Increased Plasma Leptin Levels Research Articles

Acute cold‐ and chronic heat‐exposure upregulate hepatic leptin and muscle uncoupling protein (UCP) gene expression in broiler chickens

Emerging evidence showed that variations in environmental temperature affect both leptin and uncoupling protein (UCP) gene expression in mammals, whereas a little is known about such interactions in birds. Thus, we conducted the present study to investigate the influence of acute (2 hours) cold (4 degrees C) and chronic (10 days) heat (32 degrees C) exposure on hepatic leptin and muscle UCP gene expression in 5-wk-old broiler chickens. Both cold- and heat-exposure significantly (P < 0.05 to P < 0.001) upregulated hepatic leptin (by 35 and 46%, respectively) and muscle UCP mRNA levels (by 71 and 71%, respectively) compared to the thermoneutrality (22 degrees C). This result suggests that leptin and UCP may be involved in the thermoregulation response of chickens to extreme climate (cold and hot temperatures). The upregulation of hepatic leptin gene expression was accompanied by an increase in plasma leptin levels, indicating that leptin may be regulated at transcriptional level. The increase of leptin and UCP mRNA abundance, and leptinemia we report here were not related to plasma glucose or insulin levels. In conclusion, the exposure of broiler chickens to extreme ambient temperatures (cold and heat) increases hepatic leptin and muscle UCP gene expression.

Genetic Variants of FTO Influence Adiposity, Insulin Sensitivity, Leptin Levels, and Resting Metabolic Rate in the Quebec Family Study

A genome-wide association study conducted by the Wellcome Trust Case Control Consortium recently associated single nucleotide polymorphisms (SNPs) in the FTO (fatso/fat mass and obesity associated) gene with type 2 diabetes. These associations were shown to be mediated by obesity. Other research groups found similar results in Europeans and Hispanics but not African Americans. The mechanism by which FTO influences obesity and type 2 diabetes is currently unknown. The present study investigated the role of two FTO SNPs (rs17817449 and rs1421085) in adiposity, insulin sensitivity, and body weight regulation, including energy intake and expenditure. We genotyped 908 individuals from the Quebec City metropolitan area that participated in the Quebec Family Study, a long-term study of extensively phenotyped individuals designed to investigate factors involved in adiposity. We found significant associations for both SNPs with several obesity-related phenotypes. In particular, rs17817449 was associated with BMI (P = 0.0014), weight (P = 0.0059), and waist circumference (P = 0.0021) under an additive model. In addition, this FTO SNP influenced fasting insulin (P = 0.011), homeostasis model assessment of insulin resistance (P = 0.038), and an insulin sensitivity index derived from an oral glucose tolerance test (P = 0.0091). Associations were also found with resting metabolic rate (RMR) (P = 0.042) and plasma leptin levels (P = 0.036). Adjustment for BMI abolished the associations with insulin sensitivity, RMR, and plasma leptin levels. These results confirm that genetic variation at the FTO locus contributes to the etiology of obesity, insulin resistance, and increased plasma leptin levels.

Early changes in adipokine levels and baseline limb fat may predict HIV lipoatrophy over 2 years following initiation of antiretroviral therapy*

