Soluble leptin receptor in serum of subjects with complete resistance to leptin: relation to fat mass

Leptin resistance and obesity have been related to mutations of the leptin receptor gene in rodents and, recently, in a consanguineous family. The latter mutation results in a receptor lacking transmembrane and intracellular domains. Homozygous and heterozygous individuals with this mutation had serum leptin levels higher than expected, given their BMIs: 600, 670, and 526 ng/ml and 145, 362, 294, 240, and 212 ng/ml, respectively. Their serum leptin was fractionated by gel filtration: >80% was present as a high-molecular size complex vs. 7.5% in the nonmutated sister. Western blot analysis showed a band at 146 kDa reacting specifically with an antibody directed against the leptin receptor ectodomain. In 10 obese control subjects, as in the mutated patients, free leptin levels correlated with BMI (r = 0.70, P = 0.0011) and reflected fat mass, regardless of leptin receptor functioning. In the patients, bound leptin levels correlated with BMI (r = 0.99, P = 0.0002) and were related to the number of mutated alleles. These data demonstrate that the truncated receptor is secreted into blood and binds the majority of serum leptin, markedly increasing bound and total leptin. Free serum leptin was similarly correlated with BMI in the mutated and nonmutated obese individuals, providing evidence that the relationship between BMI and circulating free leptin is preserved in this family. This finding suggests that the leptin receptor itself may not be specifically involved in the control of leptin secretion, and it supports the concept of relative resistance to leptin in common obesity.     

The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations : distinct metabolic effects of two fat compartments

Obesity is associated with insulin resistance, particularly when body fat has a central distribution. However, insulin resistance also frequently occurs in apparently lean individuals. It has been proposed that these lean insulin-resistant individuals have greater amounts of body fat than lean insulin-sensitive subjects. Alternatively, their body fat distribution may be different. Obesity is associated with elevated plasma leptin levels, but some studies have suggested that insulin sensitivity is an additional determinant of circulating leptin concentrations. To examine how body fat distribution contributes to insulin sensitivity and how these variables are related to leptin levels, we studied 174 individuals (73 men, 101 women), a priori classified as lean insulin-sensitive (LIS, n = 56), lean insulin-resistant (LIR, n = 61), and obese insulin-resistant (OIR, n = 57) based on their BMI and insulin sensitivity index (S(I)). Whereas the BMI of the two lean groups did not differ, the S(I) of the LIR subjects was less than half that of the LIS group. The subcutaneous and intra-abdominal fat areas, determined by computed tomography, were 45 and 70% greater in the LIR subjects (P < 0.001) and 2.5- and 3-fold greater in the OIR group, as compared with the LIS group. Fasting plasma leptin levels were moderately increased in LIR subjects (10.8 +/- 7.1 vs. 8.1 +/- 6.4 ng/ml in LIS subjects; P < 0.001) and doubled in OIR subjects (21.9 +/- 15.5 ng/ml; P < 0.001). Because of the confounding effect of body fat, we examined the relationships between adiposity, insulin sensitivity, and leptin concentrations by multiple regression analysis. Intra-abdominal fat was the best variable predicting insulin sensitivity in both genders and explained 54% of the variance in S(I). This inverse relationship was nonlinear (r = -0.688). On the other hand, in both genders, fasting leptin levels were strongly associated with subcutaneous fat area (r = 0.760) but not with intra-abdominal fat. In line with these analyses, when LIS and LIR subjects were matched for subcutaneous fat area, age, and gender, they had similar leptin levels, whereas their intra-abdominal fat and insulin sensitivity remained different. Thus, accumulation of intra-abdominal fat correlates with insulin resistance, whereas subcutaneous fat deposition correlates with circulating leptin levels. We conclude that the concurrent increase in these two metabolically distinct fat compartments is a major explanation for the association between insulin resistance and elevated circulating leptin concentrations in lean and obese subjects.     

