Altered distribution of adiponectin isoforms in children with Prader-Willi syndrome (PWS): association with insulin sensitivity and circulating satiety peptide hormones

Objective Prader–Willi syndrome (PWS) is a genetic syndrome characterized by relative hypoinsulinaemia and normal or increased insulin sensitivity despite profound obesity. We hypothesized that this increased insulin sensitivity is mediated by increased levels of total and high molecular weight adiponectin and associated with changes in levels of satiety hormones. Design, patients and measurements We measured total adiponectin and its isoforms [high molecular weight (HMW), middle molecular weight (MMW) and low molecular weight (LMW) adiponectin] and satiety hormones in 14 children with PWS [median age 11·35 years, body mass index (BMI) Z‐score 2·15] and 14 BMI‐matched controls (median age 11·97 years, BMI Z‐score 2·34). Results Despite comparable BMI Z‐scores and leptin levels, the PWS children exhibited lower fasting insulin and HOMA‐IR (homeostasis model assessment of insulin resistance) scores compared to obese controls. For any given BMI Z‐score, the PWS children showed higher concentrations of fasting total and HMW adiponectin and higher HMW/total adiponectin ratios. The HMW/total adioponectin ratio was preserved in children with PWS at high degrees of obesity. In PWS children, fasting plasma total adiponectin, HMW adiponectin and HMW/total adiponectin ratio correlated negatively with age (P < 0·05), HOMA‐IR (P < 0·01), BMI Z‐score (P < 0·05), insulin (P < 0·01) and leptin (P < 0·05). In addition to higher fasting ghrelin concentrations, the PWS children showed significantly higher fasting levels of total peptide YY (PYY) and gastric inhibitory polypeptide (GIP) compared to obese controls. Conclusions Relative to controls of similar age and BMI Z‐score, the PWS children had significantly higher levels of total and HMW adiponectin, and increased ratios of HMW/total adiponectin. These findings may explain in part the heightened insulin sensitivity of PWS children relative to BMI‐matched controls.     

Anorexia nervosa is characterized by increased adiponectin plasma levels and reduced nonoxidative glucose metabolism

The aim of the present study was to examine the effects of anorexia nervosa (AN) on adipocytokines (leptin and adiponectin) plasma concentrations and insulin-stimulated glucose disposal in adolescent and young adult women. Adiponectin and leptin plasma levels, along with insulin-stimulated glucose disposal (as measured by the euglycemic-hyperinsulinemic glucose clamp) and oxidative and nonoxidative glucose metabolism (as measured by indirect calorimetry during the last 60 min of the insulin clamp), were measured in 11 anorectic patients and 26 normal-weight healthy female controls. Leptin levels were significantly lower in AN patients, according to the reduced body mass index and their respective fat mass. On the contrary, adiponectin plasma levels were significantly higher in AN patients than in control women. Likewise, insulin-stimulated glucose disposal and nonoxidative glucose metabolism were significantly lower in AN patients. In conclusion, our study shows that young women affected by AN have higher adiponectin plasma levels than healthy female controls of similar age, despite the presence of an impairment of insulin-stimulated glucose disposal, with a prevalent failure of nonoxidative glucose metabolism. Taken together, these data suggest that the reduction of fat mass may play the major role in the control of adiponectin release, with respect to changes in insulin sensitivity.     

Soluble leptin receptor levels in patients with anorexia nervosa

OBJECTIVE: To examine whether changes of serum soluble leptin receptor levels (S-LEPR) can modify leptin half-life and its tissue effects. The aim of our study was to measure S-LEPR levels in patients with anorexia nervosa (AN) before and 6 weeks after partial refeeding. METHODS: Anthropometric variables, serum leptin, S-LEPR, insulin, cortisol and TNF-alpha were measured in 15 AN patients before and after partial refeeding and 15 healthy control women. RESULTS: S-LEPR levels in AN patients were significantly higher than in healthy subjects (26.8 +/- 8.1 vs. 16.36+/-2.6U/mL, p < 0.01) and were not affected by partial refeeding (26.8 +/- 8.1 vs. 24.2 +/- 6.1 U/mL). In contrast, body mass index (BMI), body fat content, and serum leptin levels in AN patients increased significantly after partial refeeding. Except for the inverse relationship of S-LEPR levels to BMI and body fat content no clear relationship of this parameter to serum leptin, cortisol, insulin or TNF-alpha was found. CONCLUSION: S-LEPR levels are significantly increased in AN patients and this increase is unaffected by partial refeeding. The possibility of etiological role of increased S-LEPR levels in AN patients by affecting leptin central and/or peripherial effects should be further elucidated.     