No biological marker has been identified that predicts the development of lipodystrophy (LD). We investigated whether metabolic and body composition parameters could predict the development of LD over 2 years in adults initiating antiretroviral therapy (ART). We used stored plasma collected at baseline and weeks 12, 24 and 48 from adults initiating combination ART. Adipocytokine, inflammatory cytokine, lipid and glycaemic parameters were measured and related to subsequent lipoatrophy (loss of limb fat mass of at least 2 kg from weeks 24 to 96 by dual-energy X-ray absorptiometry) and an increase in visceral adipose tissue (VAT; an increase of at least 18 cm(2) from baseline to week 48 by abdominal computed tomography). Risk factors associated with limb fat loss and VAT gain were analysed by logistic regression. Fifty-four HIV-infected, treatment-naïve adults were included in the study: 53 (98%) of them were men, and they had a median age of 39 years [interquartile range (IQR) 34-48 years] and a median body mass index of 22.6 kg/m(2) (IQR 20-24.8 kg/m(2)). In multivariate analysis, a higher baseline limb fat percentage, and a 1 mmol/L increase in plasma leptin levels during the first 6 months of ART, independently predicted a peripheral fat loss of > or = 2 kg [odds ratio (OR) 2.58, 95% confidence interval (CI) 1.04-6.41; OR 3.15, 95% CI 1.34-7.35, respectively). VAT changes showed a borderline association with high baseline tumour necrosis factor-alpha levels and hip circumference (OR 1.04, 95% CI 1.00-1.07; OR 1.44, 95% CI 1.07-1.95, respectively). In ART-naïve men, higher baseline limb fat and an early increase in leptin concentrations may predict the subsequent development of lipoatrophy. We did not find the same risk factors in the two different groups of patients with peripheral fat loss and central fat gain, suggesting a partially independent pathogenesis.

Free fatty acids as mediators of adaptive compensatory responses to insulin resistance in dexamethasone‐treated rats

Chronic low-dose dexamethasone (DEX) treatment in rats is associated to insulin resistance with compensatory hyperinsulinaemia and reduction in food intake. We tested the hypothesis that the elevation in circulating free fatty acids (FFAs) induced by DEX is the common mediator of both insulin resistance and insulin hyperproduction. For this purpose, an anti-lipolytic agent was administered during DEX treatment to lower lipacidaemia for several hours prior to glucose and insulin tolerance tests. Leptin expression in adipose tissue (by Northern blot) and plasma leptin levels (by radioimmunoassay) were also investigated to verify whether a rise in circulating leptin could be responsible for the anorectic effect of DEX. Our data show that a transient pharmacological reduction of elevated plasma FFA levels abates the post-loading hyperinsulinaemia and counteracts the insulin resistance induced by DEX, supporting the hypothesis that the chronic elevation in FFAs is the common mediator of DEX-induced changes. Despite enhanced leptin expression in white adipose tissue, DEX-treated rats show no significant increase in plasma leptin levels. This suggests that the anorectic effect of DEX should be mediated, at least partially, by other factors, possibly related to the influence of concomitantly elevated plasma FFA and insulin levels on the hypothalamic centers regulating feeding. Our results sustain the idea that a prolonged increase in plasma FFA levels plays an important role in the adaptive regulation of glucose and energy homeostasis, not only by potentiating insulin secretion but also by providing a signal of 'nutrient abundance' capable of restraining food intake.