Plasma leptin level and its relationship with body composition in hemodialysis patients

Leptin is a newly found hormone secreted by adipocytes that regulates food intake, thermogenesis, and body fat. We measured plasma leptin levels in 103 patients with chronic renal failure treated by hemodialysis and 167 age- and gender-matched healthy control subjects to examine the impact of renal failure on plasma leptin levels and the influence of leptin on body composition measured by dual-energy X-ray absorptiometry. Hemodialysis patients showed a significant decrease in both body fat mass and lean body mass compared with those of the control subjects. Plasma leptin was significantly elevated in the hemodialysis group over the controls. In both groups, leptin was higher in female than male subjects, and it correlated positively with percent body fat. The subjects were divided into six categories according to percent body fat, and plasma leptin levels were compared between the two groups in the same category. Leptin of hemodialysis patients was significantly higher than that of the control subjects in the percent body fat categories of 30 or greater, whereas there was no statistically significant difference in leptin concentrations in the lower percent body fat categories. This was also true in the comparison in each gender, and leptin levels in female subjects showed a more remarkable difference between the hemodialysis and control groups in obese categories. Multiple regression analysis in all subjects indicated that plasma leptin levels were independently affected by percent body fat, plasma insulin concentration, gender, and renal failure. The positive impact of renal failure on leptin remained significant in the subjects with percent body fat of 30 or greater in the multiple regression model, whereas it was no longer significant in the remaining lean subjects. In multiple regression analysis of factors affecting fat mass index and lean mass index, leptin level was selectively associated with fat mass index, but not with lean mass index, regardless of percent body fat ranges. These results indicate that renal failure is an important factor affecting plasma leptin levels, especially in obese female subjects, and that hyperleptinemia was closely related to fat mass but not to lean body mass in hemodialysis patients.     

Correlation of serum leptin concentrations with body composition and gender in Taiwanese hemodialysis patients without diabetes

OBJECTIVE: (1) To evaluate the impact of body composition and gender on serum leptin concentration in hemodialysis patients. (2) To study which marker of adiposity is most appropriate in Taiwanese hemodialysis patients without diabetes. (3) To compare the nutrition status between nonlean and lean subjects. PATIENTS AND METHODS: Serum leptin concentrations were measured by radioimmunoassay collected in 88 hemodialysis patients without diabetes. Bioimpedance analysis was performed to determine percent fat mass (%FM), lean body mass (LM), and total body water (TBW). Body mass index (BMI) was calculated as weight/height2. Albumin and transferrin were measured by standard laboratory methods. RESULTS: Serum leptin levels were more correlated with percent fat mass (r = 0.697; P < 0.001) than with body fat mass (r = 0.672; P < 0.001) or with BMI (r = 0.594; P < 0.001) in the group as a whole and in each subgroup when analyzed separately by gender. The mean (+/- SD) serum leptin levels were 32.5 +/- 34.3 ng mL(-1) in women subjects and 13.6 +/- 15.5 ng mL(-1) in men subjects (P < 0.001). Multiple regression analysis in all subjects revealed that serum leptin levels were independently affected by percent fat mass and gender. Adiposity corrected serum leptin, such as leptin/BMI, leptin/percent fat mass, and leptin/body fat mass was significantly different between sexes (P < 0.001). The significantly higher serum leptin concentrations in women than in men were observed in obese subjects with BMI > 25 kg/m2 (P < 0.001) as well as nonobese subjects with BMI < 25 kg/m2 (P < 0.05). There were no differences in lean mass and albumin between nonlean and lean subjects. CONCLUSION: Gender and adiposity had impact on serum leptin levels in hemodialysis patients without diabetes. In terms of adiposity, serum leptin levels had stronger correlation with percent fat mass than with body fat mass (FM) or BMI in Taiwanese hemodialysis patients. Steady-state serum leptin levels could serve as valuable clinical markers for the body adiposity in stable hemodialysis patients without diabetes. Protein malnutrition markers and lean mass should be checked in lean subjects for the evaluation of the protein stores of hemodialysis patients.     

