State Of Leptin Resistance Research Articles

Leptin Increase During Dexamethasone and Its Association With Hunger and Fat in Pediatric Acute Lymphoblastic Leukemia.

During treatment, children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone, which induce acute side effects. To determine the influence of a 5-day dexamethasone course on changes in leptin, fat mass, BMI, hunger, sleep, and fatigue and to explore associations between these changes. Pediatric ALL patients were included during maintenance treatment. Data were collected before (T1) and after (T2) a 5-day dexamethasone course (6 mg/m2/day). At both time points, BMI, fat mass (bioelectrical impedance analysis), and leptin were assessed, as well as parent-reported questionnaires regarding hunger, fatigue, and sleep problems. Changes between T1 and T2 were assessed using paired tests. Correlation coefficients were calculated to assess associations between these changes (Delta scores: T2-T1). Univariable regression models were estimated to study associations between covariates and elevated leptin. We included 105 children, with median age 5.4 years (range, 3.0-18.8). Leptin and fat mass, as well as hunger scores, fatigue, and sleep deteriorated after 5 days of dexamethasone (P < .001), in contrast to BMI (P = .12). No correlations between delta leptin and delta fat mass, BMI, hunger, fatigue, or sleep were found. Elevated leptin on T1 was associated with older age (odds ratio [OR] 1.51; 95% CI, 1.28-1.77), higher fat mass (OR 1.19; 95% CI, 1.07-1.33), and earlier maintenance week (OR 0.96; 95% CI, 0.92-0.99). Five days of high-dose dexamethasone treatment led to direct and significant changes in leptin, hunger scores, and fat mass. Since children with ALL are at increased risk for metabolic adverse events, understanding underlying mechanisms is important, and a dexamethasone-induced state of acute leptin resistance might play a role.

Association between serum interleukin-6, leptin and insulin in gestational diabetes mellitus - a cross- sectional study.

Gestational diabetes mellitus (GDM) is a state of leptin resistance which develops a vicious cycle of hyperinsulinemia and hyperleptinemia leading to aggravation of an inflammatory situation. This study was done to find out the association between IL-6, leptin and insulin in gestational diabetes among North Indian women. This cross-sectional study included 100 GDM, 100 non-GDM and 50 non-pregnant women. DIPSI (Diabetes in Pregnancy Study Group India) criteria was used for screening GDM among pregnant women. GDM and non-GDM pregnant women were further categorized into three groups according to the trimester of pregnancy. Serum IL-6, leptin and insulin were measured in all the enrolled women. Serum IL-6 levels were significantly higher among GDM women as compared to non-GDM and non-pregnant women. Although the mean serum leptin and insulin levels were higher in GDM, but the difference was not statistically significant. When GDM and non-GDM women were categorized into three trimester, serum leptin levels were found to be significantly higher in 3rd trimester (p < 0.002) and IL-6 in 1st trimester (p < 0.017) among GDM women. No correlation was found between serum IL-6, leptin and insulin in GDM. Absence of any significant association between leptin and IL-6 signifies that leptin may not be associated with inflammation in gestational diabetes. However, IL-6 may serve as an early marker for screening glucose intolerance during pregnancy. The online version contains supplementary material available at 10.1007/s40200-023-01188-3.

Leptin: A Potential Link Between Obstructive Sleep Apnea and Obesity.