Adiponectin in anorexia nervosa and bulimia nervosa

To study the role of adiponectin, a novel adipocyte-specific secreted protein, on the pathophysiology of eating disorders, circulating levels of fasting adiponectin, leptin, insulin, and glucose were measured in 31 female patients with anorexia nervosa (AN) and in 11 with bulimia nervosa. Hormone levels were compared with 16 age-matched, normal body weight controls, six healthy constitutionally thin subjects, and nine obese subjects. Moreover, changes in levels were reevaluated after nutritional treatment and weight gain in 13 patients with AN. Serum adiponectin concentrations in AN and bulimia nervosa were significantly lower than those in normal-weight controls. These results were unexpected because the levels were high in constitutionally thin subjects and low in obese subjects, which provide a negative correlation with body mass index (BMI) and body fat mass. In contrast, serum leptin levels correlated very well with BMI and fat mass among all the patients and controls. The insulin resistance was significantly low in AN and high in obese subjects. The concentrations of adiponectin after weight recovery increased to the normal level despite a relatively small increase in BMI. These findings suggest that abnormal feeding behavior in the patients with eating disorders may reduce circulating adiponectin level, and weight recovery can restore it.     

The role of adiponectin in increased insulin sensitivity of patients with anorexia nervosa

The aim of the present study was to determine the relationship between plasma levels of adipocytokine adiponectin and the degree of insulin sensitivity in patients with anorexia nervosa (AN). AN is a psychiatric disorder characterized mainly by severe malnutrition and loss of body fat. We measured fasting plasma adiponectin, insulin and glucose levels in ten women with a restrictive type of AN and in twelve healthy normal-weight women. Plasma adiponectin levels were significantly increased in patients with AN compared to healthy women (p < 0.01) and were negatively related to body mass index and percent body fat in both groups. Plasma adiponectin levels were negatively related to plasma insulin levels in the AN group only. Using homeostasis model assessment of insulin resistance (HOMA-IR), we found significantly increased insulin sensitivity in patients with AN compared to control women (p < 0.05). In conclusion, hyperadiponectinemia in patients with AN might contribute to increased insulin sensitivity in these patients.     

Adipokines influencing metabolic and cardiovascular disease are differentially regulated in maintenance hemodialysis

Adipokines including leptin, adiponectin, visfatin, resistin, and interleukin (IL)-6 significantly influence energy metabolism, insulin sensitivity, and cardiovascular health. In the current study, we investigated serum levels of these adipokines in diabetic and nondiabetic patients on maintenance hemodialysis (MD) as compared with controls with a glomerular filtration rate greater than 50 mL/min. Serum leptin, adiponectin, high-molecular-weight (HMW) adiponectin, visfatin, resistin, and IL-6 were determined by enzyme-linked immunosorbent assay in control (n = 60) and MD (n = 60) patients and correlated to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation. Adiponectin, visfatin, resistin, and IL-6 were significantly elevated in MD patients as compared with controls. In multivariate analyses, sex and body mass index were independently correlated with serum leptin levels in both controls and MD patients. Furthermore, insulin resistance was independently and negatively associated with adiponectin and HMW adiponectin in both groups. Moreover, circulating resistin levels were independently correlated with serum visfatin concentrations in control and MD patients. However, various independent associations were only found in either controls or patients on MD. Thus, serum IL-6 levels were strongly and independently associated with C reactive protein and resistin in MD patients but not control subjects. We show that levels of various adipokines are significantly increased in MD patients. Furthermore, regulation of adipokines in vivo strongly depends on renal function. Regulation of HMW adiponectin is similar as compared with total adiponectin in the patients studied.     