Childhood Leukemia Survivors At Risk for Harmful Obesity

Endocrinology| January 01 2008 Childhood Leukemia Survivors At Risk for Harmful Obesity AAP Grand Rounds (2008) 19 (1): 5. https://doi.org/10.1542/gr.19-1-5 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Childhood Leukemia Survivors At Risk for Harmful Obesity. AAP Grand Rounds January 2008; 19 (1): 5. https://doi.org/10.1542/gr.19-1-5 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: childhood leukemia, obesity, survivors, leptin, insulin-like growth factor i, leukemia, lymphocytic, acute, childhood Source: Janiszewski PM, Oeffinger KC, Church TS, et al. Abdominal obesity, liver fat, and muscle composition in survivors of childhood acute lymphoblastic leukemia. J Clin Endocrinol Metab. 2007;92(10):3816–3821; doi:10.1210/jc.2006–2178 Acute lymphoblastic leukemia (ALL), the most common malignancy of childhood, has an overall cure rate of approximately 80%.1 Long-term survivors of childhood ALL are at increased risk for obesity, cardiovascular disease, and related mortality in the years following treatment.2 Investigators from multiple US institutions studied young adult survivors of ALL to assess the association of cranial radiotherapy (CRT) with levels of total, regional, and ectopic fat storage, metabolic risk, IGF-1, and leptin. A total of 237 young adult survivors of childhood ALL, treated from 1970–2000 in the Dallas-Fort Worth area, were identified. Of the 189 individuals who met eligibility criteria, 114 were enrolled and completed the study. Study participants’ mean age was 23.8 years, their mean age at diagnosis was 6.2 years, the mean interval from diagnosis to study enrollment was 17.5 years, and 23.7% were of an ethnic or racial minority group. Anthropometric measures, blood pressure, metabolic status, and levels of IGF-1 and leptin were assessed in 52 male (15 CRT-treated) and 62 female (24 CRT-treated) participants. Visceral, liver, and subcutaneous fat were determined using abdominal CT scan. Data from patients treated with CRT and non-CRT survivors were compared after controlling for potentially confounding variables. Exposure to CRT had no effect on BMI, waist circumference, or liver fat. Controlling for age and race, ALL survivors treated with CRT had significantly higher body fat percentage and more abdominal and visceral fat than non-CRT patients. IGF-1 levels were significantly lower and leptin levels significantly higher in the group that received CRT. There was more evidence of insulin resistance and dyslipidemias in CRT patients compared with the non-CRT survivors. The authors conclude that among ALL survivors CRT is associated with excess accumulation of abdominal fat, particularly visceral fat, and elevated metabolic risk. Dr. Varma has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. Fortunately, we are seeing more and more long-term survivors of ALL. ALL survivors are at high risk for obesity,3 cardiovascular disease,4 and related mortality.2 CRT during ALL treatment has been shown to be the potential cause for excess weight gain among survivors.5 The authors of the current study suggest that treatment with CRT among ALL survivors is associated with increased plasma leptin levels, even when it is expressed per unit of fat mass. This observation indicates that obesity subsequent to treatment with CRT may be secondary to induced hypothalamic resistance to leptin. The abdominal and visceral obesity are warning signs for the metabolic syndrome. Since oncologists may not follow ALL survivors late into adolescence, primary care providers need to be aware of the sequelae of treatment, and monitor patients with a history of CRT for signs of obesity and other cardiovascular risks. (For discussions... You do not currently have access to this content.

Sympathetic overactivity and plasma leptin levels in Rett syndrome

Rett syndrome (RTT) is a severe developmental–neurological disorder, characterized by profound and progressive loss of intellectual functioning, occurring after a period (of at least 6 months) of normal development with classic stereotype hand movements, gait ataxia, jerky truncal ataxia, deceleration of brain and body organ growth and cardiac dysautonomia. Pathogenesis of sympathetic overactivity in RTT is unknown, but a previous study observed increased plasma leptin levels in Rett girls and it is well known the role of leptin in the regulation of sympathetic nervous system activity. Aim of our study is to evaluate a relationship between plasma leptin levels and sympathetic activity in RTT. Thirty-two female patients (12.1 ± 6.3 years), affected by RTT were enrolled in the study. In all the subjects, we analyzed heart rate variability, QT corrected interval and plasma leptin levels. A significant correlation was found between plasma leptin levels and LF/HF (expression of sympatho-vagal balance) (Spearman r = 0.44, p = 0.001). There is also a significant negative correlation between HF component (expression of vagal activity) and plasma leptin levels (Spearman r = −0.037, p = 0.03) and a positive correlation between LF component and plasma leptin levels (Spearman r = 0.047, p = 0.01). These results show that in RTT higher plasma leptin levels appear to be associated with sympathetic overactivity, suggesting a role for leptin in cardiac dysautonomia.

