and H-DE-71 male F1 only showed reduced plasma adiponectin. Using the quantitative Folch method, we found that mean liver lipid content was significantly elevated in L-DE-71 female offspring compared to controls. Oil Red O staining revealed fatty liver in female offspring and dams. General measures of adiposity, body weight, white and brown adipose tissue (BAT), and lean and fat mass were weighed or measured using EchoMRI. DE-71 did not produce abnormal adiposity, but decreased BAT depots in L-DE-71 females and males relative to same-sex VEH/CON. To begin to address potential central mechanisms of deregulated lipid metabolism, we used RT-qPCR to quantitate expression of hypothalamic genes in energy-regulating circuits that control lipid homeostasis. Both doses of DE-71 sex-dependently downregulated hypothalamic expression of Lepr, Stat3, Mc4r, Agrp, Gshr in female offspring while H-DE-71 downregulated Npy in exposed females relative to VEH/CON. In contrast, exposed male offspring displayed upregulated Stat3 and Mc4r. Intestinal barrier integrity was measured using FITC-dextran since it can lead to systemic inflammation that leads to liver damage and metabolic disease, but was not affected by DE-71 exposure. These findings indicate that maternal transfer of PBDEs disproportionately endangers female offspring to lipid metabolic reprogramming that may exaggerate risk for adult metabolic disease.

Nuclear receptor ligand screening in an iPSC-derived in vitro blood–brain barrier model identifies new contributors to leptin transport

BackgroundThe hormone leptin exerts its function in the brain to reduce food intake and increase energy expenditure to prevent obesity. However, most obese subjects reflect the resistance to leptin even with elevated serum leptin. Considering that leptin must cross the blood–brain barrier (BBB) in several regions to enter the brain parenchyma, altered leptin transport through the BBB might play an important role in leptin resistance and other biological conditions. Here, we report the use of a human induced pluripotent stem cell (iPSC)-derived BBB model to explore mechanisms that influence leptin transport.MethodsiPSCs were differentiated into brain microvascular endothelial cell (BMEC)-like cells using standard methods. BMEC-like cells were cultured in Transwell filters, treated with ligands from a nuclear receptor agonist library, and assayed for leptin transport using an enzyme-linked immune sorbent assay. RNA sequencing was further used to identify differentially regulated genes and pathways. The role of a select hit in leptin transport was tested with the competitive substrate assay and after gene knockdown using CRISPR techniques.ResultsFollowing a screen of 73 compounds, 17β-estradiol was identified as a compound that could significantly increase leptin transport. RNA sequencing revealed many differentially expressed transmembrane transporters after 17β-estradiol treatment. Of these, cationic amino acid transporter-1 (CAT-1, encoded by SLC7A1) was selected for follow-up analyses due to its high and selective expression in BMECs in vivo. Treatment of BMEC-like cells with CAT-1 substrates, as well as knockdown of CAT-1 expression via CRISPR-mediated epigenome editing, yielded significant increases in leptin transport.ConclusionsA major female sex hormone, as well as an amino acid transporter, were revealed as regulators of leptin BBB transport in the iPSC-derived BBB model. Outcomes from this work provide insights into regulation of hormone transport across the BBB.

Female and male C57BL/6J offspring exposed to maternal obesogenic diet develop altered hypothalamic energy metabolism in adulthood.

Maternal obesity is exceedingly common and strongly linked to offspring obesity and metabolic disease. Hypothalamic function is critical to obesity development. Hypothalamic mechanisms causing obesity following exposure to maternal obesity have not been elucidated. Therefore, we studied a cohort of C57BL/6J dams, treated with a control or high-fat-high-sugar diet, and their adult offspring to explore potential hypothalamic mechanisms to explain the link between maternal and offspring obesity. Dams treated with obesogenic diet were heavier with mild insulin resistance, which is reflective of the most common metabolic disease in pregnancy. Adult offspring exposed to maternal obesogenic diet had no change in body weight but significant increase in fat mass, decreased glucose tolerance, decreased insulin sensitivity, elevated plasma leptin, and elevated plasma thyroid-stimulating hormone. In addition, offspring exposed to maternal obesity had decreased energy intake and activity without change in basal metabolic rate. Hypothalamic neurochemical profile and transcriptome demonstrated decreased neuronal activity and inhibition of oxidative phosphorylation. Collectively, these results indicate that maternal obesity without diabetes is associated with adiposity and decreased hypothalamic energy production in offspring. We hypothesize that altered hypothalamic function significantly contributes to obesity development. Future studies focused on neuroprotective strategies aimed to improve hypothalamic function may decrease obesity development.NEW & NOTEWORTHY Offspring exposed to maternal diet-induced obesity demonstrate a phenotype consistent with energy excess. Contrary to previous studies, the observed energy phenotype was not associated with hyperphagia or decreased basal metabolic rate but rather decreased hypothalamic neuronal activity and energy production. This was supported by neurochemical changes in the hypothalamus as well as inhibition of hypothalamic oxidative phosphorylation pathway. These results highlight the potential for neuroprotective interventions in the prevention of obesity with fetal origins.

