Obesity is associated with decreasing levels of the circulating soluble leptin receptor in humans

OBJECTIVE: Leptin plays a major role in the regulation of body weight. It circulates in both free and bound form. One of the leptin receptor isoforms exists in a circulating soluble form that can bind leptin. In the present study, we measured the soluble leptin receptor (SLR) levels in lean and obese humans. We investigated the relationship between plasma SLR levels, plasma leptin levels and the degree of obesity. We also examined whether SLR concentrations could be modulated by fat mass loss induced by a 3 month weight-reducing diet. SUBJECTS: A total of 112 obese (age 18-50 y; body mass index (BMI) 30-44 kg/m2; 23 men and 89 women), 38 overweight (age 19-48 y; BMI 25-29 kg/m2; 10 men and 28 women) and 63 lean (age 18-50 y; BMI 17-24 kg/m2; 16 men and 47 women) humans. MEASUREMENTS: A direct double monoclonal sandwich enzyme-linked immunosorbent assay (ELISA) was used for the quantitative measurement of the soluble human leptin receptor. Leptin was measured by radioimmunoassay (RIA). Body composition was assessed by biphotonic absorptiometry DEXA (dual energy X-ray absorptiometry). RESULTS: We observed that the SLR is present in human plasma (range 10-100 ng/ml). SLR levels were lower in obese and overweight than lean subjects (28.7+/-8.8, 40.2+/-14.9, 51.2+/-12.5 ng/ml, respectively) and were inversely correlated to leptin and percentage of body fat (r=-0.74 and r=-0.76; respectively; P<0.0001). The ratio of circulating leptin to SLR was strongly related to the percentage of body fat (r=0.91; P<0.0001). Interestingly a gender difference was observed in SLR levels, which were higher in obese and overweight men than in obese and overweight women. In obese subjects after a 3 month low-calorie diet, SLR levels increased in proportion to the decrease in fat mass. In the gel filtration profile, SLR coeluted exactly with the bound leptin fractions. CONCLUSION: Obesity, in humans is associated with decreasing levels of the circulating soluble leptin receptor (SLR). The relationship of SLR with the degree of adiposity suggests that high SLR levels may enhance leptin action in lean subjects more than in obese subjects.     

Effect of short-term fasting on free and bound leptin concentrations in lean and obese women

Plasma leptin exists in protein-bound and free forms, which may affect its hormonal bioactivity. Therefore, the relationship between bound and free leptin may be particularly important during physiological conditions that cause rapid alterations in total plasma leptin concentration, such as fasting. The purpose of this study was to evaluate the effect of short-term fasting on bound and free plasma leptin concentrations and leptin binding capacity (a measure of plasma leptin-binding protein content) in lean and obese women. Six lean (body mass index, 21 +/- 1 kg/m2) and 6 abdominally obese (BMI, 36 +/- 1 kg/m2) women were studied after 14 h and 22 h of fasting. Although total plasma leptin concentration was more than 6-fold greater in obese (45.4 +/- 7.6 microg/liter) compared with lean (7.4 +/- 1.0 microg/liter) women at 14 h of fasting (P < 0.05), the percentage of leptin in the bound form was greater in lean than obese subjects (29 +/- 2% vs. 12 +/- 3%; P < 0.05). Arterial total, free, and bound plasma leptin concentrations all declined between 14 h and 22 h of fasting in both lean and obese groups, but the relative decline of these fractions was greater in lean (36 +/- 4%, 60 +/- 9%, and 51 +/- 13%, respectively) than in obese (19 +/- 5%, 21 +/- 8%, and 12 +/- 7%, respectively) subjects (all P < 0.05). In contrast, leptin binding capacity was unchanged. The percentage of total plasma leptin present in bound form was constant between 14 h and 22 h of fasting in lean subjects and increased slightly but significantly in obese subjects. These data demonstrate that both free and bound fractions of leptin in plasma decrease quickly in response to energy restriction, but the decline is blunted in abdominally obese compared with lean women. In addition, the equilibrium between bound and free leptin fractions is maintained during brief fasting and is not regulated by leptin binding capacity.     