Chronic intermittent hypoxia (CIH), a pathophysiological manifestation of obstructive sleep apnea (OSA), is strongly correlated with obesity, as patients with the disease experience weight gain while exhibiting elevated plasma levels of leptin. This study was done to determine whether a relationship may exist between CIH and obesity, and body energy balance and leptin signaling during CIH. Sprague-Dawley rats were exposed to 96 days of CIH or normoxic control conditions, and were assessed for measures of body weight, food and water intake, and food conversion efficiency. At the completion of the study leptin sensitivity, locomotor activity, fat pad mass and plasma leptin levels were determined within each group. Additionally, the hypothalamic arcuate nucleus (ARC) was isolated and assessed for changes in the expression of proteins associated with leptin receptor signaling. CIH animals were found to have reduced locomotor activity and food conversion efficiency. Additionally, the CIH group had increased food and water intake over the study period and had a higher body weight compared to normoxic controls at the end of the study. Basal plasma concentrations of leptin were significantly elevated in CIH exposed animals. To test whether a resistance to leptin may have occurred in the CIH animals due to the elevated plasma levels of leptin, an acute exogenous (ip) leptin (0.04 mg/kg carrier-free recombinant rat leptin) injection was administered to the normoxic and CIH exposed animals. Leptin injections into the normoxic controls reduced their food intake, whereas CIH animals did not alter their food intake compared to vehicle injected CIH animals. Within ARC, CIH animals had reduced protein expression of the short form of the obese (leptin) receptor (isoform OBR100) and showed a trend toward an elevated protein expression of the long form of obese (leptin) receptor (OBRb). In addition, pro-opiomelanocortin (POMC) protein expression was reduced, but increased expression of the phosphorylated extracellular-signal-regulated kinase 1/2 (pERK1/2) and of the suppressor of cytokine signaling 3 (SOCS3) proteins was observed in the CIH group, with little change in phosphorylated signal transducer and activator of transcription 3 (pSTAT3). Taken together, these data suggest that long-term exposure to CIH, as seen in obstructive sleep apnea, may contribute to a state of leptin resistance promoting an increase in body weight.

Activating thermogenesis to combat obesity: hot topic or cold front?

Activating thermogenesis to combat obesity: hot topic or cold front?

COVID-19 Severity in Obesity: Leptin and Inflammatory Cytokine Interplay in the Link Between High Morbidity and Mortality.

Obesity is one of the foremost risk factors in coronavirus infection resulting in severe illness and mortality as the pandemic progresses. Obesity is a well-known predisposed chronic inflammatory condition. The dynamics of obesity and its impacts on immunity may change the disease severity of pneumonia, especially in acute respiratory distress syndrome, a primary cause of death from SARS-CoV-2 infection. The adipocytes of adipose tissue secret leptin in proportion to individuals’ body fat mass. An increase in circulating plasma leptin is a typical characteristic of obesity and correlates with a leptin-resistant state. Leptin is considered a pleiotropic molecule regulating appetite and immunity. In immunity, leptin functions as a cytokine and coordinates the host’s innate and adaptive responses by promoting the Th1 type of immune response. Leptin induced the proliferation and functions of antigen-presenting cells, monocytes, and T helper cells, subsequently influencing the pro-inflammatory cytokine secretion by these cells, such as TNF-α, IL-2, or IL-6. Leptin scarcity or resistance is linked with dysregulation of cytokine secretion leading to autoimmune disorders, inflammatory responses, and increased susceptibility towards infectious diseases. Therefore, leptin activity by leptin long-lasting super active antagonist’s dysregulation in patients with obesity might contribute to high mortality rates in these patients during SARS-CoV-2 infection. This review systematically discusses the interplay mechanism between leptin and inflammatory cytokines and their contribution to the fatal outcomes in COVID-19 patients with obesity.

Obesity and SARS-CoV-2 Infection a Multifaceted Interplay - Adipose Tissue Inflammation, Adipokine Disbalance and Immunity

Overweight and obesity are the most common comorbidities in SARSCoV- 2 patients, requiring hospitalization in intensive care units. The multifaceted nature of obesity including its effects on respiratory mechanics and immunity can fundamentally alter the pathogenesis of acute respiratory distress syndrome and pneumonia, which are the major causes of death due to SARS-CoV-2 infection. Most coronaviruses overcome host antiviral defense, and the pathogenicity of the virus is related to its capacity to suppress host immunity. Hyperleptinemia, insulin resistance and adipose tissue inflammation are hallmarks of obesity, which is associated with a leptin and insulin resistant state. Leptin regulates appetite and metabolism and through the Jak/STAT and Akt pathways modulates T cell number and function; insulin receptor signaling is closely engaged in T cell proliferation, whereas low garde adipose tissue inflammation provokes aberrant inflammasome activation. The review discusses these phenomena. It presents the reasons for susceptibility to respiratory viral infections in obese patients, as well as, the immunomodulatory effects of obesity to the outcome.