Significance of leptin and high-molecular weight adiponectin in the general population of Japanese male adolescents

Adipokines play crucial roles in obesity-related insulin resistance in adults, but little is known in the general adolescent population. This study was designed to investigate the relationships between adipokines and metabolic parameters, the insulin resistance index, and proinflammatory cytokines in the general population of Japanese male adolescents. We studied 662 Japanese male high school students aged 16 to 17 years and 282 healthy Japanese male adults aged 30 to 61 years who received annual health checkups. High-molecular weight (HMW) adiponectin levels were significantly lower in adolescents (4.18 +/- 2.24 microg/mL) than in adults (4.84 +/- 3.20 microg/mL), despite body mass index (BMI) being significantly lower in adolescents. The HMW adiponectin levels correlated negatively with BMI and the homeostasis model assessment of insulin resistance index (HOMA-IR) in adults. In adolescents, HMW adiponectin correlated negatively with BMI and waist circumference, but not with HOMA-IR or other metabolic parameters except high-density lipoprotein cholesterol. Leptin levels correlated positively with HOMA-IR, triglycerides, tumor necrosis factor alpha, interleukin 6, and monocyte chemoattractant protein 1 and negatively with high-density lipoprotein cholesterol even after adjustment for BMI. These findings suggest that serum leptin is a more useful biomarker of fat accumulation-related insulin resistance, inflammation, and metabolic abnormalities than HMW adiponectin in the general population of male adolescents. The inverse correlation between adiponectin and insulin resistance may manifest in the later phase of obesity development.     

Plasma concentrations of fibroblast growth factors 19 and 21 in patients with anorexia nervosa

Context: Fibroblast growth factor 19 (FGF19) and FGF21 are novel metabolic regulators that improve insulin sensitivity and decrease adiposity in mice. However, little is known about the nutritional regulation of these factors in humans. Objective: The objective of this study was to measure plasma FGF19 and FGF21 levels in patients with anorexia nervosa (AN) and to explore its relationship with anthropometric and endocrine parameters. Design: This was a single-center cross-sectional study. Setting: The study was performed in a university hospital. Patients: Seventeen untreated women with a restrictive type of AN and 17 healthy women (control group) were included. Main Outcome Measures: Fasting plasma FGF19 and FGF21, serum insulin, leptin, soluble leptin receptor, adiponectin, resistin, and C-reactive protein were the main outcome measures. Results: Plasma FGF19 levels did not significantly differ between the groups studied, whereas plasma FGF21 levels were significantly reduced in AN relative to the control group. Plasma FGF21 positively correlated with body mass index and serum leptin and insulin and was inversely related to serum adiponectin in both groups. In contrast, plasma FGF19 was not related to any of parameters studied. Partial realimentation significantly reduced plasma FGF21 levels in AN. Conclusion: Circulating levels of FGF21 but not FGF19 are strongly related to body weight and serum levels of leptin, adiponectin, and insulin in both anorectic and normal-weight women. We suggest that reduced plasma FGF21 levels could be involved in the pathophysiology of AN or in a complex adaptive response to this disease.     

Adiponectin gene expression in subcutaneous adipose tissue of obese women in response to short-term very low calorie diet and refeeding

Adiponectin is an adipocyte-derived protein suggested to be involved in energy homeostasis and in lipid and glucose metabolism. Little is known regarding the consequence of acute changes in energy balance on adiponectin mRNA expression in human adipose tissue. Using a real-time RT-PCR assay, we investigated the effects of 2-d very low calorie diet (VLCD) and subsequent refeeding on adiponectin mRNA expression in sc adipose tissue of morbidly obese women. Basal adiponectin mRNA abundance of the obese women showed a wide distribution (2.6-14.3 mRNA/18S rRNA; coefficient of variation, 51.2%) and was significantly lower than that of lean controls (P < 0.001). In the obese group, the VLCD caused a 33% rise (P < 0.01) in the average level of mRNA, whereas refeeding caused a 32.8% fall (P < 0.05). In contrast, the change in leptin mRNA expression with either VLCD or refeeding was not statistically significant. The obese subjects who showed an acute adiponectin mRNA response to the changes in energy intake had a higher basal level of adiponectin mRNA (P = 0.02) and a borderline-significantly lower body mass index compared with the subjects who showed no or weak adiponectin mRNA response. Insulin sensitivity of the responder subgroup significantly increased by 89% (P = 0.008) after the VLCD, whereas insulin sensitivity of the nonresponder subgroup only increased by 24% (P = 1.56). This study indicates that adiponectin mRNA in sc adipose tissue can acutely respond to short-term energy changes in some obese subjects. Both the levels of adiposity and insulin sensitivity may contribute to the variation in adiponectin gene expression in response to acute energy changes.     