Impact of Leptin on the Expression Profile of Macrophages during Mechanical Strain In Vitro.

Childhood obesity is a growing problem in industrial societies and associated with increased leptin levels in serum and salvia. Orthodontic treatment provokes pressure and tension zones within the periodontal ligament, where, in addition to fibroblasts, macrophages are exposed to these mechanical loadings. Given the increasing number of orthodontic patients with these conditions, insights into the effects of elevated leptin levels on the expression profile of macrophages during mechanical strain are of clinical interest. Therefore, the aim of this in vitro study was to assess the influence of leptin on the expression profile of macrophages during simulated orthodontic treatment. RAW264.7 macrophages were incubated with leptin and lipopolysaccharides (LPS) from Porphyromonas gingivalis (P. gingivalis) or with leptin and different types of mechanical strain (tensile, compressive strain). Expression of inflammatory mediators including tumor necrosis factor (TNF), Interleukin-1-B (IL1B), IL6, and prostaglandin endoperoxide synthase (PTGS2) was assessed by RT-qPCR, ELISAs, and immunoblot. Without additional mechanical loading, leptin increased Tnf, Il1b, Il6, and Ptgs2 mRNA in RAW264.7 macrophages by itself and after stimulation with LPS. However, in combination with tensile or compressive strain, leptin reduced the expression and secretion of these inflammatory factors. By itself and in combination with LPS from P. gingivalis, leptin has a pro-inflammatory effect. Both tensile and compressive strain lead to increased expression of inflammatory genes. In contrast to its effect under control conditions or after LPS treatment, leptin showed an anti-inflammatory phenotype after mechanical stress.

Comparison of anthropometric, BIA measures and serum leptin with genotypes of Q223R leptin receptor single nucleotide polymorphism and association with obesity and serum leptin

BackgroundLiterature provides evidence for the association of Q223R Leptin Receptor Single Nucleotide Polymorphism (LEPR SNP) with obesity. Genetics in the development of obesity is hardly studied in Sri Lanka. Aim of the studyThe aim of the present study was to compare measures of body composition assessed by anthropometric and bio-impedance analysis (BIA) methods and selected biochemical parameters between individuals with the 3 genotypes of Q223R polymorphism; (QQ-Homozygous Q allele, QR-heterozygous, RR-homozygous R allele) and the association of Q223R polymorphism with obesity and serum leptin levels. MethodsHealthy 347 young adult volunteers residing in Colombo district, Sri Lanka were recruited. Written informed consent was taken from each of the volunteer participants. Anthropometric and BIA methods were used to assess body composition. Serum leptin, insulin and fasting blood glucose levels were measured. Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) was calculated. Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) was used for genotyping. Independent sample t-test, ANOVA and binary logistic regression were used for statistical analysis. ResultsThe mean age of the female and male groups was 26 (±4) and 27 (±5) years respectively. Most of the measured parameters did not show significant differences between genotypes. Q223R polymorphism was not associated with the obesity defined by either BMI or body fat percentage. In the female population, R allele (OR = 2.253, 95% CI = 1.015–4.999, p = 0.046) was significantly associated with elevated serum leptin. ConclusionsBody composition measures, serum leptin and IR are not significantly higher among individuals with the R allele of Q223R polymorphism. Allele R was not associated with obesity and associated with serum leptin levels only in the female population.

Abstract 120: Midgestation Eplerenone Treatment Ablates Leptin-induced Hypertension And Endothelial Dysfunction But Not Fetal Growth Restriction In Preeclamptic Mice

Elevated leptin (lep) in pregnant women strongly associates with preeclampsia (PE), a hypertensive pregnancy disorder. Our lab established a mid-late gestation lep-infusion model of PE, which induces endothelial dysfunction, hypertension and fetal growth restriction (FGR); deletion of endothelial mineralocorticoid receptors (MR) ablated these PE characteristics in pregnant mice. Whether pharmacological MR antagonism ablates lep-induced PE, however, is unknown. We hypothesized that MR antagonism (eplerenone) ablates lep-induced PE characteristics in pregnant mice. We infused pregnant BALB/c mice with leptin (lep, 0.9mg/kg/day) or saline (sham) via osmotic minipump alongside eplerenone (Eplr, 200mg/kg/day) or vehicle in drinking water from gestation day (GD)11-18. We measured vascular function via wire myography of 2 nd order mesenteric vessels and pup/placental weights on GD18 (n=5-7). We implanted radiotelemeters in separate mice (n=1-3) prior to mating and measured mean arterial pressure (BP) from GD11-18. Pre-pregnancy BP did not differ between treatment groups. Preliminary data indicates lep increased BP compared to sham from GD11-18 (112.7±4.5 lep vs 89.4 sham mmHg,) and Eplr decreased BP in lep pregnant mice (97.2±7.2 lep+Eplr mmHg, P=0.09 vs lep student’s t-test). Vascular relaxation to endothelial-dependent acetylcholine (ACh) decreased in lep+vehicle compared to sham+vehicle (*P&lt;0.05, 2-Way ANOVA w/ RM). Eplr+lep restored ACh-mediated vascular relaxation (*P&lt;0.05 vs lep+vehicle). LNAME pre-incubation did not ablate differences in ACh-mediated relaxation between lep+vehicle and lep+eplr (P&gt;0.05) indicating that Eplr restored a non-NO mechanism to improve endothelial function. Lep as a variable decreased pup weight in both vehicle and Eplr pregnant mice, however, Eplr did not increase pup weight in either vehicle or lep mice (0.74±0.01sham+veh, 0.71±0.01 lep+veh, 0.70±0.01 sham+eplr, 0.67±0.01 lep+eplr (g), *P&lt;0.05, 2-Way ANOVA). Collectively these data indicate that Eplr improves lep-induced endothelial dysfunction and hypertension, but may not prevent FGR when given from GD11-18. Therefore, further studies will determine whether MR antagonism promises therapeutic potential in lep-induced PE.