Leptin level as a biomarker of uncontrolled eating in obesity and overweight.

Uncontrolled eating (UE) showed important relationships with the development of obesity. Homeostatic regulations of feeding and energy balance, as well as hedonic eating, are regulated by leptin. The aims of this study were (1) to assess eating behaviors of Algerian adults as measured by the 51-item eating inventory; we also evaluate changes in the Three-Factor Eating Questionnaire (TFEQ) scores according to the body mass index (BMI) category; (2) to examine the association between the scores of the three TFEQ factors and the BMI values of the participants; and (3) to examine whether leptin concentrations are associated with eating behavior. Our hypothesis is that participants with obesity and high concentrations of leptin might display uncontrolled eating behavior. The subjects were 190 participants (60 obese, 60 overweight, and 70 lean subjects). The eating behavior was measured by using the 51-item eating inventory. Serum insulin concentrations were assessed by radioimmunoassay and were used to calculate homeostasis model assessment (HOMA). Serum leptin was quantified by the enzyme-linked immunosorbent assay (ELISA). Obese and overweight subjects showed hyperphagic behavior, i.e., uncontrolled eating. The logistic regression analysis showed an effect of leptin, HOMA, uncontrolled eating, and emotional eating on BMI. Leptin levels were associated with the uncontrolled eating and influenced by insulin sensitivity. The uncontrolled eating reflects hyperphagic eating behavior in obese and overweight subjects. Coexistence of uncontrolled eating and high level of leptin demonstrates a state of leptin resistance resulting in an inability to detect satiety. High circulating leptin can be considered a potential biomarker of uncontrolled eating.

Obesity, the most common comorbidity in SARS-CoV-2: is leptin the link?

Overweight and obesity are major risk factors for diabetes, cardiovascular disease, and lung disease. These diseases are the most commonly reported health conditions that predispose individuals with SARS-CoV-2 infection to require hospitalization including intensive care unit admissions. The innate immune response is the host’s first line of defense against a human coronavirus infection. However, most coronaviruses are armed with one strategy or another to overcome host antiviral defense, and the pathogenicity of the virus is related to its capacity to suppress host immunity. The multifaceted nature of obesity including its effects on immunity can fundamentally alter the pathogenesis of acute respiratory distress syndrome and pneumonia, which are the major causes of death due to SARS-CoV-2 infection. Elevated circulating leptin concentrations are a hallmark of obesity, which is associated with a leptin-resistant state. Leptin is secreted by adipocytes in proportion to body fat and regulates appetite and metabolism through signaling in the hypothalamus. However, leptin also signals through the Jak/STAT and Akt pathways, among others, to modulate T cell number and function. Thus, leptin connects metabolism with the immune response. Therefore, it seems appropriate that its dysregulation would have serious consequences during an infection. We propose that leptin may be the link between obesity and its high prevalence as a comorbidity of the SARS-CoV-2 infection. In this article, we present a synthesis of the mechanisms underpinning susceptibility to respiratory viral infections and the contribution of the immunomodulatory effects of obesity to the outcome.

Changes in Expression of the Genes for the Leptin Signaling in Hypothalamic-Pituitary Selected Areas and Endocrine Responses to Long-Term Manipulation in Body Weight and Resistin in Ewes.

Both long-term undernutrition and overnutrition disturb metabolic balance, which is mediated partially by the action of two adipokines, leptin and resistin (RSTN). In this study, we manipulated the diet of ewes to produce either a thin (lean) or fat (fat) body condition and investigated how RSTN affects endocrine and metabolic status under different leptin concentrations. Twenty ewes were distributed into four groups (n = 5): the lean and fat groups were administered with saline (Lean and Fat), while the Lean-R (Lean-Resistin treated) and Fat-R (Fat-Resistin treated) groups received recombinant bovine resistin. Plasma was assayed for LH, FSH, PRL, RSTN, leptin, GH, glucose, insulin, total cholesterol, nonesterified fatty acid (NEFA), high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides. Expression levels of a suppressor of cytokine signaling (SOCS-3) and the long form of the leptin receptor (LRb) were determined in selected brain regions, such as the anterior pituitary, hypothalamic arcuate nucleus, preoptic area and ventro- and dorsomedial nuclei. The results indicate long-term alterations in body weight affect RSTN-mediated effects on metabolic and reproductive hormones concentrations and the expression of leptin signaling components: LRb and SOCS-3. This may be an adaptive mechanism to long-term changes in adiposity during the state of long-day leptin resistance.