Transcytosis of gastric leptin through the rat duodenal mucosa

Leptin is secreted into the gastric juice by epithelial Chief cells and reaches the duodenum in a biologically intact active form. We assessed the possibility that this gastric leptin crosses the intestinal mucosa by transcytosis through enterocytes to reach blood circulation. Endogenous gastric leptin secretion was triggered by cholinergic stimulation. In another set of experiments, recombinant leptin was inserted in vivo into the duodenal lumen. Plasma levels of leptin were assessed by enzyme immunoassay and Western blot, and duodenal tissue was processed for immunocytochemistry. We first observed that leptin was found inside duodenal enterocytes from fed rats but not inside those from fasted ones. Stimulation of gastric secretion by a cholinergic agent led to rapid increases in plasma leptin levels (202 +/- 39%) except when the pylorus was clamped. Insertion of recombinant leptin into the duodenal lumen raised plasma leptin concentrations (558 +/- 34%) quite rapidly, whereas carrier solution without leptin had no effect. The use of FITC-tagged leptin reinforced these results. Light and electron microscopy revealed the cellular compartments involved in its transcytosis, namely, the enterocyte microvilli, the endocytotic vesicles, the Golgi complex, and the basolateral interdigitations. Leptin was also present in the lamina propria, in capillary endothelial cell plasmalemmal vesicles, and in capillary lumina. These results demonstrate that gastric exocrine leptin is internalized by duodenal enterocytes and delivered to the lamina propria and blood circulation. It may thus be able to play important paracrine and endocrine functions for the control of gastric emptying and nutrient absorption.

Leptin induces elongation of cardiac myocytes and causes eccentric left ventricular dilatation with compensation

One of the major manifestations of obesity is an increased production of the adipocyte-derived 16-kDa peptide leptin, which acts mainly on hypothalamic leptin receptors. Leptin receptors are widely distributed in various tissues, including the heart. Whereas increased plasma leptin levels have been reported in patients with congestive heart failure, systemic alterations induced by obesity can affect cardiac hypertrophy, and the direct effects of leptin on cardiac structure and function still remain to be determined. We first exposed primary cardiac myocytes from neonatal rats to leptin for 48 h. This resulted in a significant increase in myocyte long-axis length (P < 0.05 at 50 ng/ml) but not in the short-axis width. Leptin induced the rapid phosphorylation of STAT3 and its DNA binding in cardiac myocytes. Administration of a JAK2 inhibitor, AG-490, completely inhibited all of these effects by leptin. Furthermore, we examined the effect of continuous infusion of leptin for 4 wk following myocardial infarction in mice. Echocardiography demonstrated that left ventricular fractional shortening in the leptin-infused group (28.4 +/- 2.8%) was significantly higher than that in the PBS-infused group (18.4 +/- 2.2%) following myocardial infarction. Interestingly, left ventricular diastolic dimension in the leptin-infused group (4.56 +/- 0.12 mm) was also higher than that in the PBS-infused group (4.13 +/- 0.09 mm). These results demonstrate that leptin induces the elongation of cardiac myocytes via a JAK/STAT pathway and chronic leptin infusion causes eccentric dilatation with augmented systolic function after myocardial infarction.

Human soluble leptin receptor concentration in healthy offspring of hypertensive parents.

Essential hypertension is associated with increased plasma leptin levels and decreased human soluble leptin receptor (hsLR) concentration. The aim of this study was to determine whether the concentration of hsLR differs among offspring of hypertensive compared with nonhypertensive parents. Subjects in the 2 groups were matched for age, sex, and body mass index. Forty-six (24 male, 22 female; mean age, 18+/-3 years; body mass index, 22.4+/-1.4 kg/m2) healthy offspring of hypertensive parents (group A) and 50 (28 male, 22 female; mean age, 18+/-3.2 years; body mass index, 22.6+/-1.7 kg/m2) healthy offspring of healthy parents (group B) were studied. The hsLR concentration (enzyme-linked immunosorbent assay method) and leptin plasma levels (radioimmunoassay method) were determined in the study population. Plasma leptin levels were significantly higher (10+/-5 vs 6+/-3 ng/mL; P<.001), while hsLR concentration was significantly lower (20+/-7 vs 29+/-8 U/mL; P<.001) in group A compared with group B. Our findings suggest that offspring of hypertensive parents have significantly higher plasma leptin levels and significantly lower hsLR concentrations compared with healthy offspring of healthy normotensive parents. Further studies are needed to determine the clinical significance of these observations.

