Amylin and leptin activate overlapping signalling pathways in an additive manner in mouse GT1-7 hypothalamic, C2C12 muscle and AML12 liver cell lines

Aims/hypothesis  

It has been suggested that amylin amplifies leptin’s effects and affects energy homeostasis synergistically with leptin in animals and humans. However, no previous study has reported on amylin and leptin signalling in hypothalamic, muscle and liver cells.     

The influence of leptin on Th1/Th2 balance in obese children with asthma

OBJECTIVE:

In individuals with asthma, obesity induces the production of leptin and is associated with disease severity. Our objective was to evaluate the levels of serum leptin and their effect on Th1/Th2 balance in obese and non-obese children with asthma, as well as to investigate the association between serum leptin levels and clinical outcomes.

METHODS:

We evaluated 50 atopic children with physician-diagnosed moderate-to-severe persistent asthma and 20 controls. The children with asthma were divided into two groups, by body mass index percentile: obese (n = 25) and non-obese (n = 25). From all subjects, we collected peripheral blood samples in order to determine the levels of leptin, IFN-γ, and IL-4. Asthma severity was assessed by an asthma symptom score, and the results were correlated with the parameters studied.

RESULTS:

Serum leptin levels were significantly higher in the obese asthma group than in the non-obese asthma group, as well as being significantly higher in the children with asthma than in the controls, whereas IFN-γ levels were significantly higher and IL-4 levels were significantly lower in the obese asthma group than in the non-obese asthma group. In addition, the obese asthma group showed higher asthma symptom scores and significantly lower FEV₁ (% of predicted) than did the non-obese asthma group. There was a significant positive correlation between leptin and IFN-γ levels only in the obese asthma group.

CONCLUSIONS:

Although leptin is involved in the pathogenesis of asthma in obese and non-obese children, its effect is more pronounced in the former. In the presence of high leptin levels, only obese children with asthma exhibited Th1 polarization, with higher IFN-γ levels and greater asthma severity.     

The effect of <Emphasis Type="Italic">H. pylori</Emphasis> eradication on meal-associated changes in plasma ghrelin and leptin

Background  

Appetite and energy expenditure are regulated in part by ghrelin and leptin produced in the gastric mucosa, which may be modified by H. pylori colonization. We prospectively evaluated the effect of H. pylori eradication on meal-associated changes in serum ghrelin and leptin levels, and body weight.     

Effects of pioglitazone treatment on blood leptin levels in patients with type 2 diabetes

Aims/Introduction

The aim of the present study was to carry out a meta‐analysis of randomized controlled trials (RCTs) that investigated the effects of pioglitazone on blood leptin levels in patients with type 2 diabetes.

Materials and Methods

Literature searches were carried out using Medline, the Cochrane Controlled Trials Registry and ClinicalTrials.gov, and RCTs that investigated the effects of pioglitazone on blood leptin levels in patients with type 2 diabetes were selected. Standardized mean differences and 95% confidence intervals were calculated.

Results

A total of 10 RCTs met the eligibility criteria and were included in the meta‐analysis. Significantly lower blood leptin levels were observed in the pioglitazone group (standardized mean difference ?0.58, 95% confidence interval ?1.12 to ?0.05%, P = 0.03) than in the placebo group. There was no significant difference in blood leptin levels observed between the pioglitazone and oral antidiabetic drug groups (standardized mean difference ?0.01, 95% confidence interval ?0.20 to 0.19%, P = 0.93).

Conclusions

There was a significant difference in blood leptin levels between the pioglitazone and placebo groups. However, relatively few RCTs were included in the study, and there was a high level of statistical heterogeneity; we believe that this could have affected the results.

     

Estradiol and luteinizing hormone regulation of insulin-like growth factor binding protein production by bovine granulosa and thecal cells

To determine the effects of estradiol and luteinizing hormone (LH) on insulin-like growth factor-binding protein (IGFBP) production by bovine granulosa and thecal cells, both cell types were collected and cultured in serum-free medium with various hormone treatments, arranged in three experiments. In thecal cells, insulin stimulated (p < 0.05) production of IGFBP-2 and IGFBP-5, but had no effect (p > 0.10) on IGFBP-3 and IGFBP-4 production; LH stimulated (p < 0.05) production of IGFBP-2 and IGFBP-3 but had no effect (p > 0.05) on IGFBP-4 and IGFBP-5. Estradiol had no effect (p > 0.10) on IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 production by thecal cells. Production of IGFBP-2/-5 by granulosa cells from small follicles was inhibited (p < 0.05) by insulin, but estradiol and LH did not influence (p > 0.10) insulin's inhibitory effect on basal IGFBP-2/-5 production. Insulin, LH, and estradiol each inhibited IGFBP-4 production by small-follicle granulosa cells, but their effects were not additive. IGFBP-3 was not produced by small-follicle granulosa cells. In large-follicle granulosa cells, insulin and LH inhibited (p < 0.05) production of IGFBP-2/-5 and IGFBP-3, whereas estradiol had no effect. Insulin alone had no effect (p > 0.10) on production of IGFBP-4, but estradiol and LH inhibited (p < 0.05) production by large-follicle granulosa cells, and their effects were not additive. These results suggest that production of IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 by granulosa and thecal cells is differentially affected by hormonal stimuli.     