Relationships of serum leptin to clinical and anthropometric findings in obese patients

Background: The authors evaluated the relationship between leptin and the clinical, anthropometric and metabolic variables connected to the metabolic syndrome in obese individuals. Methods: A large group of patients with different degrees of obesity was investigated: body mass index (BMI) values, serum leptin, fasting glucose and insulin, triglycerides and HDL-cholesterol concentrations, insulin resistance index and blood pressure were measured. Results: On multiple regression analysis, serum leptin levels appeared to be positively correlated to the BMI and to the serum HDL-cholesterol concentration. Principal component factor analysis revealed three factors, explaining 61.3% of the total variance of the sample. General features of these factors were: factor 1 - BMI values and serum leptin and fasting glucose concentration; factor 2 - systolic and diastolic blood pressure and serum triglycerides and HDL-cholesterol concentration; factor 3 - fasting serum insulin concentration and insulin resistance index. Conclusions: In obese subjects multiple factors underlie the metabolic syndrome and therefore more than one mechanism may account for the clustering characteristics. In obese patients leptin loads only one factor, and therefore leptin does not appear to be a key feature in the metabolic syndrome. On the contrary, multiple correlation and factor analysis data give rise to the hypothesis that in obese patients, leptin may play a protective role against cardiovascular risk.     

Relationship between BMI, total testosterone, sex hormone-binding-globulin, leptin, insulin and insulin resistance in obese men

The objective of this work was to evaluate the relationship between sex steroid hormones, sex hormone-binding-globulin, leptin, insulin and insulin resistance in obese men. Anthropometrical indexes, total testosterone (Tt), free testosterone (fT), estradiol (E), sex hormone-binding-globulin (SHBG), glucemia, insulin and leptin were measured in 77 men, with ages between 20 and 60 years. According to their body mass index (BMI), subjects were grouped into three categories: normal body weight (< 24.9 kg/m2), overweight (25-29.9 kg/m2) and obese group (> 30 kg/m2). Insulin resistance index was obtained by the homeostasis assessment model for insulin resistance (HOMA-IR). Total testosterone and SHBG concentrations were lower in the obese group compared with normal and overweight subjects (p < 0.05). The mean insulin concentration was significantly higher in the obese group compared with the other groups (p < 0.05). T was negatively correlated with the BMI (r = -0.447; p < .01), WC (r = -0.464); p < .01, leptin (r = -0.382; p < .01), insulin (r = -0.391; p < 0.01) and also with the HOMA-IR (r = -0.416; p < 0.01). The SHBG negatively and significantly correlated with BMI (r = -0.334; p < 0.01) and WC index (= -0.322; p < 0.01), as well with insulin levels (r = -0.313; p < 0.01) and insulin resistance (= -0.266; p < 0.05). Our results shows that in a sample of men, Tt and SHBG concentrations proportionally diminished with both the increase of BMI and insulin resistance index.     

Plasma Leptin Levels after Vertical Banded Gastroplasty for Morbid Obesity: Effects of an Acidified Meal

Background: Leptin is considered one of the anorectic messengers to the central nervous system in lean subjects. Although it is secreted by the gastric mucosa, there are contradictory evidences of its involvement in mediating the acute satiety effect of the meal in obese patients. The effects of restrictive operations on meal-stimulated leptin secretion are unknown. Methods: The effects of a standard acidified (pH 3) meal on leptin release were investigated in obese patients, before and after vertical banded gastroplasty (VBG). 8 morbidly obese patients (BMI 49.1±6.5) had serum leptin determination after an overnight fast. Samples were taken basally and every 30 minutes after the meal for 3 hours. The test was repeated after 20% BMI reduction. 5 lean volunteers (BMI 22.5±1.7) served as the control group. Results: In obese patients, basal serum leptin fell from 62±20.4 to 23.8±15.7 ng/ml after the operation (P <0.01) but still with significant differences vs the control group (5.6±3 ng/ml). The meal was associated with a significant decrease of serum leptin (ANOVA test, P <0.01), and significant differences between obese patients after surgery and lean subjects were found. Conclusion: Serum leptin was reduced by the meal in obese patients and VBG did not attain satiety through serum leptin changes.     