Inverse regulation of leptin mRNA expression by short- and long-chain fatty acids in cultured bovine adipocytes

Leptin is an adipose tissue-derived cytokine plays key roles in the regulation of food intake and energy expenditure. However, regulatory mechanisms of leptin gene expression are not fully elucidated in ruminants that utilize short-chain fatty acids (SCFA), known as volatile fatty acids, as principal energy sources. In this study, we determined effects of SCFA and long-chain fatty acids (LCFA) on leptin expression in bovine adipocytes. Bovine stromal vascular cells isolated from subcutaneous adipose tissue of Holstein cows were cultured to confluence and treated sequentially with dexamethasone and isobutylmethylxanthine for 2 days and insulin and troglitazone for 12 days to achieve full differentiation to adipocytes. The cells started to accumulate lipids 4 days after the onset of treatment, with increased mRNA expression of leptin, as well as aP2, adiponectin, and PPAR-γ. Removal of fetal calf serum and reduction of glucose in the culture medium of differentiated adipocytes decreased leptin mRNA expression. Subsequent addition of acetate, butyrate, or propionate dose-dependently restored and rather increased leptin expression, while addition of LCFA suppressed it. The stimulatory effect of acetate was abolished by prior treatment of the cells with pertussis toxin and by addition of LCFA. Furthermore, cows fasted for 48 h and fed thereafter, elaborate reduced and increased plasma leptin levels, respectively. Thus, these results suggest that plasma leptin levels in cows are inversely controlled at the transcription level by VFA and LCFA, and that the effects of SCFA possibly act through a G protein-coupled receptor for SCFA.

Leptin enhances in vitro secretion of IgG antiplatelet antibodies by splenocytes and peripheral blood mononuclear cells from patients with chronic idiopathic thrombocytopenic purpura

Chronic idiopathic thrombocytopenic purpura (ITP) is an organ-specific autoimmune disease characterized by the production of antibodies against antigens on the membranes of platelets, resulting in enhanced destruction of the platelets by macrophages. Leptin, a cytokine-like hormone, plays a role in the pathogenesis of several autoimmune diseases. In this study, we observed significantly increased plasma leptin levels combined with decreased soluble leptin receptor (sOB-R) levels in 18 chronic ITP patients compared with 14 controls. We also demonstrated significantly elevated mRNA expression of long form leptin receptor (Ob-Rb) on peripheral blood mononuclear cells (PBMCs) from chronic ITP patients. Treatment with recombinant leptin or serum with high leptin levels enhanced in vitro secretion of IgG antiplatelet antibodies by splenocytes and PBMCs from patients with chronic ITP. After depletion of CD4+ T cells from splenocytes, leptin lost this function. Further studies showed that leptin could increase platelet reactive T cells. These findings suggest that leptin may be involved in the pathogenesis of chronic ITP and might offer a potential target for the treatment of this disease.

Melanocortin-4 Receptor Mediates Chronic Cardiovascular and Metabolic Actions of Leptin

This study tested whether the melanocortin 4-receptor (MC4R) is essential for the chronic cardiovascular and metabolic actions of leptin. Twenty- to 22-week-old male wild-type (WT) C57BL/6J and obese MC4R (-/-) mice (N=5 to 6 per group) were implanted with radiotelemetric transmitters and catheters for measuring mean arterial pressure (MAP) and heart rate 24 hours per day and intravenous infusions. After a 3-day stable control period, leptin was infused (2 microg/kg per minute IV) for 7 days in WT, obese ad libitum-fed MC4R (-/-), and nonobese pair-fed MC4R (-/-) mice. WT mice receiving vehicle for 7 days served as controls. MC4 (-/-) mice were 30% heavier and had 4- and 11-fold increases in plasma insulin and leptin levels, respectively, compared with WT mice. Despite obesity, MAP and heart rate tended to be lower in MC4R (-/-) mice compared with WT mice. Chronic leptin infusion in the different groups increased plasma leptin levels to 45 to 65 ng/mL. Seven-day leptin infusion in WT mice increased MAP by 12+/-3 mm Hg despite a 35% reduction in food intake and an 8% reduction in body weight. Leptin did not alter plasma glucose but reduced plasma insulin in WT mice (5.9+/-1.0 versus 3.0+/-0.5 microU/mL). These cardiovascular and metabolic actions of leptin were abolished in obese and nonobese MC4R (-/-) mice. These data suggest that MC4R deficiency, and not obesity-induced leptin resistance, abolished the cardiovascular and metabolic actions of leptin in obese MC4R (-/-) mice. Thus, a functional MC4R is essential for the chronic cardiovascular and metabolic actions of leptin.