Acute regulation of plasma leptin by isoprenaline in lean and obese fasted subjects

AIM: In human obesity, there is some evidence for impaired adrenergic sensitivity with respect to catecholamine-induced lipolysis. The beta-adrenoceptor agonist isoprenaline has been shown to suppress plasma leptin levels in lean humans in vivo. We hypothesized that a reduced adrenergic sensitivity in obese humans would result in impaired suppression of leptin secretion. METHODS: Eight obese [Ob, body mass index (BMI) = 33.3 kg/m2] and seven lean (Ln, BMI = 21.8 kg/m2) men were studied after an overnight fast. Intravenous isoprenaline infusion was initiated at a rate of 8 ng/kg/min, titrated up to 24 ng/kg/min over 30 min and continued at this rate for a further 120 min with continuous electrocardiogram monitoring. RESULTS: Baseline fasting plasma leptin was higher in obese compared with lean subjects (Ob 12.2 +/- 1.8, Ln 2.6 +/- 0.6 ng/ml, p < 0.05 unpaired t-test). Baseline fasting glycerol as a measure of lipolysis was similar in both groups (Ob 62.9 +/- 7.6, Ln 42.4 +/- 8.9 micromol/l) and increased from baseline to 150 min by equivalent amounts (Ob +66.9%, Ln +81.2%, p = NS). Plasma leptin decreased from baseline to 150 min with similar relative changes in both groups (Ob -29.2%, Ln -27.8%). CONCLUSIONS: Obese subjects show a similar lipolytic and leptin response to acute isoprenaline infusion compared with lean subjects. Impaired beta-adrenergic-induced inhibition of leptin secretion does not appear to contribute to hyperleptinaemia in obese human subjects.     

Comparisons of leptin,incretins and body composition in obese and lean patients with hypopituitarism and healthy individuals

OBJECTIVE: To identify possible abnormalities specific for obesity in hypopituitary patients. STUDY DESIGN: Cross-sectional case-control study. MEASUREMENTS AND STUDY SUBJECTS: Body composition (DEXA) and measurements of fasting plasma levels of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptides (GLPs), insulin, C-peptide, glucose, leptin and lipids were performed in 25 hypopituitary patients (15 obese, 10 normal weight) and 26 BMI and age-matched healthy controls (16 obese, 10 normal weight). All hypopituitary patients had GH deficiency and received adequate substitution therapy on this and other deficient axes (3 +/- 1). RESULTS: Fasting GIP-levels were significantly higher in obese hypopituitary patients compared to lean hypopituitary patients (P < 0.01), while the fasting concentrations of GLP-1 and GLP-2 were comparable between obese and lean hypopituitary patients. The same trend was seen in obese healthy controls vs. lean controls. No differences were observed in glucose, insulin or C-peptide between the hypopituitary patients and the controls. Leptin levels were increased in obese hypopituitary patients compared to lean hypopituitary patients when adjusted for gender. At least a 2-fold higher level of leptin was observed in women compared to men in both patient groups and healthy controls. Lean female hypopituitary patients had higher leptin levels than matched controls. CONCLUSIONS: Fasting levels of GIP were elevated in obese substituted hypopituitary patients, while fasting concentrations of GLPs were similar. Obese hypopituitary patients had the same degree of hyperinsulinaemia, affected glucose tolerance, dyslipoproteinaemia and central obesity as obese healthy controls. Further studies are required to identify the possible biochemical reasons for obesity in patients with apparently well-substituted hypopituitarism.     