Single-Nucleus RNA Sequencing of the Hypothalamic Arcuate Nucleus of C57BL/6J Mice After Prolonged Diet-Induced Obesity.

Prolonged obesity is associated with blunted feeding and thermogenic autonomic responses to leptin, but cardiovascular responses to leptin are maintained. This state of selective leptin resistance is, therefore, proposed to contribute to the pathogenesis and maintenance of obesity-associated hypertension. Cells of the arcuate nucleus of the hypothalamus detect leptin, and although the cellular and molecular mechanisms remain unclear, altered arcuate nucleus biology is hypothesized to contribute to selective leptin resistance. Male C57BL/6J mice were fed a high-fat diet (HFD) or chow from 8 to 18 weeks of age, as this paradigm models selective leptin resistance. Nuclei were then isolated from arcuate nucleus for single-nucleus RNA sequencing. HFD caused expected gains in adiposity and circulating leptin. Twenty-three unique cell-type clusters were identified, and Ingenuity Pathway Analysis was used to explore changes in gene expression patterns due to chronic HFD within each cluster. Notably, gene expression signatures related to leptin signaling exhibited suppression predominantly in neurons identified as the Agouti-related peptide (Agrp) subtype. Ingenuity Pathway Analysis results were also consistent with alterations in CREB (cAMP response element-binding protein) signaling in Agrp neurons after HFD, and reduced phosphorylated CREB was confirmed in arcuate nucleus after prolonged HFD by capillary electrophoresis-based Western blotting. These findings support the concept that prolonged HFD-induced obesity is associated with selective changes in Agrp neuron biology, possibly secondary to altered CREB signaling.

Hesperidin improves insulin resistance via down-regulation of inflammatory responses: Biochemical analysis and in silico validation.

Leptin resistance and co-existing insulin resistance is considered as hallmark of diet-induced obesity. Here, we investigated therapeutic potential of hesperidin to improve leptin and insulin resistance using high fat diet (HFD)-induced obese experimental animal model. We also performed in silico studies to validate therapeutic effectiveness of hesperidin by performing protein-ligand docking and molecular dynamics simulation studies. Group 1 was identified as control group receiving vehicle only. Group 2 was marked as non-treated group receiving 60% HFD. While, other groups were treated daily with orlistat (120 mg/kg/d), hesperidin (55 mg/kg/d), combination of hesperidin (55 mg/kg/d) + orlistat (120 mg/kg/d). Hesperidin alone (P<0.001) and particularly in combination with orlistat (P<0.001), resulted in controlling the levels of HFD-altered biomarkers including random and fasting state of glycemia, leptin and insulin resistance. Similarly, hesperidin also improved the serum and tissue levels of leptin, interleukin-6 and tumor necrosis factor-alpha more significantly (P<0.05) when compared with that of orlistat. These results were found to be in accordance with the results of histopathological examination of pancreas, liver and adipose tissues. In-silico studies also proved that hesperidin binds to leptin receptor with higher affinity as compared to that of orlistat and induces the favorable variations in geometrical conformation of leptin receptor to promote its association with leptin which may lead to the cascades of reactions culminating the lipolysis of fats that may ultimately lead to cure obesity. The results of this study may be a significant expectation among the forthcoming treatment strategies for leptin and insulin resistance.

The Influence of Photoperiod on the Action of Exogenous Leptin on Gene Expression of Proinflammatory Cytokines and Their Receptors in the Thoracic Perivascular Adipose Tissue (PVAT) in Ewes.