Leptin receptor-deficient obese Zucker rats reduce their food intake in response to hypobaric hypoxia

Exposure to hypoxia induces anorexia in humans and rodents, but the role of leptin remains under discussion and that of orexigenic and anorexigenic hypothalamic neuropeptides remains unknown. The present study was designed to address this issue by using obese (Lepr(fa)/Lepr(fa)) Zucker rats, a rat model of genetic leptin receptor deficiency. Homozygous lean (Lepr(FA)/Lepr(FA)) and obese (Lepr(fa)/Lepr(fa)) rats were randomly assigned to two groups, either kept at ambient pressure or exposed to hypobaric hypoxia for 1, 2, or 4 days (barometric pressure, 505 hPa). Food intake and body weight were recorded throughout the experiment. The expression of leptin and vascular endothelial growth factor (VEGF) genes was studied in adipose tissue with real-time quantitative PCR and that of selected orexigenic and anorexigenic neuropeptides was measured in the hypothalamus. Lean and obese rats exhibited a similar hypophagia (38 and 67% of initial values at day 1, respectively, P < 0.01) and initial decrease in body weight during hypoxia exposure. Hypoxia led to increased plasma leptin levels only in obese rats. This resulted from increased leptin gene expression in adipose tissue in response to hypoxia, in association with enhanced VEGF gene expression. Increased hypothalamic neuropeptide Y levels in lean rats 2 days after hypoxia exposure contributed to accounting for the enhanced food consumption. No significant changes occurred in the expression of other hypothalamic neuropeptides involved in the control of food intake. This study demonstrates unequivocally that altitude-induced anorexia cannot be ascribed to anorectic signals triggered by enhanced leptin production or alterations of hypothalamic neuropeptides involved in anabolic or catabolic pathways.

Lessons from the leptin paradox in cardiac regulation--too much versus too little.

Lessons from the leptin paradox in cardiac regulation--too much versus too little.

Plasma leptin concentration increases early during highly active antiretroviral therapy for acquired immunodeficiency syndrome, independent of body weight

Leptin, the protein product of the obese gene (ob), is secreted by adipocytes. Circulating leptin levels correlate with fat mass in humans, including individuals infected with HIV. Leptin serves as an adipostatic hormone, a permissive factor for reproduction and a modulator of immune function. Leptin is a cytokine, and has been demonstrated to enhance CD4 cell proliferation and IL-2 secretion from CD4 cells in vitro. The role of leptin in HIV-positive patients treated with highly active antiretroviral therapy (HAART) has not been well defined. We haveevaluated leptin levels in HIV-infected individualsduringthe early phase of HAART. We measured plasma leptin levels in 15 antiretroviral-naive HIV positive patients at baseline and after 1 and 4 weeks of HAART. After the first week of therapy, mean leptin level and CD4 count were increased compared to baseline, 6.0 vs 7.2 ng/ml (p = 0.004) and 377 vs 432 cells/ul (p = 0.014), respectively. In contrast, mean body mass index (BMI) remained unchanged 27.0 vs 26.8 kg/m2 (p < 0.08). After four weeks of therapy, leptin and BMI values were unchanged compared to baseline, 6.0 vs 5.9 (p < 0.4) and 27.0 vs 26.9 (p < 0.5), respectively, whereas CD4 count continued to increase to 491 cells/ul (p < 0.012 compared to baseline). These data demonstrate an early transient increase in plasma leptin levels in HIV positive patients initiated on HAART, despite a lack of change in BMI. It is unclear if the transient increase in leptin is related to its role as a cytokine, a metabolic regulator, or reproductive factor.