Spontaneous diurnal thyrotropin secretion is enhanced in proportion to circulating leptin in obese premenopausal women

CONTEXT: Recent evidence implicates leptin as an important modulator of thyroid axis activity. OBJECTIVE: The objective of this study was to study spontaneous 24-h TSH secretion and 24-h circulating leptin concentrations in obese and lean women. DESIGN: This was a prospective parallel study (2004). SETTING: This study was conducted at the Clinical Research Center (Leiden University Medical Center, Leiden, The Netherlands). PARTICIPANTS: Twelve healthy obese premenopausal women (body mass index, 33.2 +/- 0.9 kg/m2) and 11 lean controls (body mass index, 21.4 +/- 0.5 kg/m2) were studied in the follicular phase of their menstrual cycle. INTERVENTION(S): There were no interventions in this study. MAIN OUTCOME MEASURE(S): Spontaneous 24-h TSH concentrations (10-min time intervals) and secretion were calculated using waveform-independent deconvolution technique (pulse). Twenty-four-hour circulating leptin concentrations (20-min time intervals) were measured. RESULTS: Mean TSH concentration (obese, 1.9 +/- 0.2 vs. lean, 1.1 +/- 0.1 mU/liter; P = 0.009) and secretion rate (obese, 43.4 +/- 5.5 vs. lean, 26.1 +/- 2.2 mU/liter distribution volume.24 h; P = 0.011) were substantially enhanced in obesity, whereas the fasting free T4 (fT4) concentrations were similar (fT4 in obese, 15.4 +/- 1.5 vs. in lean, 16.4 +/- 1.5 pmol/liter; P = 0.147). TSH secretion was positively related to 24-h leptin concentrations (r2= 0.31; P = 0.007). CONCLUSIONS: TSH release is enhanced in the face of normal plasma fT4 concentrations in obese premenopausal women, and hyperleptinemia may well be involved in this neuroendocrine alteration.     

Effect of small doses of dexamethasone on plasma leptin levels in normal and obese subjects: a dose-response study

To further elucidate the role of glucocorticoids in the regulation of leptin secretion, we studied the effects of overnight small doses of dexamethasone on plasma leptin levels in normal weight controls and in obese patients and correlated the results with indexes of insulin sensitivity and body fat distribution. In 114 subjects (81 obese patients, 49 women and 32 men, BMI 37.4 +/- 0.77 kg/m2 and 33 normal-weight subjects, 17 women and 16 men, BMI 22.1 +/- 0.41 kg/m2) plasma F and leptin levels were measured at 08:00 h basally and after the administration of different doses of dexamethasone (a fixed dose of 1-mg and 0.0035, 0.007, 0.015-mg/kg bw, given po at 23:00 h the night before). Tests were performed one week apart with bw remaining stable over the study period. Basal leptin levels were significantly higher in obese than in normal subjects (31.9 +/- 2.41 vs 7.7 +/- 0.93 ng/ml, p<0.0001). In obese patients, leptin levels increased significantly by 1-mg (from 31.9 +/- 2.41 to 35.0 +/- 2.59 ng/ml, p<0.005) and the 0.015-mg/kg bw dose (from 31.5 +/- 2.34 to 33.7 +/- 2.44 ng/ml, p<0.05), while they were unaffected by each dose of dexamethasone in normal subjects. However, after splitting subjects by gender, mean leptin levels rose from 39.3 +/- 2.97 to 43.3 +/- 3.12 ng/ml after the 1-mg dose, p<0.005, from 39.1 +/- 2.87 to 43.6 +/- 2.91 ng/ml after the 0.015-mg/kg bw dose, p<0.005, from 39.3 +/- 2.90 to 42.2 +/- 2.90 ng/ml after the 0.007-mg/kg bw dose, p<0.05 and from 38.8 +/- 2.66 to 41.1 +/- 2.87 ng/ml after the 0.0035-mg/kg bw dose, p=0.055, only in obese women. Conversely, no leptin changes were seen in the other groups and no differences were observed in the leptin response between groups. After the 1-mg dose, in the whole group, the absolute leptin variation was weakly but significantly related to BMI values (r=0.231, p<0.02) while in all sessions the percent leptin changes over baseline were not significantly correlated with age, BMI, waist, WHR, insulin, HOMA index, a marker of insulin sensitivity, plasma dexamethasone concentrations and to the percent cortisol variation following dexamethasone. In conclusion, in obese women but not in obese men and in normal weight subjects, small overnight increases in plasma glucocorticoid concentrations induced gender-related plasma leptin elevations that were unrelated to body fat distribution and insulin sensitivity. A greater sensitivity of female adipose tissue to glucocorticoids probably underlies this sexually dimorphic pattern of leptin response. These findings provide an additional piece of information on the regulation of leptin secretion exerted by glucocorticoids.     