Leptin resistance is either a condition induced by human obesity or a natural phenomenon associated with seasonality in ruminants. In the cardiovascular system, the leptin resistance state presence is a complex issue. Moreover, the perivascular adipose tissue (PVAT) appears to be crucial as a source of proinflammatory cytokines and as a site of interaction for leptin contributing to endothelium dysfunction and atherosclerosis progression. So the aim of this study was to examine the influence of the photoperiod on the action of exogenous leptin on gene expression of selected proinflammatory cytokines and their receptors in thoracic PVAT of ewe with or without prior lipopolysaccharide (LPS) stimulation. The experiment was conducted on 48 adult, female ewes divided into 4 group (n = 6 in each): control, with LPS intravenous (iv.) injection (400 ng/kg of BW), with leptin iv. injection (20 μg/kg BW), and with LPS and 30-minute-later leptin injection, during short-day (SD) and long-day (LD) seasons. Three hours after LPS/control treatment, animals were euthanized to collect the PVAT adherent to the aorta wall. The leptin injection enhanced IL1B gene expression only in the LD season; however, in both seasons leptin injection intensified LPS-induced increase in IL1B gene expression. IL1R2 gene expression was increased by leptin injection only in the SD season. Neither IL6 nor its receptor and signal transducer gene expressions were influenced by leptin administration. Leptin injection increased TNFA gene expression regardless of photoperiodic conditions. Only in the SD season did leptin treatment increase the gene expression of both TNFα receptors. To conclude, leptin may modulate the inflammatory reaction progress in PVAT. In ewe, the sensitivity of PVAT on leptin action is dependent upon the photoperiodic condition with stronger effects stated in the SD season.

Leptin resensitisation: a reversion of leptin-resistant states.

Leptin resistance refers to states in which leptin fails to promote its anticipated effects, frequently coexisting with hyperleptinaemia. Leptin resistance is closely associated with obesity and also observed in physiological situations such as pregnancy and in seasonal animals. Leptin resensitisation refers to the reversion of leptin-resistant states and is associated with improvement in endocrine and metabolic disturbances commonly observed in obesity and a sustained decrease of plasma leptin levels, possibly below a critical threshold level. In obesity, leptin resensitisation can be achieved with treatments that reduce body adiposity and leptinaemia, or with some pharmacological compounds, while physiological leptin resistance reverts spontaneously. The restoration of leptin sensitivity could be a useful strategy to treat obesity, maintain weight loss and/or reduce the recidivism rate for weight regain after dieting. This review provides an update and discussion about reversion of leptin-resistant states and modulation of the molecular mechanisms involved in each situation.

Central, but not systemic, thermoregulatory effects of leptin are impaired in rats with obesity: interactions with GABAB agonist and antagonist.

Leptin is an adipokine that regulates body weight by decreasing appetite and increasing energy expenditure. Besides the effects on food intake, leptin can regulate energy expenditure at least in part by modulating thermogenesis. Many of the effects of leptin are attributable to action in the central nervous system, particularly in the hypothalamus. Common forms of obesity are associated with increased leptin levels and a failure to suppress feeding and mediate weight loss in response to exogenous leptin. This apparent leptin ineffectiveness defines a state of so-called leptin resistance. We examined the effect of leptin on core body temperature in rats with normal weight and diet-induced obesity (DIO), as well as thermoregulatory interactions between leptin and GABAB-agonist and an antagonist. We found that leptin retains the ability to induce hyperthermic effect in rats with DIO. Additionally, temperature responses produced by GABAB agonist and antagonist are altered in a state of obesity and by administration of leptin. We evaluated whether the medial preoptic area of the anterior hypothalamus (MPA) still remains sensitive to leptin action during DIO. Using extracellular recordings of neurons and phospho-signal transducer and the activator of transcription 3 (pSTAT3) immunohistochemistry, we have provided strong evidence that leptin signaling in the MPA is impaired in obese rats. We believe that leptin resistance in the MPA may play a role in the pathogenesis of obesity and obesity-related disease states.

Impaired hypothalamic leptin sensitivity in pseudopregnant rats treated with chronic prolactin to mimic pregnancy.