PPARα activators may be good candidates as antiaging agents

Aging is associated with a metabolic decline characterized by the development of changes in fat distribution, obesity, and insulin resistance. Dysfunctional humoral and cell-mediated immune responses occur with age, and these aberrations have been implicated in the increased incidence of infectious diseases, hyporesponsiveness to vaccination, and the etiology of numerous chronic degenerative diseases. All these metabolic and immune alterations are associated with a variety of age-related diseases that subsequently result in increased mortality. Leptin can modulate many of the metabolic alterations characteristic of aging. Leptin resistance has been implicated in the pathogenesis of obesity-related complications involving abnormalities of lipid metabolism that resemble those of old age. Increased plasma leptin levels with aging suggest resistance to leptin action and may explain why elderly subjects have abdominal obesity and insulin resistance. Leptin's failure may be considered for the metabolic decline seen with aging. Peroxisome proliferator-activated receptor (PPAR)-alpha, the transcription factor for the mitochondrial and peroxisomal enzymes of beta-oxidation, and its target enzymes, are upregulated by hyperleptinemia. PPARalpha has been shown to mediate the action of the hypolipidemic drugs of the fibrate class on lipid and lipoprotein metabolism. PPARalpha activators furthermore improve glucose homeostasis and influence body weight and energy homeostasis. The administration of agents capable of activating the PPARalpha was found to restore the cellular redox balance, evidenced by a lowering of tissue lipid peroxidation, an elimination of constitutively active NF-kappaB, loss in spontaneous inflammatory cytokine production, and ailing in the aging immunity.

Leptin induces elongation of cardiac myocytes through the activation of JAK2/STAT3 cascade

Leptin, one of cytokines, secreted from the fat and acts mainly on the hypothalamic leptin receptors. Subsequent studies demonstrate that leptin receptors widely distributed in various tissues including the heart. While increased plasma leptin levels have been reported in patients with congestive heart failure, direct effects of leptin on cardiac structure and function are unknown. To begin to address this question, we exposed primary cardiac myocytes from neonatal rats to leptin at the concentration of 0, 5, 50, and 500 ng/ml for 48 hours. Treatment of cardiomyocytes with leptin results in concentration dependent increase in cell surface area. We found that leptin significantly increased the long axis length of myocytes (10.9 ± 3.9%: 50ng/ml, p < 0.05; 13.6 ± 4.3%: 500ng/ml, p < 0.05), but not the short one. Western blotting and electromobility shift assays revealed no activation of MAP kinases including ERK, p38MAPK, and JNK. However, by immunohistochemical analysis, we showed that leptin treatment caused translocation of STAT3 into the nuclei in cardiac myocytes. Furthermore, leptin caused phophorylation of STAT3 as early as 5 minutes after the treatment and enhanced its DNA binding activity. Administration of a JAK2 inhibitor, AG490 (1microM), completely inhibited these effects by leptin. These results suggest that leptin induces elongation of cardiac myocytes and that this effect is mediated, in part, through the activation of JAK2/STAT3 cascade.

Treatment with interleukin-11 affects plasma leptin levels in inflamed and non-inflamed rabbits

Treatment with the anti-inflammatory cytokine, interleukin-11 (IL-11), in rabbits with TNBS-colitis reduces tissue damage but does not normalize body weight loss despite an increase in plasma levels of motilin, known to stimulate food intake. We investigated whether IL-11 could increase plasma levels of the anorectic peptide, leptin in non-inflamed and inflamed rabbits. In addition, the effect of IL-11 and leptin on motilin mRNA expression in the T84 cell line was tested. Five days post-inflammation, weight loss amounted 10.7±1.2%, but plasma leptin and motilin levels were unaffected. During IL-11 treatment, weight loss remained and plasma leptin levels dose-dependently increased with 27±5% (4 μg/kg day) and 108±7% (720 μg/kg day). Motilin levels increased in parallel with 23±12% or 256±97%. In non-inflamed animals, a prompt decrease in weight (−11.9±1%) was observed after treatment with the highest dose of IL-11 and this was associated with an increase in plasma leptin (70±18%) and motilin levels (113±7%). Both IL-11 and leptin stimulated motilin mRNA expression in T84 cells with a different time profile. In conclusion, the increase in plasma leptin levels during IL-11 treatment induces wasting in normal rabbits and may be one of the major factors involved in the maintenance of body weight loss in rabbits with colitis. Increase of motilin expression by leptin may be part of a feedback mechanism.