Differences and similarities regarding adiponectin investigated in African and Caucasian women

OBJECTIVE: Concentrations of adiponectin, an adipocytokine with insulin-sensitizing actions, may vary according to ethnic group. This study aimed to determine whether fasting adiponectin levels of Caucasian and African women differ. A second objective was to determine which components of the metabolic syndrome are more closely related to adiponectinemia in both groups. DESIGN: A cross-sectional study including 102 urban African and 115 Caucasian women with a wide range of obesity aged 20-55 years. METHODS: Anthropometric measurements were taken, namely weight, height, body mass index, waist circumference, and hip circumference. Cardiovascular measurements included blood pressure and arterial compliance. Fasting blood samples were taken to determine glucose, insulin, C-peptide, leptin, adiponectin, and lipid levels. RESULTS: Mean adiponectin levels of the whole groups did not differ, but normal weight African women (N = 38) showed marginally lower adiponectin levels than their Caucasian counterparts (N = 41; P = 0.047). No differences in adiponectin were shown for overweight and obese women. Separate multiple regression analyses for ethnic groups showed that only homeostasis model assessment-insulin resistance (HOMA-IR) significantly contributed to the variance in adiponectin levels of African women, whereas leptin, triacylglycerol levels and HOMA-IR contributed significantly to adiponectin variance in Caucasian women. An additional multiple regression analysis in a combined ethnic group (N = 217) showed ethnicity to be a significant contributor to variances in adiponectin levels. CONCLUSIONS: Even though adiponectin levels of these ethnic groups are similar, different associations of adiponectin with leptin and triacylglycerol levels might indicate that there are ethnic differences regarding the mechanistic functions of adiponectin within the scope of the metabolic syndrome.     

The effect of renal transplantation on adiponectin and its isoforms and receptors

Insulin resistance (IR) and other proatherogenic risk factors associated with end-stage kidney disease (ESKD) are improved by renal transplantation. Adiponectin is a protein with insulin-sensitizing, anti-inflammatory, and antiatherogenic properties. It exists in several isoforms, but the high molecular weight (HMW) isoform correlates best with insulin sensitivity. Paradoxically, the levels of this protein and its HMW isoform are increased in ESKD. We measured the homeostasis model assessment for insulin resistance (HOMA-IR), plasma adiponectin and its isoforms, and messenger RNA for adiponectin receptors (AdipoR1 and AdipoR2) on peripheral blood mononuclear cells in 54 stable transplant recipients, 50 patients established on hemodialysis, and 52 controls; groups were matched for body mass index and sex. HOMA-IR values were significantly higher in patients with ESKD compared with controls (P < .0005) and transplant patients (P < .05) but there was no difference between the latter 2 groups. Adiponectin levels were also higher in patients with ESKD compared with controls (P < .0005), and although levels were lower in the transplant group, they remained higher than in controls (P < .0001). However, although the absolute amount of HMW isoform in transplant patients remained higher than in controls (P < .0001), the proportion was similar, and less than in patients with ESKD (P < .005). The absolute amount of the HMW isoform correlated with superior metabolic indices in all 3 cohorts. AdipoR1 and AdipoR2 messenger RNA levels after transplantation were significantly lower than those of ESKD subjects (P < .0001, P < .01), but transplant patients had less AdipoR1 than controls, although their AdipoR2 levels were higher. AdipoR1 correlated with AdipoR2 in all 3 cohorts. We conclude that HOMA-IR was lower in the transplant group compared with the group on hemodialysis and this coincided with lower total adiponectin levels and absolute amount of the HMW isoform and AdipoR on peripheral blood mononuclear cells. Lower AdipoR after transplantation may be secondary to immunosuppression and/or an improvement in glomerular filtration rate and the uremic milieu.     