Pregnancy in rodents is associated with hyperphagia, increased fat deposition, elevated leptin concentrations and insensitivity to the satiety action of leptin. To investigate the hormonal mechanisms involved in the development of this state of pregnancy-induced leptin resistance, we have used a pseudopregnancy rat model. We have previously demonstrated that pseudopregnant rats have a normal feeding response to leptin, although, if pseudopregnancy is extended using chronic i.c.v. ovine prolactin infusion along with progesterone implants, then leptin no longer suppresses food intake. The present study aimed to investigate the effect of chronically high lactogen levels, as seen in mid-pregnancy, on leptin-induced activation of hypothalamic Janus kinase/signal transducer and activator of transcription (JAK/STAT) signal transduction and mRNA expression of leptin (LepR-B) and prolactin (Prlr-L) receptors, using pseudopregnant rats chronically infused with ovine prolactin. Groups of virgin (dioestrous) and pseudopregnant rats were treated with chronic i.c.v. infusion of either prolactin (2.5μgμL-1 h-1 for 5days) or vehicle (artificial cerebrospinal fluid [aCSF]) via a minipump connected to a cannula surgically implanted into the lateral ventricle. Rats were fasted overnight and then received an i.c.v. injection of leptin (400ng) or vehicle (aCSF) and were perfused 30minutes later. In chronic vehicle-infused pseudopregnant rats, i.c.v. leptin increased the number of phosphorylated STAT3 positive cells in the arcuate nucleus and ventromedial nucleus (VMH) of the hypothalamus, similar to all acute-leptin treated virgin groups. This effect of leptin, however, was not observed in the pseudopregnant rats that were chronically infused with prolactin. A quantitative polymerase chain reaction analysis also showed decreased expression of LepR-B in the arcuate and VMH nuclei, as well as decreased Prlr-L in the arcuate nucleus of prolactin-infused "extended pseudopregnancy" rats. These data suggest that the attenuation of the leptin-induced suppression of food intake caused by chronically high lactogen levels in pseudopregnant rats is associated with impaired leptin-induced activation of the JAK/STAT pathway in specific hypothalamic nuclei.

Evaluation of Liraglutide Effect on Serum Adipocytokines of Adults Male Wistar Rats with Insulin Resistance That Induced by High Fat Diet

Insulin resistance (IR) is the state in which insulin-stimulated glucose uptake is blunted in the insulin sensitive-tissue leading to state of prediabetes and T2DM, IR characterized by hyperglycemia and hyperinsulinemia in the fasting state, elevated glycosylated hemoglobin (HbA1c) level, hyperlipidemia, postprandial hyperglycemia, elevated plasma levels of pro-inflammatory markers and hypoadiponectinemia. Type 2 diabetes mellitus reported with peripheral insulin resistance (IR) and reduced production of insulin from pancreatic β-cells, IR elevates plasma fatty acids, decreasing glucose transportation to muscles and increased breakdown of fat finally leads to increased glucose production from the liver. This study was designed to evaluate the effect of liraglutide on serum adipocytokines of adult male rats with insulin resistance that induced by high fat diet, Chronic high fats diet feeding is a common cause of disturbing leptin signaling in hypothalamus leading to the state of hyperphagic obesity and leptin resistance. Liraglutide improve meal-stimulated insulin secretion so it's called incretin mimetic. It is glucagon like peptide-1 receptor agonist that adjust weight loss and glucose control via glucagon like peptide-1 receptors in the central nervous system or indirectly through activation of peripheral neurons. Current study utilized thirty-six adult male wistar rats (weighing 200-220gm), they were divided into two main groups: normal diet group (group A) that includes 12 rats receiving normal pellets and high fat diet group (group B and C) which has 24 rats feeding high fat diet pellets. Animals fed high fat diet pellets for 8 weeks to induce insulin resistance were divided into two groups: Group B received high fat diet pellets for 8 weeks then administered 0.5ml/kg normal saline intraperitoneal for four weeks. Group C received high fat diet pellets for 8 weeks then received 600μg/kg/day intraperitoneal liraglutide +0.5ml/kg normal saline four weeks along with high fat diet. High fat diet pellets caused a significant increase in body weight and blood glucose of high fat diet group. Liraglutide revealed a significant elevation in serum level of anti-inflammatory adipokines of group C. It also produces a significant reduction in serum level of pro-inflammatory cytokines of group C when compared with group B and control group. As conclusion, anti-inflammatory effects of liraglutide significantly elevate serum level of anti-inflammatory cytokines as well as significantly reduce serum level of pro-inflammatory cytokines.