Circulating fetuin-A levels are not affected by short and long-term energy deprivation and/or by leptin administration

Objective

Fetuin-A may mediate cross-talk between the liver and adipose tissue. We studied the physiologic regulation of fetuin-A and explored its potential regulation by leptin.

Design and Methods

Fetuin-A levels were measured in three interventional studies as well as in in vitro experiments. Study 1: 15 lean subjects received placebo or physiologic replacement-dose recombinant human leptin (metreleptin) following short term complete caloric deprivation to induce severe hypoleptinemia; Study 2: 7 women with relative leptin deficiency due to strenuous exercise or low weight received 3 months of metreleptin; Study 3: 17 women with relative leptin deficiency were randomized to receive metreleptin or placebo over 9 months. In study 4 human hepatoma Hep G2 cells were treated with leptin. Fetuin-A mRNA expression and secretion were measured.

Results

Complete caloric deprivation significantly decreased leptin but had no effect on fetuin-A levels. Normalizing leptin levels with metreleptin in hypoleptinemic subjects had no effect on circulating fetuin-A levels. Leptin treatment had no effect on fetuin-A mRNA expression and secretion in vitro.

Conclusions

Circulating fetuin-A levels are not affected by short and long-term energy deprivation. Furthermore, both in vivo and in vitro experiments confirm that fetuin-A is not regulated by leptin.     

Association of coffee consumption with serum adiponectin,leptin, inflammation and metabolic markers in Japanese workers: a cross-sectional study

Background:

Mechanisms underlying coffee''s beneficial actions against cardiovascular disease and glucose metabolism are not well understood. Little information is available regarding association between coffee consumption and adipocytokines.

Objective:

We investigated potential associations between coffee consumption and adiponectin, leptin, markers for subclinical inflammation, glucose metabolism, lipids and liver enzymes. We then investigated whether adipocytokines played a role in the association between coffee consumption and these markers.

Design and subjects:

This is a cross-sectional study comprising 2554 male and 763 female Japanese workers. Potential relations between coffee consumption and adipocytokines or other markers were evaluated using a multiple linear regression model adjusted for confounding factors. We evaluated whether adiponectin and leptin partly explain the associations between coffee consumption and each marker by multiple mediation analysis.

Results:

Coffee consumption showed significant positive associations with adiponectin and total and low-density lipoprotein cholesterol, and inverse associations with leptin, high sensitivity C-reactive protein (hs-CRP), triglycerides and liver enzymes (all P<0.05). An adjustment for adiponectin and leptin significantly attenuated the associations between coffee consumption and hs-CRP or triglycerides, but not for liver enzymes. No associations were observed between coffee consumption and glucose metabolism-related markers.

Conclusion:

Coffee consumption was associated with high adiponectin and low leptin levels. We speculated that adipocytokines mainly explain the associations of coffee consumption with lipids and hs-CRP. Factors other than adipocytokines may explain the association between coffee consumption and liver function.     

Positive association of plasma leptin with sleep quality in obese type 2 diabetes patients

Aims/Introduction

Poor sleep quality is associated with obesity and diabetes. The adipocyte‐derived hormone, leptin, was recently shown to underlie the link between abnormal sleep and obesity. We aimed to investigate the association between leptin and sleep quality in type 2 diabetes patients.

Materials and Methods

In the present cross‐sectional study, we studied 182 type 2 diabetes patients, among whom 113 were diagnosed with obesity (body mass index ≥25 kg/m²). Fasting plasma leptin levels were measured, and sleep architecture was assessed using single‐channel electroencephalography.

Results

Using unadjusted analyses, the obese type 2 diabetes patients, but not their non‐obese counterparts, showed a positive correlation between plasma leptin levels and a parameter for deep sleep assessed by delta power during the first sleep cycle. Multivariate analysis showed that plasma leptin levels were positively associated with delta power, but not with the total sleep time, after adjusting for potential confounders including age, body mass index and the apnea–hypopnea index, in the obesity group. However, neither delta power nor total sleep time was associated with leptin in the non‐obesity group.