Altered levels of adipocytokines in association with insulin resistance in patients with systemic lupus erythematosus

OBJECTIVE: The metabolic syndrome, closely associated with cardiovascular disease, is characterized by increased insulin resistance (IR). Although accelerated atherosclerosis is frequently observed in systemic lupus erythematosus (SLE), the prevalence and significance of IR remain to be elucidated. We evaluated IR in association with plasma concentrations of adipocytokines in patients with SLE. METHODS: Outpatients with SLE (n = 37) and healthy controls (n = 80) were studied. A value of the homeostasis model assessment index (HOMA-IR) > 2.0 was considered to be IR. Plasma concentrations of adiponectin and tumor necrosis factor-a (TNF-a) were measured by ELISA and leptin by radioimmunoassay. RESULTS: HOMA-IR indices of the SLE patients were significantly higher than those of controls (2.3 +/- 2.3 vs 1.3 +/- 1.0, respectively; p < 0.01), although both groups exhibited a similar body mass index. The prevalence of hypertension and diabetes mellitus was significantly higher in patients with SLE compared with controls (48.6% vs 8.8% and 10.8% vs 0%). Twelve SLE patients (32%) with IR exhibited significantly higher incidence of hypertension and current proteinuria than SLE patients without IR. Plasma leptin, TNF-a, and, unexpectedly, adiponectin levels were higher in SLE patients than controls (adiponectin, 13.7 +/- 5.0 vs 9.5 +/- 3.9 microg/ml). Among the SLE patients, patients with IR showed significantly lower adiponectin levels than patients without IR (10.9 +/- 4.6 vs 15.4 +/- 4.4 microg/ml). Serum levels of adiponectin were significantly correlated inversely with HOMA-IR in SLE patients. CONCLUSIONS: Elevated levels of adiponectin in SLE, despite inverse correlation with IR, suggest the possible involvement of adiponectin in IR and alterations in its effect on insulin sensitivity.     

Fenofibrate increases high molecular weight adiponectin in subjects with hypertriglyceridemia

Beneficial effects of peroxisome proliferator-activated receptor alpha (PPAR alpha) agonists have been reported in improving insulin sensitivity and raising serum total adiponectin. High molecular weight (HMW) adiponectin, which is secreted from adipocytes, and visfatin, which is also expressed in adipose tissue, is related to glucose metabolism. In view of the additive effects of PPAR alpha agonists on these adipocytokines and glucose metabolism, we investigated male hypertriglyceridemic subjects who were treated with fenofibrate. Eleven male subjects with hypertriglyceridemia were treated with fenofibrate and serum total cholesterol (T-cho), triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting glucose, fasting insulin, total and HMW adiponectin, and serum visfatin levels were determined before and 3 months after treatment. Fenofibrate treatment significantly lowered T-cho, triglyceride, and LDL-C levels. There was a statistically significant increase of HDL-C. No differences in insulin sensitivity indices (G/I ratio and HOMA-IR) were observed between before and after treatment with fenofibrate. The treatment did not alter the levels of serum total adiponectin and visfatin in the hypertriglyceridemic patients, while serum HMW adiponectin increased significantly. This study demonstrates that fenofibrate increases serum HMW adiponectin levels, whereas visfatin is not regulated by fenofibrate in hypertriglyceridemic subjects. Further investigations are warranted to determine whether the elevation of HMW adiponectin caused by fenofibrate might improve insulin sensitivity.     