Evaluation of Liraglutide Effect on Serum Adipocytokines of Adults Male Wistar Rats with Insulin Resistance That Induced by High Fat Diet

Insulin resistance (IR) is the state in which insulin-stimulated glucose uptake is blunted in the insulin sensitive-tissue leading to state of prediabetes and T2DM, IR characterized by hyperglycemia and hyperinsulinemia in the fasting state, elevated glycosylated hemoglobin (HbA1c) level, hyperlipidemia, postprandial hyperglycemia, elevated plasma levels of pro-inflammatory markers and hypoadiponectinemia.&#x0D; Type 2 diabetes mellitus reported with peripheral insulin resistance (IR) and reduced production of insulin from pancreatic β-cells, IR elevates plasma fatty acids, decreasing glucose transportation to muscles and increased breakdown of fat finally leads to increased glucose production from the liver.&#x0D; This study was designed to evaluate the effect of liraglutide on serum adipocytokines of adult male rats with insulin resistance that induced by high fat diet, Chronic high fats diet feeding is a common cause of disturbing leptin signaling in hypothalamus leading to the state of hyperphagic obesity and leptin resistance. Liraglutide improve meal-stimulated insulin secretion so it's called incretin mimetic. It is glucagon like peptide-1 receptor agonist that adjust weight loss and glucose control via glucagon like peptide-1 receptors in the central nervous system or indirectly through activation of peripheral neurons.&#x0D; Current study utilized thirty-six adult male wistar rats (weighing 200-220gm), they were divided into two main groups: normal diet group (group A) that includes 12 rats receiving normal pellets and high fat diet group (group B and C) which has 24 rats feeding high fat diet pellets. Animals fed high fat diet pellets for 8 weeks to induce insulin resistance were divided into two groups: Group B received high fat diet pellets for 8 weeks then administered 0.5ml/kg normal saline intraperitoneal for four weeks. Group C received high fat diet pellets for 8 weeks then received 600μg/kg/day intraperitoneal liraglutide +0.5ml/kg normal saline four weeks along with high fat diet.&#x0D; High fat diet pellets caused a significant increase in body weight and blood glucose of high fat diet group. Liraglutide revealed a significant elevation in serum level of anti-inflammatory adipokines of group C. It also produces a significant reduction in serum level of pro-inflammatory cytokines of group C when compared with group B and control group.&#x0D; As conclusion, anti-inflammatory effects of liraglutide significantly elevate serum level of anti-inflammatory cytokines as well as significantly reduce serum level of pro-inflammatory cytokines.

Changes in Visceral Adipose Tissue Plasma Membrane Lipid Composition in Old Rats Are Associated With Adipocyte Hypertrophy With Aging.

Increased adiposity, through adipocyte hypertrophy, and/or hyperplasia, characterizes aging and obesity. Both are leptin-resistant states, associated with disturbed lipid metabolism, reduced insulin sensitivity and inflammation. Nevertheless, fat tissue dysfunction appears earlier in obesity than in normal aging. In contrast, lipodystrophy is accompanied by diabetes, and improving the fat cell capacity to expand rescues the diabetic phenotype. Fat tissue dysfunction is extensively studied in the diet-induced obesity, but remains relatively neglected in the aging-associated obesity. In the Wistar rat, as occurs in humans, early or middle aging is accompanied by an increase in adiposity. Using this experimental model, we describe the molecular mechanisms contributing to the white adipose tissue (WAT) hypertrophy. WAT from middle-old age rats is characterized by decreased basal lipogenesis and lipolysis, increased esterification, as demonstrated by the higher TAG and cholesterol content in visceral WAT, and the maintenance of total ceramide levels within normal values. In addition, we describe alterations in the adipose tissue plasma membrane lipid composition, as increased total ether-phosphatidylcholine, sphingomyelin, and free cholesterol levels that favor an enlarged fat cell size with aging. All these metabolic changes may be regarded as a survival advantage that prevents the aged rats from becoming overtly diabetic.