Normal serum alanine aminotransferase activity in uncomplicated obesity

AIM: To evaluate serum alanine aminotransferase (ALT) activity in a well-characterized group of uncomplicated obese subjects and its correlation with insulin resistance, plasma adiponectin, and leptin concentrations. METHODS: One hundred and five uncomplicated obese subjects (87 women, 18 men, age 34.3±9.6 years, BMI 39.9±8.3 kg/m2)were studied. Serum ALT activity was evaluated. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp (M index) and fasting insulin. Plasma leptin and adiponectin levels were also measured. RESULTS: Serum ALT concentration in the whole group of uncomplicated obese subjects was 17.73±6.33 U/L with none of the subjects presenting ALT levels greater than 43 U/L and only 9 (11%) women and 3 (19%) men showed ALT levels >19 and >30 U/L for women and men, respectively. No significant difference was detected in serum ALT levels between severe obese subjects (BMI >40 kg/m2) and those with BMI <40 kg/m2 (18.63±6.25 vs 17.26±6.02 U/L). ALT was significantly correlated with fasting insulin (r=0.485, P= 0.02) and triglycerides (r= 0.358, P=0.03). CONCLUSION: Serum ALT activity is practically normal in uncomplicated obese subjects, independently of their obesity degree. These findings suggest the role of obesityrelated comorbidities and not of BMI as main risk factors for elevated ALT levels in obese subjects.     

Skeletal muscle potassium increases after diet and weight reduction in obese subjects with normal and impaired glucose tolerance

Body composition calculated from total body potassium and skeletal muscle potassium were studied in middle-aged obese men and women with normal and impaired glucose tolerance as well as Type II diabetes before and after advice on calorie reduction during twelve months. The subjects were compared with healthy lean men and women. Mean weight loss was 6.6 kg (P less than 0.05). Lean body mass and body fat decreased 2.0 kg (P less than 0.05) and 4.6 kg (P less than 0.05), respectively. Total body potassium decreased by a mean of 146 +/- 49 mmol (P less than 0.01). Obese men with Type II diabetes and impaired glucose tolerance had lower total body potassium and muscle potassium levels than obese healthy men. After dieting, the obese men and women increased their muscle potassium levels with a mean of 2.8 mmol/100 fat-free dry weight to 42.6 +/- 2.6 mmol/100 g fat-free dry weight (P less than 0.05), but they were still below the levels of the lean controls, 44.4 +/- 1.3 MMOL/100 g fat-free dry weight, (P less than 0.01). Increase in skeletal muscle potassium was correlated to decrease in body weight, r = 0.55 (P less than 0.01) and to decrease in fasting blood glucose, r = 0.42 (P less than 0.05).     

Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy

Leptin, an adipocyte hormone, when replaced in patients with lipodystrophy, improves insulin resistance, hyperglycemia, dyslipidemia, and hepatic steatosis. Changes in body composition accompany this metabolic improvement. We studied 14 patients (3 men and 11 women); 12 of who had generalized lipodystrophy (7 congenital, 5 acquired), and 2 patients had partial lipodystrophy. Body composition and related parameters were evaluated at baseline and after 4 and 12 months of leptin therapy. Baseline body mass index (BMI) was 21.7 +/- 0.8 kg/m(2), the percent body fat was 9.5% +/- 1.6%, and the serum leptin level was 1.7 +/- 0.3 ng/mL. On treatment, serum leptin levels increased by 10-fold. All patients reported a decrease in appetite on therapy. After 4 months, both daily caloric intake and resting energy expenditure (REE) decreased. The liver volume decreased (baseline = 3,055 +/- 281 cm(3); 4 months = 2,433 +/- 243 cm(3), P =.006). Dual energy x-ray absorptiometry (DEXA) demonstrated significant decreases in fat mass (5.4 +/- 0.8 kg to 5.0 +/- 0.8 kg; P =.003) and lean body mass (51.2 +/- 3.2 kg to 48.3 +/- 3.4 kg; P =.003) at 4 months on therapy. There was no impact of leptin therapy on bone mineral content, mineral density, and metabolism. Changes in body composition occurred during the first 4 months of leptin therapy, but then stabilized and were sustained thereafter.     