Conclusions

Plasma leptin levels are independently associated with sleep quality in obese, but not in non‐obese, type 2 diabetes patients. The present study indicates a favorable relationship between leptin and sleep quality in obese type 2 diabetes patients.     

Serum leptin response to the acute and chronic administration of growth hormone (GH) to elderly subjects with GH deficiency

In human studies, the principal determinant of serum leptin concentrations is fat mass (FM), but lean mass (LM) also has a significant negative influence. GH treatment in GH deficiency (GHD) alters body composition, increasing LM and decreasing FM, and thus would be expected to alter leptin concentrations. We have therefore examined the acute and chronic effects of GH on serum leptin in 12 elderly GHD subjects (ages 62-85 yr; 3 women and 9 men). FM (kilograms) and LM (kilograms) were determined by dual energy x-ray absortiometry. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 were measured by specific immunoassays. Leptin, insulin, and IGFBP-1 concentrations were log10 transformed, and data were expressed as the geometric mean (-1, +1 tolerance factor). All other data are presented as the mean +/- SD. In the acute study, patients received a single bolus dose of GH (0.1 mg/kg BW) at time zero, with blood samples drawn at 0, 12, 24, 48, and 72 h and 1 and 2 weeks. There was a significant rise in leptin, insulin, and IGF-I at a median time of 24 h, followed by a significant fall, and nadir concentrations were reached at a median time of 1.5 weeks (leptin) or 2 weeks (insulin and IGF-I). IGFBP-3 concentrations were also significantly increased, but peak concentrations were not achieved until 48 h. IGF-II, IGFBP-1, and IGFBP-2 exhibited transient decreases before returning to baseline levels. There was no relationship between increased leptin concentrations and either insulin or IGF-I concentrations. In the chronic study, patients received daily GH treatment at doses of 0.17, 0.33, and 0.5 mg/day, each for 3 months (total time on GH, 9 months), and were then followed off GH for a further 3 months. Dual energy x-ray absortiometry was undertaken at 0, 3, 6, 9, and 12 months, and blood samples were drawn at these time points. Over 9 months on GH there was a significant fall in FM and a significant rise in LM, but no change in leptin. There were also significant increments in insulin, IGF-I, and IGFBP-3, whereas IGF-II, IGFBP-1, and IGFBP-2 did not change over 9 months of GH treatment. After 3 months off GH, there was a significant rise in FM and leptin. High dose single bolus GH led to an increase in serum leptin within 24 h apparently independent of changes in insulin or IGF-I. Despite the changes in body composition during chronic GH treatment, there was no change in leptin. However, discontinuation of GH led to a rapid reversal of the favorable body composition and a rise in serum leptin.     

Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia

Aims/hypothesis  

The postpartum phase following gestational diabetes (GDM) is characterised by subtle metabolic defects, including the beta cell dysfunction that is believed to mediate the increased future risk of type 2 diabetes in this patient population. Low circulating levels of adiponectin and increased leptin and C-reactive protein (CRP) have recently emerged as novel diabetic risk factors, although their relevance to GDM and subsequent diabetes has not been characterised. Thus, we sought to determine whether adiponectin, leptin and CRP levels during pregnancy relate to the postpartum metabolic defects linking GDM with type 2 diabetes.     

Impact of Obesity and Leptin on Protein Expression Profiles in Mouse Colon

Background  

Elevated leptin levels in obesity are associated with increased risk of colon pathology, implicating leptin signaling in colon disease. However, leptin-regulated processes in the colon are currently uncharacterized. Previously, we demonstrated that leptin receptors are expressed on colon epithelium and that increased adiposity and elevated plasma leptin in rats are associated with perturbed metabolism in colon tissue. Thus, we hypothesize that obesity disrupts expression of proteins regulated by leptin in the colon.     

Low serum 25-hydroxyvitamin D level predicts progression to type 2 diabetes in individuals with prediabetes but not with normal glucose tolerance

Aims/hypothesis  

Vitamin D deficiency may increase the risk of type 2 diabetes. We therefore investigated whether serum concentrations of 25-hydroxyvitamin D [25(OH)D] would predict the development of prediabetes (impaired fasting glucose, impaired glucose tolerance or the two combined) and type 2 diabetes, either on their own or when combined with serum concentrations of IGF-1 or IGF-binding protein-1 (IGFBP-1), which may interact with 25(OH)D.     