The involvement of IGF-I, leptin and some intracellular signalling mechanisms in nutrition-induced changes in rabbit ovarian cell functions

The aim of our experiments was to examine the role of IGF-I, leptin (the hormone of adipose tissue), in controlling ovarian function in different species, as well as of some protein kinases in mediating IGF-I and leptin effects. In in-vivo experiments, rabbits were subjected to food restriction (50% of normal intake) and IGF-I (2µg/animal) treatments, whilst plasma leptin and IGF-I levels were measured using RIA/EIA. In in-vitro experiments, rabbit ovarian cells were cultured in the presence of leptin, antiserum against IGF-I, inhibitors of MAP kinase and of CDC2 kinase or their combination. Expression of intracellular peptides associated with proliferation (PCNA), apoptosis (bax),CDC2/p34 kinase, cyclin B, protein kinase A, ERK1, 2 MAP kinase, CREB-1 and IGF-I, as well as the secretion of progesterone (P), estradiol (E), IGF-I, and IGFBP-3 were determined using SDS PAGE-Western blotting, immunocytochemistry, RIA and ELISA. Food restriction in rabbits in the periovulatory period results in a significant reduction in plasma leptin levels, which was associated with a significant decrease in IGF-I plasma concentrations. IGF-I addition signicantly increased plasma leptin levels. In in-vitro experiments there was no accumulation of immunoreactive leptin in culture medium conditioned by rabbit granulosa cells. Both leptin and IGF-I additions altered progesterone, estradiol, IGF-I and IGFBP-3 release by cultured granulosa cells, as well as changing the expression of IGF-I, PCNA, bax, protein kinase A, ERK1, 2 MAP kinase, p34 CDC2 kinase, cyclin B and CREB within these cells. Previous food restriction enhanced the response of ovarian cells to leptin and IGF-I treatment. The present observations suggest

Partial reversal of Cachexia by β-adrenergic receptor blocker therapy in patients with chronic heart failure

BackgroundCachexia is a common problem in chronic heart failure (CHF) that may be partly mediated by activation of the sympathetic nervous system. The effects of β-adrenergic receptor blocker (BB) therapy on body weight in cachectic and noncachectic subjects with CHF has not been previously reported. Methods and resultsBody weight and plasma norepinephrine, leptin, and insulin levels were measured in 27 subjects with CHF before and after 6 months of β-adrenergic receptor blockade with carvedilol or long-acting metoprolol. Before BB therapy, baseline weight, plasma leptin, and plasma insulin levels did not differ between cachectic and noncachectic subjects. Baseline plasma norepinephrine levels were increased in cachectic subjects when compared with noncachectic subjects (930±248 pg/mL versus 503±109 pg/mL, P=.063). After 6 months of BB therapy, subjects with baseline cachexia demonstrated significantly greater weight gain (+5.2±9.6 versus +0.8±5.0 kg, P=.027), greater increase in plasma leptin levels (+3.7±3.9 versus +1.2±4.3 ng/mL, P=.030), and greater decrease in plasma norepinephrine levels (–374±261 versus –41±122 pg/mL, P=.012) when compared with noncachectic subjects. ConclusionsSix months of BB therapy with carvedilol or long-acting metoprolol is associated with differential effects on body weight and hormonal levels in cachectic and noncachectic subjects with CHF. Further work is needed to determine the role the sympathetic nervous system in the pathogenesis of cachexia in patients with CHF.