Effects of a 3-week integrated body weight reduction program on leptin levels and body composition in severe obese subjects

The effects of short-term (3 weeks) integrated body weight reduction (BWR) program (including energy-restricted diet, aerobic and strength exercise (5 days/week), nutritional education and psychological counseling) on plasma leptin levels and body composition were investigated in 54 morbidly obese patients (38 females/16 males; mean BMI +/- SE: 41.8 +/- 0.1 kg/m2, range 35-58 kg/m2; mean age: 29.8 +/- 1.0 yr, age range: 18-46 yr). The BWR program induced a significant (p < 0.001) weight loss (BMI reduction: -4.8%) and a significant modification in body composition, consisting in a fat mass (FM) decrease (-7.0 +/- 0.4%, p < 0.001) with a concomitant fat-free (FFM) mass increase (1.8 +/- 0.3%, p < 0.001). On average, plasma leptin levels decreased significantly both in males (from 19.4 +/- 2.6 ng/ml to 11.6 +/- 1.3 ng/ml, p < 0.001) and in females (from 41.1 +/- 3.6 ng/ml to 29.9 +/- 3.0 ng/ml, p < 0.001). Both before and after weight loss, leptin levels were positively correlated (p < 0.001) with BMI and percent fat mass (FM) values. Weight changes after the BWR program were negatively correlated with baseline leptin concentrations both in absolute terms and expressed per unit FM. In conclusion, a short-term diet plus aerobic/strength training effectively induces body composition changes and reduces plasma leptin levels. Body FM reduction appears to be not the unique determinant of leptin levels regulation and the degree of leptin over-expression may negatively affect weight loss in morbidly obese patients.     

Effect of obesity on susceptibility to fatty acid-induced peripheral tissue insulin resistance

Elevation of plasma nonesterified fatty acid (NEFA) levels has been shown to impair the actions of insulin on peripheral glucose uptake and suppression of hepatic glucose output (HGO). These studies have been conducted almost exclusively in healthy, lean men. We therefore set out to test the hypothesis that obese subjects, because they are already insulin-resistant, are less susceptible than lean subjects to the inhibitory effects of elevated NEFA on insulin-stimulated glucose disposal. We studied 15 lean (11 men, 4 women; age, 45 +/- 3 years [mean +/- SE]; body mass index [BMI], 22.7 +/- 0.6 kg/m(2)) and 15 obese normal subjects (11 men, 4 women; 49 +/- 3 years; 31.7 +/- 1.0 kg/m(2)). Each subject underwent two 5-hour 80-mU/m(2)/min hyperinsulinemic euglycemic clamps with measurement of glucose kinetics (intravenous 3-(3)H-glucose). Plasma NEFA levels were elevated in one study for 3 hours before and during the clamp ( approximately 1 mmol/L in both groups) by infusion of 20% Intralipid (60 mL/h) and heparin (900 U/h). The obese subjects had higher fasting insulin levels (9.1 +/- 1.1 v 4.8 +/- 0.6 mU/L, P <.005) and were insulin-resistant (glucose disposal rate [GDR] at the end of the control glucose clamps: obese, 7.96 +/- 0.55, lean, 10.24 +/- 0.35 mg/kg/min, P <.002). Contrary to our hypothesis, elevation of plasma NEFA had a similar effect in the lean and obese subjects, both in terms of the absolute reduction of insulin stimulated GDR in the lean (1.82 +/- 0.36 mg/kg/min decrement) and obese subjects (2.03 +/- 0.37 mg/kg/min decrement) and the overall percentage reduction in GDR (lean, 17.1% +/- 3.1%; obese, 24.5% +/- 4.2%; difference not significant [NS]). Suppression of HGO during the lipid clamps was also impaired to a similar extent in the 2 groups. Findings were similar for the 9 obese subjects with a BMI of 30 kg/m(2) or more. Combining the 2 groups, the NEFA induced reduction of insulin stimulated GDR did not correlate with BMI (r = 0.08, NS) or with insulin sensitivity (GDR) measured in the control study (r = 0.11, NS). In summary, the effect of a short term elevation of plasma NEFA levels on insulin stimulated GDR and suppression of HGO is comparable in lean and moderately obese subjects.     