Circulating IGFBP-2 levels are incrementally linked to correlates of the metabolic syndrome and independently associated with VLDL triglycerides

Objective: To assess whether plasma IGFBP-2 is independently associated with components of the lipoprotein-lipid profile and to suggest a cutoff value that could identify subjects with the features of the metabolic syndrome. Methods: In this cross-sectional study, 379 Caucasian men from the general population and covering a wide range of BMI were recruited through the media. Subjects with type 2 diabetes, BMI values > 40 kg/m², or taking medication targeting glucose or lipid metabolism or blood pressure were excluded. Anthropometric data were collected and plasma IGFBP-2 concentrations, glucose tolerance and an extensive plasma lipid profile were determined after an overnight fast. Results: Subjects with low IGFBP-2 levels were characterized by increased fat mass (p < 0.0001), impaired insulin sensitivity (p < 0.0001) and higher plasma triglyceride (TG) levels (p < 0.0001). When divided into 6 quantiles, only subjects with the highest IGFBP-2 levels (>221.5 ng/mL) did not meet the NCEP ATP III criteria for the clinical diagnosis of the metabolic syndrome. In addition, circulating IGFBP-2 levels were significantly associated with VLDL-TG (r = −0.51, p < 0.0001) and HDL-C (r = −0.27, p < 0.0001) levels. After adjustments, plasma IGFBP-2 was found to be independently associated with VLDL-TG levels but not with HDL-C concentrations. Conclusions: In our cohort, IGFBP-2 levels <221.5 ng/mL are incrementally associated with a detrimental plasma lipoprotein-lipid profile. After adjustment for covariates, IGFBP-2 remained independently associated with VLDL-TG but not HDL-C levels. This study supports further investigations in other populations and validation of IGFBP-2 as a biomarker of early dyslipidemia.     

<Emphasis Type="Italic">Chlamydia trachomatis</Emphasis>growth inhibition and restoration of LDL-receptor level in HepG2 cells treated with mevastatin

Background  

Perihepatitis is rare but consistently occurring extragenital manifestation of untreated Chlamydia trachomatis infection. Despite of possible liver involvement in generalized C. trachomatis infection, the ability of the pathogen to propagate in the hepatic cells and its impact on liver functions is not thoroughly investigated. The effect of mevastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, on C. trachomatis growth in human hepatoma cell line HepG2 has been studied. Bacterial growth was assessed by immunostaining with FITC-labeled monoclonal antibody against chlamydial lipopolysaccharide and by RT-PCR for two chlamydial genetic markers (16S rRNA and euo).     

Leptin prevents the metabolic effects of adiponectin in L6 myotubes

Aims/hypothesis  

Adiponectin and leptin are negatively and positively correlated with human obesity respectively, and have both been shown to regulate energy metabolism in skeletal muscle. However, little is known about their signalling and functional crosstalk. Here we investigated the effects of leptin on metabolic actions of (1) globular adiponectin (gAd) and (2) full-length adiponectin (fAd) in L6 cells.     

Expression and clinical significance of leptin,the functional receptor of leptin (OB-Rb) and HER-2 in non-small-cell lung cancer: a retrospective analysis

Background  

The human epidermal growth factor receptor 2 (HER-2) and leptin/OB-R system have been reported to be intertwined in several cancer types. However, limited research has been conducted with regard to this interaction in lung cancers. In this study, we investigated the relationship between the expression levels of these proteins and the development, progression and prognosis of non-small-cell lung cancer (NSCLC).     

Association between serum insulin-like growth factor I or IGF-binding protein 3 and estimated glomerular filtration rate: results of a population-based sample

Background

Insulin-like growth factor I (IGF-I), which is mostly carried in blood by IGF-binding protein 3 (IGFBP-3), was associated to the glomerular filtration rate and chronic kidney disease in a multiethnic study among US adults. The aim of the present study was to investigate whether serum IGF-I or IGFBP-3 are associated with estimated glomerular filtration rate (eGFR) in a population-based study of Caucasian adults.

Methods

Data from 4028 subjects (2048 women) aged 20 to 81 years from the Study of Health in Pomerania (SHIP) were analyzed. Total serum IGF-I and IGFBP-3 concentrations were determined by chemiluminescence immunoassays and categorized into sex- and age-specific quartiles.