Positional candidate gene analysis of Lim domain homeobox gene (Isl-1) on chromosome 5q11-q13 in a French morbidly obese population suggests indication for association with type 2 diabetes

The Lim domain homeobox gene (Isl-1) is a positional candidate gene for obesity that maps on chromosome 5q11-q13, a locus linked to BMI and leptin levels in French Caucasians. Isl-1 might be involved in body weight regulation and glucose homeostasis via the activation of proglucagon gene expression, which encodes for glucagon and glucagon-like peptides. By mutation screening of 72 obese subjects, we identified three single-nucleotide polymorphisms (SNPs) in the Isl1 gene. The allele frequencies in the morbidly obese group did not differ from that of the control group. In the obese group, the -47G allele was associated with a decreased risk of type 2 diabetes (odds ratio 0.41, P = 0.019). The AG bearers displayed a higher maximal BMI than the AA bearers in the whole obese group (P = 0.026) as well as in the type 2 diabetic obese subgroup (P = 0.014). In obese families, this allele was not preferentially transmitted from heterozygous parents to their obese siblings, indicating that Isl-1 does not contribute to the linkage with obesity on 5cen-q. However, in French Caucasian morbidly obese subjects, the Isl1-47A-->G SNP may modulate the risk for type 2 diabetes and may increase body weight in diabetic morbidly obese subjects.     

Omentin plasma levels and gene expression are decreased in obesity

Central obesity and the accumulation of visceral fat are risk factors for the development of type 2 diabetes and cardiovascular disease. Omentin is a protein expressed and secreted from visceral but not subcutaneous adipose tissue that increases insulin sensitivity in human adipocytes. To determine the impact of obesity-dependent insulin resistance on the regulation of two omentin isoforms, gene expression and plasma levels were measured in lean, overweight, and obese subjects. Omentin 1 was shown to be the major circulating isoform in human plasma. Lean subjects had significantly higher plasma omentin 1 levels than obese and overweight subjects. In addition, higher plasma omentin 1 levels were detected in women compared with men. Plasma omentin 1 levels were inversely correlated with BMI, waist circumference, leptin levels, and insulin resistance as measured by homeostasis model assessment and positively correlated with adiponectin and HDL levels. Both omentin 1 and omentin 2 gene expression were decreased with obesity and were highly correlated with each other in visceral adipose tissue. In summary, decreased omentin levels are associated with increasing obesity and insulin resistance. Therefore, omentin levels may be predictive of the metabolic consequences or co-morbidities associated with obesity.     

肝癌患者血清瘦素、胰岛素的水平测定及相关性分析

目的探讨瘦素、胰岛素在原发性肝癌及肝硬化患者中的变化。方法采用放射免疫分析法和电化学发光免疫法检测70例肝癌患者、30例肝硬化患者及30例健康者的血清瘦素、胰岛素水平并进行比较分析。结果肝癌及肝硬化患者较正常对照组血清瘦素、胰岛素显著升高,体重指数（body mass index,BMI）显著降低;BMI、胰岛素和性别均为影响肝癌患者血清瘦素浓度的显著因素。结论瘦素、胰岛素可能参与了肝癌及肝硬化患者营养不良的发生。     

Free serum leptin but not bound leptin concentrations are elevated in patients with end-stage renal disease.