Leptin resistance during pregnancy is also exerted at the periphery.

Pregnancy is a physiological state with a great demand of energy and nutrients in mammals and is characterized by hyperphagia, increase in fat mass, hyperleptinemia, and central resistance to leptin. In order to evaluate whether pregnancy is also a state of leptin resistance at the periphery, we studied the response to leptin in the liver and subcutaneous adipose tissue (SAT). We demonstrated reduced levels of phosphoryalated signal transducer and activator of transcription 3 (p-STAT3) and phosphorylated protein kinase B (p-AKT) after intravenous leptin in both tissues in mid-term pregnant rats (G13) and a restored response in late pregnancy (G18). As underlying mechanisms of the peripheral leptin resistance of mid-gestation we found decreased leptin receptor b (LepRb) mRNA levels and increased content of suppressor of cytokine signaling 3 (SOCS3). Furthermore, we demonstrated that in G13 rats the main lipogenic molecules and activity (sterol regulatory element binding transcription protein 1 (SREBP-1) and fatty acid synthase (FAS)) were elevated in the liver and SAT, and the molecules involved in β-oxidation (peroxisome proliferator activated receptor α (PPARα) and carnitine palmitoyltransferase 1 (CPT-1)) were reduced, as it happens in early pregnancy. In G18, the opposite pattern is observed. This probably reflects that in G13 the peripheral resistance to the hyperleptinemia might help maintaining the lipogenic metabolism of early pregnancy. In contrast, the recovery of the response to leptin in late pregnancy would favor a catabolic metabolism. Finally, using a pseudogestation model we showed that progesterone and prolactin are not involved in the gestational peripheral leptin resistance. In conclusion, during mid-pregnancy a state of leptin resistance is also exerted at the periphery, and is probably involved in the characteristic lipid regulation of this physiological state.

Selective Deletion of Leptin Signaling in Endothelial Cells Enhances Neointima Formation and Phenocopies the Vascular Effects of Diet-Induced Obesity in Mice.

Obesity is associated with elevated circulating leptin levels and hypothalamic leptin resistance. Leptin receptors (LepRs) are expressed on endothelial cells, and leptin promotes neointima formation in a receptor-dependent manner. Our aim was to examine the importance of endothelial LepR (End.LepR) signaling during vascular remodeling and to determine whether the cardiovascular consequences of obesity are because of hyperleptinemia or endothelial leptin resistance. Mice with loxP-flanked LepR alleles were mated with mice expressing Cre recombinase controlled by the inducible endothelial receptor tyrosine kinase promoter. Obesity was induced with high-fat diet. Neointima formation was examined after chemical carotid artery injury. Morphometric quantification revealed significantly greater intimal hyperplasia, neointimal cellularity, and proliferation in End.LepR knockout mice, and similar findings were obtained in obese, hyperleptinemic End.LepR wild-type animals. Analysis of primary endothelial cells confirmed abrogated signal transducer and activator of transcription-3 phosphorylation in response to leptin in LepR knockout and obese LepR wild-type mice. Quantitative PCR, ELISA, and immunofluorescence analyses revealed increased expression and release of endothelin-1 in End.LepR-deficient and LepR-resistant cells, and ET receptor A/B antagonists abrogated their paracrine effects on murine aortic smooth muscle cell proliferation. Reduced expression of peroxisome proliferator-activated receptor-γ and increased nuclear activator protein-1 staining was observed in End.LepR-deficient and LepR-resistant cells, and peroxisome proliferator-activated receptor-γ antagonization increased endothelial endothelin-1 expression. Our findings suggest that intact endothelial leptin signaling limits neointima formation and that obesity represents a state of endothelial leptin resistance. These observations and the identification of endothelin-1 as soluble mediator of the cardiovascular risk factor obesity may have relevant therapeutic implications.