Maternal exposure to di-2-ethylhexyl phthalate (DEHP) depresses lactation capacity in mice.

Increasing evidence shows that di-2-ethylhexyl phthalate (DEHP), mostly commonly used phthalate for the production of flexible polyvinyl chloride (PVC), has the potential to induce serious health risks in humans. However, the understanding of DEHP-induced lactation performance remains largely unknown. We sought to investigate the adverse effects of DEHP on lactation and examine the underlying mechanism linking DEHP exposure with the lactation alterations. We successfully adapted a maternal DEHP exposure model in female pregnant/lactating mice. Then we determined effects of DEHP exposure on food intake, body weight and milk production as well as the alterations in endocrine factors in lactating mice. The integrated metabonomic and transcriptomic analyses of the mammary gland were performed to measure the changed metabolites and genes related to DEHP exposure-induced lactation alterations. We observed the reduced food intake with elevated blood leptin and the decreased milk yield as well as the reduced levels of serum prolactin, growth hormone, insulin-like growth factor 1 and insulin after exposed to DEHP. Furthermore, 208 metabolites and 3452 genes were separately identified as differentially expressed features associated with DEHP exposure. Integrated metabonomic and transcriptomic analyses demonstrated that DEHP caused lactation depression mainly through impairing energy generation, inducing stress responses along with the hypoactivation of inflammation, reducing the production of antioxidants, disrupting hormone homeostasis and repressing the synthesis of milk constituents (the lower glucose availability for lactose synthesis; the disruption of milk fat globule membrane for lipid droplet formation; the ribosomal dysfunction and disruption of post-modifications for milk protein synthesis). We demonstrated that DEHP disrupted several lactation-related hormone homeostasis and multiple processes like energy insufficiency, inflammation activation, oxidative stress aggravation and disturbance of milk production in the mammary gland of female lactating mice. Our results provide valuable information for the health risk of plastic additive (DEHP) on female lactation dysfunction.

LEP G2548A polymorphism is associated with increased serum leptin and insulin resistance among T2DM Malaysian patients.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic syndrome that is rapidly increasing across the world, especially in Malaysia. Leptin plays a vital role in the regulation of metabolism through its effect on peripheral tissues. G2548A polymorphism in the LEP gene promoter has been associated with insulin resistance, leptin, and type 2 diabetes mellitus across different population, but has not been inclusively reported within the Malaysian population. Thus, our study aimed to investigate the impact of G2548A polymorphism on serum leptin levels and insulin resistance among Malaysian T2DM patients. This case-control study involved 150 T2DM patients and 150 non-diabetic volunteers from ethnic Malays, Chinese and Indians. Genotyping of G2548A polymorphism was carried out using PCR-RFLP. Serum leptin and insulin levels were determined via ELISA. ANOVA and Chi-square tests were used to determine the distribution of genotypes and allelic frequencies based on serum leptin and insulin levels. Frequency of AA genotype and A allele of G2548A variant were significantly (P < 0.05) higher in T2DM patients of Malay and Indian ethnicities (4%, 35%, and 36%, 57%, respectively) as compared to the control groups (0%, 22%, and 18%, 35%, respectively). Fasting serum leptin levels were significantly (P < 0.001) higher in T2DM patients compared to non-diabetic subjects (166.78 pg/ml, 101.94 pg/ml, respectively). Additionally, elevated serum leptin, insulin levels, and BMI in diabetic patients were found to be associated with the AA genotype of this variant, compared to GG, and GA genotypes (P < 0.05). Our findings suggest a significant association between G2548A polymorphism among Malaysian T2DM subjects, particularly among Malay and Indian ethnic groups. Moreover, the A allele frequency of the G2548A variant significantly increased the risk of T2DM and is significantly associated with increased serum leptin, insulin levels, and elevated BMI.