BACKGROUND: Leptin is a 16-kDa protein that is thought to be a regulator of food intake and body weight. Although total serum leptin levels have been reported to be elevated in obese and normal weight patients with end-stage renal disease (ESRD), it is not known whether serum-free leptin concentrations are also increased in patients with ESRD with no apparent nutritional problems. Furthermore, there are no data on how different dialysis modes (high-flux haemodiafiltration and low-flux dialysis) influence serum leptin subfractions. METHODS: We measured fasting serum free and bound leptin levels in three groups of male subjects: patients on haemodiafiltration with high flux dialysers (n=11), patients on haemodialysis with low-flux dialysers (n=17) and healthy age (61+/-8 years) and BMI (23.8+/-3.1 kg/m(2)) matched control subjects (n=28). Both leptin components were determined before and after a single dialysis session. RESULTS: Body mass indices were correlated with serum free leptin levels in both patients (r=0.69, P<0.001) and controls (r=0.77, P<0.001). Mean (SD) serum free leptin levels were significantly higher in ESRD patients than in control subjects (91+/-33 vs 41+/- 21 pmol/l; P<0.01). Bound leptin levels did not differ in both groups (0.67+/-0.12 vs 0.56+/-0.11 nmol/l, NS). Elevated serum-free leptin levels in ESRD patients could be reduced by haemodiafiltration with high-flux membranes, but not with low-flux haemodialysis membranes.The former led to a reduction of initial serum free leptin values to 76+/-17% (P<0.01), whereas bound leptin remained unaffected. CONCLUSION: Serum-free leptin levels are elevated in ESRD without any apparent effect on body weight. In contrast, serum bound leptin levels remain stable, thus central feedback regulation via the bound form of the hormone may serve as an alternative explanation in the regulation of food intake and energy expenditure in chronic patients on haemodialysis with no apparent nutritional problems.     

Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1, but not with leptin,in obese children and adolescents

Ghrelin is a novel growth hormone-releasing peptide isolated from human and rat stomach that induces weight gain by increasing food intake and reducing fat utilization. Although recent data indicate that ghrelin is downregulated in human adult obesity, the characteristics of human obesity are heterogeneous, especially in children and adolescents, and depend on the distribution of subcutaneous and visceral fat tissue. We measured fasting plasma ghrelin concentrations by radioimmunoassay in 49 obese Japanese children and adolescents (38 boys and 11 girls; mean age 10.2 +/- 2.8 years; BMI 28.0 +/- 4.5 kg/m(2), percent overweight 56.0 +/- 20.7%), and analyzed associations of their ghrelin concentrations with their body composition, insulin resistance, and adipocytokine concentrations. Fasting plasma ghrelin levels were negatively correlated with BMI and waist circumference, but not with percent overweight or percent body fat, whereas fasting leptin levels were positively correlated with all of the following parameters: BMI, waist circumference, percent overweight, and percent body fat. Plasma ghrelin levels were negatively correlated with fasting immunoreactive insulin, homeostasis model assessment insulin resistance index, and quantitative insulin sensitivity check index values. There was no correlation between plasma ghrelin and leptin, but ghrelin was negatively correlated with the PAI-1 concentrations. The results suggest that the downregulation of ghrelin secretion may be a consequence of higher insulin resistance associated with visceral fat accumulation and elevated PAI-1 concentrations, and not a consequence of total body fat accumulation associated with elevated leptin concentrations.     

Association of serum leptin with hypoventilation in human obesity

BACKGROUND: Leptin is a protein hormone produced by fat cells of mammals. It acts within the hypothalamus via a specific receptor to reduce appetite and increase energy expenditure. Plasma leptin levels correlate closely with total body fat mass operating via a central feedback mechanism. In human obesity serum leptin levels are up to four times higher than in lean subjects, indicating a failure of the feedback loop and central leptin resistance. In leptin deficient obese mice (ob/ob mice) leptin infusion reverses hypoventilation. It was hypothesised that a relative deficiency in CNS leptin, indicated by high circulating leptin levels, may be implicated in the pathogenesis of obesity hypoventilation syndrome (OHS). METHODS: Fasting morning leptin levels were measured in obese and non-obese patients with and without daytime hypercapnia (n=56). Sleep studies, anthropometric data, spirometric parameters, and awake arterial blood gas tensions were measured in each patient. RESULTS: In the whole group serum leptin levels correlated closely with % body fat (r=0.77). Obese hypercapnic patients (mean (SD) % body fat 43.8 (6.0)%) had higher fasting serum leptin levels than eucapnic patients (mean % body fat 40.8 (6.2)%), with mean (SD) leptin levels of 39.1 (17.9) and 21.4 (11.4) ng/ml, respectively (p<0.005). Serum leptin (odds ratio (OR) 1.12, 95% CI 1.03 to 1.22) was a better predictor than % body fat (OR 0.92, 95% CI 0.76 to 1.1) for the presence of hypercapnia. CONCLUSIONS: Hyperleptinaemia is associated with hypercapnic respiratory failure in obesity. Treatment with leptin or its analogues may have a role in OHS provided central leptin resistance can be overcome.     

Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance

OBJECTIVE

Metreleptin has been efficacious in improving metabolic control in patients with lipodystrophy, but its efficacy has not been tested in obese patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

We studied the role of leptin in regulating the endocrine adaptation to long-term caloric deprivation and weight loss in obese diabetic subjects over 16 weeks in the context of a double-blinded, placebo–controlled, randomized trial. We then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro.

RESULTS

In obese patients with diabetes, metreleptin administration for 16 weeks did not alter body weight or circulating inflammatory markers but reduced HbA_1c marginally (8.01 ± 0.93–7.96 ± 1.12, P = 0.03). Total leptin, leptin-binding protein, and antileptin antibody levels increased, limiting free leptin availability and resulting in circulating free leptin levels of ∼50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at ∼50 ng/mL, with no major differences in timing or magnitude of leptin-activated STAT3 phosphorylation in tissues from male versus female or obese versus lean humans in vivo, ex vivo, or in vitro. We also observed for the first time that endoplasmic reticulum (ER) stress in human primary adipocytes inhibits leptin signaling.

CONCLUSIONS

In obese patients with diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA_1c marginally. ER stress and the saturable nature of leptin signaling pathways play a key role in the development of leptin tolerance in obese patients with diabetes.Metreleptin has consistently been shown to dramatically improve insulin resistance and HbA_1c in several clinical trials involving hypoleptinemic subjects with lipodystrophy, hypoleptinemia, insulin resistance, and the metabolic syndrome (1). No prior study has evaluated in detail the effect of metreleptin in obese subjects, with garden variety diabetes, obesity, and high circulating leptin levels, who are presumably resistant or tolerant to the effects of leptin (2). Furthermore, no prior study has evaluated mechanisms underlying such leptin tolerance.In the context of a large, randomized, placebo–controlled trial, we examined for the first time the efficacy of metreleptin in regulating body weight, glycemic control, and immune function in hyperleptinemic obese subjects with type 2 diabetes. We subsequently examined whether the observed suboptimal efficacy of circulating leptin in regulating adiposity and immune function in obese diabetic individuals is attributable to specific, identifiable mechanisms at the cellular and molecular level. In this respect, we methodically explored mechanisms previously shown to underlie other hormone resistance syndromes, e.g., insulin resistance or underlying immunogenicity seen with use of other biologics. To further elucidate the role of leptin in regulating human adiposity and immune function and to study potential mechanisms underlying the development of leptin resistance or tolerance, we then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro.More specifically, we first discovered that levels of leptin-binding protein (LBP) and antibodies against metreleptin increased in response to metreleptin treatment, limiting circulating free leptin to ∼50 ng/mL despite total leptin levels of ∼982.7 ng/mL in obese diabetic subjects. We then proceeded to study whether mechanisms that have been described to affect leptin signaling and thus leptin resistance in mice, i.e., endoplasmic reticulum (ER) stress (3–6), are also operative in humans. Subsequently, we investigated intracellular leptin signaling in vivo in response to metreleptin administration in lean and obese subjects by comparatively studying metreleptin signaling in human adipose tissue (hAT) and human peripheral blood mononuclear cells (hPBMCs) from both lean and obese humans in vivo. Finally, we extended these observations by studying leptin signaling in vitro and ex vivo in hAT and hPBMCs from lean and obese subjects to determine whether neuroendocrine changes induced by metreleptin in vivo or paracrine mechanisms ex vivo may differentially affect leptin signaling in humans in vivo versus ex vivo or in vitro.     

Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats

Leptin exerts important effects on the regulation of food intake and energy expenditure by acting in the brain. Leptin is secreted by adipocytes into the bloodstream and must gain access to specific regions in the brain involved in regulating energy balance. Its action is mediated by interaction with a receptor that is mainly expressed in the hypothalamus but is also present in other cerebral areas. To reach these target areas, leptin most likely needs to cross the blood-brain barrier (BBB). In this study, we compared the permeability of leptin at the BBB in homozygous lean (FA/FA), high-fat diet-induced (HFD) obese rats (FA/FA rats on a highfat diet), and genetically obese fa/fa Zucker rats by quantifying the permeability coefficient surface area (PS) product after correction for the residual plasma volume (Vp) occupied by leptin in the vessel bed of different brain regions. The intravenous bolus injection technique was used in the cannulated brachial vein and artery using leptin radioiodinated with 2 isotopes of iodine (125I and 131I) to separately determine the PS and Vp values. The PS for leptin at the BBB in lean FA/FA rats ranged from 11.0 +/- 1.6 at the cortex to 14.8 +/- 1.4 x 10(-6) ml x g(-1) x ml(-1) at the posterior hypothalamus. The PS for leptin in HFD obese FA/FA and obese fa/fa rats ranged from 3.0- to 4.0-fold lower than in lean FA/FA rats. The Vp values were not significantly different among the 3 groups studied. SDS-PAGE analysis of the radioiodinated leptin after 60 min of uptake revealed intact protein in the 8 different brain regions. Plasma leptin levels were significantly higher in both obese rat groups compared with those in lean FA/FA rats. Leptin levels in cerebrospinal fluid were not significantly different among the 3 groups of rats. These findings strongly suggest that the leptin receptor (OB-R) in the BBB can be easily saturated. Saturation of the BBB OB-R in obese individuals would explain the defect in leptin transport into the brain described in this study.     

Serum leptin levels, hepatic leptin receptor transcription, and clinical predictors of non-alcoholic steatohepatitis in obese bariatric surgery patients

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a major cause of liver disease in morbidly obese patients. Clinical predictors of NASH remain elusive, as do molecular mechanisms of pathogenesis. METHODS: A series of 35 morbidly obese patients undergoing bariatric surgery had a liver biopsy performed for standard histologic analysis. In addition, RNA was obtained from liver tissue and analyzed for leptin receptor gene expression. Regression analysis was used to correlate clinical variables, including serum leptin levels and hepatic leptin receptor gene expression, with the presence of histologically confirmed NASH. RESULTS: Of the 35 subjects enrolled, 29% had steatosis only, 60% had NASH, and 11% had normal liver histology. Among the clinical variables studied, only diabetes mellitus was an independent predictor of NASH. There was a trend toward lower levels of mRNA encoding the long form of the leptin receptor in hepatic tissue from patients with NASH compared to those with steatosis only. CONCLUSIONS: Diabetes mellitus is associated with an increased risk of NASH in obese patients. Downregulation of hepatic leptin receptor may play a role in the pathogenesis of NASH.     

A common promoter variant of the leptin gene is associated with changes in the relationship between serum leptin and fat mass in obese girls

Mutations in the leptin gene lead to rare obese syndromes of Mendelian inheritance in humans and rodents. However, no relevant mutations are found in the coding region of leptin gene DNA in patients with common multifactorial obesity. These obese patients tend to have an elevation of serum leptin proportional to their adiposity but with a rather wide dispersion of leptin levels for a given body fat content, which in part is attributable to sexual dimorphism. The current study, performed in two independent Caucasian cohorts of obese girls, shows that a frequent promoter variant of the leptin gene is associated with changes in the relationship between serum leptin and body fatness. Girls of comparable adiposity have different circulating leptin levels, depending on their genotype at this locus. Girls with the -/- Lep -2,549 genotype have 25% lower mean leptin levels than the girls with other genotypes, as reflected by differences in the regression slopes of leptin-to-fat mass. Therefore, genetic factors related to the leptin gene may be important in defining the set point of obese individuals (i.e., the circulating leptin level for a given degree of body fatness). This definition may be of both physiological and therapeutic relevance, although a phenotypic association with an individual single-nucleotide polymorphism is not sufficient to assign function to this particular nucleotide site.     