Hyperadiponectinaemia in anorexia nervosa

OBJECTIVE: Adiponectin (ApN) is a fat-derived hormone that enhances insulin sensitivity, controls body weight, prevents atherosclerosis and negatively regulates haematopoiesis and immune functions. In contrast to many proteins secreted by adipose tissue, the circulating level of ApN falls in obesity and insulin resistance states. The influence of starvation-induced depletion of fat stores on ApN concentrations is yet unknown. We therefore investigated plasma ApN in anorexia nervosa (AN). PATIENTS AND DESIGN: We measured plasma ApN in 26 female anorectic patients and examined its relationships to several anthropometric or metabolic parameters. Twenty-four age-matched healthy female controls (C) were also studied. RESULTS: Body mass index (BMI) and fat mass were markedly decreased in AN. However, plasma ApN levels were 30% higher in anorectic than in control subjects (P < 0.01), while a reverse pattern was observed for leptin concentrations. When normalized for fatness, ApN values almost doubled in AN. ApN levels were negatively correlated with BMI and fat mass (P < 0.05 in the combined population, AN + C). Insulin sensitivity tended to be 40% higher in AN (n = 7) than in C (n = 12) subjects, and plasma ApN levels were positively correlated with insulin sensitivity (P < 0.05 in AN + C subgroups). Total and low density lipoprotein (LDL)-cholesterol were higher, or tended to be higher, in AN, but there were no correlations between plasma ApN and plasma lipids. By contrast, ApN was related to the lipid profile, in a manner consistent with its antiatherogenic role, in healthy controls [i.e. negatively correlated with triglycerides, total and LDL-cholesterol and total/high density lipoprotein (HDL) cholesterol; P < 0.05 or less for each parameter]. In a multiple regression analysis, BMI and insulin sensitivity in AN were independent determinants for ApN levels, explaining up to approximately 80% of the variance in this measure. CONCLUSIONS: Plasma adiponectin levels are increased in anorexia nervosa. This may, at least in part, be due to the lack of negative feedback exerted by fat mass on adiponectin production and/or to enhanced insulin sensitivity. We speculate that hyperadiponectinaemia could, in turn, contribute to maintain a state of enhanced insulin sensitivity and possibly exacerbate haematological and infectious complications of anorexia nervosa.     

Total and high molecular weight (HMW) adiponectin levels and measures of glucose and lipid metabolism following pioglitazone treatment in a randomized placebo-controlled study in polycystic ovary syndrome

Objective Recent studies suggested that the effect of adiponectin on insulin‐stimulated glucose metabolism is mediated primarily by the high molecular weight (HMW) form of adiponectin. In the present study we evaluated total and HMW adiponectin in polycystic ovary syndrome (PCOS) patients and controls and examined possible mechanisms for increased insulin sensitivity during pioglitazone treatment. Study subjects Thirty PCOS patients randomized to pioglitazone, 30 mg/day, or placebo for 16 weeks and 14 weight‐matched healthy females were studied. Design Total and HMW adiponectin levels were measured, and euglycaemic hyperinsulinaemic clamps and indirect calorimetry were performed. Δ‐values denoted changes during pioglitazone treatment (16 weeks – basal). Results Pretreatment adiponectin levels were decreased in PCOS patients vs. controls (P < 0·05), whereas no significant differences were found in HMW adiponectin levels. Following pioglitazone treatment, total and HMW adiponectin increased (all P < 0·05), whereas no significant changes were observed with placebo. Δ‐total adiponectin levels correlated positively with the rate of Δ‐insulin‐stimulated glucose disposal (R_d) (r = 0·89) and Δ‐oxidative glucose metabolism (r = 0·71) and inversely with Δ‐fasting free fatty acid (FFA) levels (r = –0·69) and Δ‐lipid oxidation (r = –0·73) during insulin stimulation (all P < 0·01). Weaker correlations were found between Δ‐HMW adiponectin levels and Δ‐measures of glucose and lipid metabolism during insulin stimulation than with Δ‐total adiponectin. Conclusion A close correlation between increased total adiponectin levels and increased insulin‐stimulated glucose metabolism during pioglitzone treatment supports the hypothesis that the insulin‐sensitizing effect of pioglitazone in PCOS is, at least in part, mediated by adiponectin. Measures of changes in HMW adiponectin did not add further information to this relationship.     

Serum adiponectin and insulin secretion: A direct or inverse association?