Results

After adjusting for age, waist circumference and type 2 diabetes mellitus, analysis of variance (ANOVA) revealed inverse associations between serum IGF-I concentrations and eGFR in men as well as between serum IGFBP-3 concentrations and eGFR in men and women. Logistic regression analyses confirmed these findings and showed that high IGF-I or IGFBP-3 concentrations were associated with an increased risk of decreased eGFR (<60 mL/min/1.73 m²) in men or women. These relations became stronger when lower eGFR cut-offs were used for the analyses.

Conclusion

Our data revealed associations of increased serum IGF-I concentrations and decreased eGFR in men but not in women and an association of increased serum IGFBP-3 concentrations and decreased eGFR in both sexes.

     

L‐carnitine prevents metabolic steatohepatitis in obese diabetic KK‐Ay mice

Aim

Pharmacological treatment for metabolic syndrome‐related non‐alcoholic steatohepatitis has not been established. We investigated the effect of L‐carnitine, an essential substance for β‐oxidation, on metabolic steatohepatitis in mice.

Methods

Male KK‐A^y mice were fed a high‐fat diet (HFD) for 8 weeks, with supplementation of L‐carnitine (1.25 mg/mL) in drinking water for the latter 4 weeks.

Results

Serum total carnitine levels were decreased following HFD feeding, whereas the levels were reversed almost completely by L‐carnitine supplementation. In mice given L‐carnitine, exacerbation of hepatic steatosis and hepatocyte apoptosis was markedly prevented even though HFD feeding was continued. Body weight gain, as well as hyperlipidemia, hyperglycemia, and hyperinsulinemia, following HFD feeding were also significantly prevented in mice given L‐carnitine. High‐fat diet feeding elevated hepatic expression levels of carnitine palmitoyltransferase 1A mRNA; however, production of β‐hydroxybutyrate in the liver was not affected by HFD alone. In contrast, L‐carnitine treatment significantly increased hepatic β‐hydroxybutyrate contents in HFD‐fed mice. L‐carnitine also blunted HFD induction in sterol regulatory element binding protein‐1c mRNA in the liver. Furthermore, L‐carnitine inhibited HFD‐induced serine phosphorylation of insulin receptor substrate‐1 in the liver. L‐carnitine decreased hepatic free fatty acid content in 1 week, with morphological improvement of swollen mitochondria in hepatocytes, and increases in hepatic adenosine 5’‐triphosphate content.

Conclusions

L‐carnitine ameliorates steatohepatitis in KK‐A^y mice fed an HFD, most likely through facilitating mitochondrial β‐oxidation, normalizing insulin signals, and inhibiting de novo lipogenesis in the liver. It is therefore postulated that supplementation of L‐carnitine is a promising approach for prevention and treatment of metabolic syndrome‐related non‐alcoholic steatohepatitis.

     

Circulating IGF-axis protein levels and their relation with levels of plasma adipocytokines and macronutrient consumption in women

ObjectiveCirculating free insulin-like growth factor (IGF)-I and its binding proteins, most notably, IGFBP-1 and IGFBP-2, have been prospectively associated with incident type 2 diabetes in women. However, little is known regarding the factors that may influence these IGF-axis protein levels. The aim is to study the relation of IGF-axis protein levels with adipcytokines, macronutrient consumption, and other factors related to diabetes.DesignFasting plasma from 558 controls enrolled in a nested case–control study within the Nurses' Health Study of incident type 2 diabetes in women was tested for: IGF-axis proteins (free and total IGF-I, IGFBP-1, IGFBP-2, IGFBP-3), adipocytokines (leptin, adiponectin, resistin), soluble leptin receptor (sOB-R), inflammatory factors (IL-18 and C-reactive protein (CRP)), insulin, and glycated hemoglobin (HbA1C).ResultsIn multivariate models, each 1% increase in sOB-R (mean 34.9 ng/mL, standard deviation (SD) ± 11.3) was associated with − 0.20% total IGF-I (P = 0.0003) and − 0.42% free IGF-I (P = 0.002), as well as 0.73% higher IGFBP-1 (P < 0.0001) and 0.27% IGFBP-2 (P = 0.003). For example, a one SD change from the mean sOB-R level was associated with 11% lower free IGF-I. Insulin levels (mean 6.8 μU/mL ± 5.3) were inversely and adiponectin (mean 18.3 μg/mL ± 7.4) positively associated with IGFBP-1 and IGFBP-2 (all P < 0.01). Consumption of dairy protein, monounsaturated fats, and saturated fats, was also correlated with IGF-axis protein levels (all P < 0.05).ConclusionsSeveral molecular factors and macronutrients were independently associated with plasma IGF-axis protein levels. Which of these, if any, reflect biologic relationships that can be intervened upon to influence IGF-axis protein concentrations warrants further investigation.