血清瘦素与绝经后2型糖尿病女性患者骨密度的相关性研究

目的探索血清瘦素与绝经后2型糖尿病患者骨密度的相关性。方法共纳入98名2型糖尿病女性进行分析,通过双能X线骨密度仪对受试者髋部BMD进行检查,并测定T评分,按照骨密度检测结果分为骨质疏松症组(PMOPW)以及非骨质疏松组(PMW)。对照组按照BMI与骨质疏松症受试者匹配。通过酶联免疫吸附法(ELISA)测定检测血清瘦素水平。结果两组血清瘦素和BMD值差异均有统计学意义(瘦素,(18.23±8.56) ng/m L vs (22.44±9.56) ng/m L,P0.05)和(BMD,(-0.74±0.13) vs(-3.127±0.55),P0.05)。在PMOPW中,血清瘦素和BMD与体重、BMI、腰围、臀围显著相关。多元线性逐步回归分析显示PMW和PMOPW的体重和BMI是BMD的独立预测因子。未发现血清瘦素水平是两组BMD的预测因子。结论体重和BMI对2型糖尿病患者BMD影响显著,但是未发现血清瘦素与PMW和PMOPW的BMD有关。     

Correlation of Serum Leptin Concentrations with Body Composition and Gender in Taiwanese Hemodialysis Patients without Diabetes

Objective.?(1) To evaluate the impact of body composition and gender on serum leptin concentration in hemodialysis patients. (2) To study which marker of adiposity is most appropriate in Taiwanese hemodialysis patients without diabetes. (3) To compare the nutrition status between nonlean and lean subjects. Patients and Methods.?Serum leptin concentrations were measured by radioimmunoassay collected in 88 hemodialysis patients without diabetes. Bioimpedance analysis was performed to determine percent fat mass (%FM), lean body mass (LM), and total body water (TBW). Body mass index (BMI) was calculated as weight/height². Albumin and transferrin were measured by standard laboratory methods. Results.?Serum leptin levels were more correlated with percent fat mass (r = 0.697; P<0.001) than with body fat mass (r = 0.672; P<0.001) or with BMI (r = 0.594; P<0.001) in the group as a whole and in each subgroup when analyzed separately by gender. The mean (±SD) serum leptin levels were 32.5 ± 34.3 ng mL^?1 in women subjects and 13.6 ± 15.5 ng mL^?1 in men subjects (P<0.001). Multiple regression analysis in all subjects revealed that serum leptin levels were independently affected by percent fat mass and gender. Adiposity corrected serum leptin, such as leptin/BMI, leptin/percent fat mass, and leptin/body fat mass was significantly different between sexes (P<0.001). The significantly higher serum leptin concentrations in women than in men were observed in obese subjects with BMI >25 kg/m² (P<0.001) as well as nonobese subjects with BMI<25 kg/m² (P<0.05). There were no differences in lean mass and albumin between nonlean and lean subjects. Conclusion.?Gender and adiposity had impact on serum leptin levels in hemodialysis patients without diabetes. In terms of adiposity, serum leptin levels had stronger correlation with percent fat mass than with body fat mass (FM) or BMI in Taiwanese hemodialysis patients. Steady-state serum leptin levels could serve as valuable clinical markers for the body adiposity in stable hemodialysis patients without diabetes. Protein malnutrition markers and lean mass should be checked in lean subjects for the evaluation of the protein stores of hemodialysis patients.