We investigated the association between serum high molecular weight (HMW) adiponectin and insulin secretion in a population‐based study, with or without adjustment for insulin sensitivity. A total of 488 participants (263 women) were included in the present study. Insulin secretion was estimated using the homeostasis model assessment of β‐cell function ± adjustment for insulin resistance using the disposition index. Multivariate analysis showed that HMW adiponectin was significantly and inversely associated with homeostasis model assessment of β‐cell function (partial regression coefficient ?0.19, 95% confidence interval ?0.28, ?0.10, P < 0.0001). However, HMW adiponectin was significantly and positively associated with disposition index (partial regression coefficient 0.15, 95% confidence interval 0.06, 0.24, P = 0.0016). The present study showed that a positive association between HMW adiponectin levels and insulin secretion evaluated using an index incorporating adjustment for insulin resistance was identified, and vice versa using an index that did not adjust for insulin resistance.     

Hormonal and body composition predictors of soluble leptin receptor, leptin, and free leptin index in adolescent girls with anorexia nervosa and controls and relation to insulin sensitivity

Anorexia nervosa (AN) is associated with very low levels of leptin, a cytokine secreted by adipose tissue and known to suppress appetite. Leptin may play a permissive role in onset of puberty and in resumption of gonadal function in conditions of undernutrition. The soluble leptin receptor (sOB-R) is the main leptin binding protein, and the ratio of serum leptin to sOB-R provides a measure of the free leptin index (FLI), which may be a more accurate determinant of leptin function. Determinants of sOB-R and FLI have not been examined in an adolescent population. We examined levels of sOB-R, leptin, and FLI, and body composition and hormonal determinants of these variables in 23 adolescent girls with AN and 21 healthy adolescent girls of comparable maturity prospectively over 1 yr. Measures of insulin resistance and adiponectin were also examined. We determined changes in levels of sOB-R, leptin, and FLI with weight recovery (defined as an increase in body mass index of >/=10%, n = 11), and with resumption of menstrual cycles (n = 13).Girls with AN had significantly higher levels of sOB-R (P = 0.0008) and significantly lower levels of leptin and FLI (P < 0.0001 for both) than healthy controls, and levels of FLI were reduced more than levels of leptin in girls with AN compared with controls. An inverse correlation was noted between levels of leptin and sOB-R for the group as a whole (r = -0.64, P < 0.0001) but not in girls with AN considered alone. The most important predictor of levels of sOB-R was cortisol in the group as a whole (r = 0.61, P < 0.0001) and in girls with AN considered alone (r = 0.66, P = 0.0008). Other independent predictors of sOB-R levels for the entire group were percent body fat (r = -0.44, P = 0.003) and levels of IGF-I (r = -0.37, P = 0.01). The most important predictors of leptin and FLI were body mass index and percent body fat. An inverse relationship was noted between measures of insulin resistance and sOB-R levels, whereas a positive association was noted between these measures and leptin and FLI. Adiponectin values did not differ in girls with AN compared with healthy controls and did not correlate with sOB-R, leptin, or FLI. Weight recovery resulted in significant decreases in levels of the sOB-R (24.7 +/- 1.7 to 17.6 +/- 1.2 U/ml, P = 0.004), and increases in levels of leptin (4.4 +/- 1.0 to 13.7 +/- 2.9 microg/liter, P = 0.02). Resumption of menstrual function, but not weight recovery alone, was associated with significant increases in FLI (0.19 +/- 0.04 to 0.50 +/- 0.09 microg/U x 10(-3), P = 0.02).We demonstrate an increase in levels of sOB-R and a decrease in the FLI in adolescent girls with AN, and also demonstrate that cortisol is the most important predictor of levels of sOB-R in this condition. Levels of leptin and FLI, conversely, are primarily predicted by body composition. Weight recovery is associated with a decrease in sOB-R and an increase in leptin. Resumption of menses is associated with significant increases in the FLI, suggesting that free leptin may be an important determinant of menstrual recovery.     

Effects of fasting and refeeding on serum leptin, adiponectin and free fatty acid concentrations in young and old male rats

BACKGROUND: Regulatory mechanisms of metabolic homeostasis undergo important alterations during ageing. The age-related changes become often evident only during stimulation of basic functions that occurs, e.g. during fasting and refeeding which represent natural challenge to energy metabolism. Objective: To determine the effect of short-term fasting and subsequent refeeding on serum levels of key hormones and metabolites in young adult 5- and 24-month-old male Wistar rats. METHODS: Control rats were fed ad libitum. Animals were fasted for 48 h or fasted and refed for 24 h. Metabolite serum concentrations were measured by standard methods. Leptin and insulin were determined by rat-specific RIA, and adiponectin serum levels by mouse/rat-specific ELISA. RESULTS: (1) Control serum levels of key metabolites and hormones were similar in both age groups except for increased triglycerides (TG) in old fed rats. (2) Fasting caused a significant decrease of leptin, insulin, glucose, and TG serum levels in both age groups, and an increase of free fatty acids (FFA) concentration, however, only in young animals. (3) Upon refeeding serum glucose, TG and insulin reversed to control levels in both age groups, however, FFA concentration decreased to control values only in young rats. (4) In contrast to young animals, refeeding of old rats did not increase serum leptin concentration to control level. (5) Neither fasting nor refeeding changed adiponectin serum levels in both age groups. CONCLUSION: Aging suppresses leptin secretion and metabolism of FFA during refeeding that follows short-term starvation. In old rats serum levels of FFA are refractive to the alterations induced by fasting/refeeding in young ones.     

Adipose tissue and liver lipid metabolism in obese children: role of the body mass index and the presence of acanthosis nigricans.

AIMS: The aims of our study were to determine if insulin resistance is associated with increased plasma levels of non-esterified fatty acids (NEFA), glycerol, 3-hydroxybutyrate and triglycerides in obese children. We also studied whether the presence of acanthosis nigricans (AN) led to further alterations in the above parameters. METHODS: A total of 101 children were studied on their first visit to the paediatric endocrine clinic. Seventy-four were obese, 30 of them with AN. The remaining 27 were non-obese healthy children (control group). NEFAs, glycerol, triglycerides, 3-hydroxybutyrate, insulin, leptin, adiponectin and glucose were determined in blood samples obtained after overnight fasting. The insulin resistance index (IRI) was calculated following the homeostasis model assessment (HOMA). Data from the three groups were compared using appropriate statistical tests. RESULTS: No differences in age, sex ratio and pubertal stage were observed among the three groups. The group of children with the highest body mass index (BMI) showed higher plasma levels of insulin and leptin, higher IRI and lower plasma levels of adiponectin. As insulin and IRI increased, NEFA and 3-hydroxybutyrate decreased and triglycerides increased. When obese children were categorized by BMI, the presence of AN further exacerbated these differences. CONCLUSIONS: In obese children, insulin resistance is associated with plasma lipid alterations suggestive of both decreased adipose tissue lipolysis and hepatic beta-oxidation and increased hepatic synthesis of triglycerides. Such a metabolic condition may facilitate fat storage and hinder weight loss.     

Absence of exercise-induced variations in adiponectin levels despite decreased abdominal adiposity and improved insulin sensitivity in type 2 diabetic men

OBJECTIVE: We investigated the effect of an intensive training program on fasting leptin and adiponectin levels. METHODS: Sixteen middle-aged men with type 2 diabetes were randomly assigned to either a training or control group. The training program consisted of 8 weeks of supervised endurance exercise (75% VO(2peak), 45 min) twice a week, with intermittent exercise (five 2 min exercises at 85% VO(2peak) separated by 3 min exercises at 50% VO(2peak)) once a week, on an ergocycle. RESULTS: Training decreased abdominal fat by 44%, increased mid-thigh muscle cross-sectional area by 24%, and improved insulin sensitivity by 58% without significant change in body weight. Compared with controls, no significant variation in leptin or adiponectin levels was observed. However, in the trained group, change in adiponectin correlated with change in body weight (Spearman rank correlation, r(s):-0.76, P=0.03) but not with insulin sensitivity or abdominal adiposity variations. CONCLUSIONS: An 8 week intensive training program inducing a marked reduction in abdominal fat and increase in insulin sensitivity does not affect adiponectin and leptin levels in men with type 2 diabetes.