The effect of an increased free fatty acid concentration on thermogenesis and substrate oxidation in obese and lean men

OBJECTIVE: To examine whether a certain increase in plasma free fatty acid (FFA) concentration leads to similar increases in lipid oxidation and energy expenditure in obese and lean men. DESIGN: The study protocol consisted of a 30 min baseline period after which subjects received an i.v. bolus of 1000 IE heparin. Then consecutive infusions of 4.9, 9.8 and 19.6 microl/kg fat-free mass (FFM).min of a lipid heparin mixture were started, each infusion for 30 min. SUBJECTS: Eleven obese and 13 lean men with a mean body mass index (BMI) of 34.2+/-1.0 (+/-s.e.m.) and 23.9+/-0.5 kg/m(2) and age 46.0+/-1.0 and 42.6+/-1.5 y, respectively. MEASUREMENTS: Energy expenditure, respiratory exchange ratio (RER) and carbohydrate and lipid oxidation were continuously measured by indirect calorimetry. At the end of each infusion period, a blood sample was taken for FFA, glycerol, insulin, beta-hydroxybutyrate, noradrenaline and adrenaline determination. RESULTS: At baseline, plasma FFA levels were comparable in both groups. Lipid heparin infusion increased plasma FFA concentration by 301+/-47 micromol/l and 332+/-27 micromol/l in obese and lean men. Energy expenditure increased similarly in obese and lean men (0.34+/-0.08 vs 0.40+/-0.08 kJ/min, NS) during lipid heparin infusion, whereas RER decreased similarly in both groups. Lipid oxidation rates were comparable at baseline and increased similarly in obese and lean men (19+/-5 vs 13+/-4 mg/min, NS). Baseline plasma insulin levels were higher in the obese, but did not change during lipid heparin infusion. Plasma beta-hydroxybutyrate concentrations were similar at baseline, but increased significantly less in the obese during lipid heparin infusion. Baseline noradrenaline and adrenaline concentrations did not differ significantly between groups. During lipid heparin infusion, plasma noradrenaline levels decreased significantly, but plasma adrenaline levels remained unchanged in both groups. CONCLUSION: A certain increase in plasma FFA concentration leads to similar increases in lipid oxidation and energy expenditure in obese and lean men. The accumulation of fat in obese subjects may therefore be more likely to be due to a defect in adipose tissue lipolysis than a defect in lipid oxidation. International Journal of Obesity (2001) 25, 33-38     

Effect of short-term exercise training on leptin and insulin action

The purpose of the study was to determine the effect of short-term exercise training (7 consecutive days for 60 min/d at 75% maximal oxygen consumption [VO2 max]), which did not change body mass on fasting plasma leptin concentration and insulin action. Young, lean subjects (n = 16; age, 21.9 +/- 0.6 years; body fat, 17.5% +/- 1.5%) and older subjects with relatively more adipose tissue (n = 14; age, 58.6 +/- 1.4 years; body fat, 28.3% +/- 1.3%) were studied (mean +/- SE). Fasting plasma leptin was significantly (P < .05) related to adiposity (fat mass, r = .58; % body fat, r = .76) in this population. Body mass did not change (P < .05) in any of the groups with training (71.8 +/- 2.5 v 71.9 +/- 2.5 kg). The insulin sensitivity index (SI determined from an intravenous glucose tolerance test (IVGTT) improved significantly (P < .05) in both the young group (4.8 +/- 0.6 v6.9 +/- 0.8 x 10(-4)/ min (microU/mL) and the older group (3.2 +/- 0.6 v 5.9 +/- 1.0 x 10(-4)/min (microU/mL)). Fasting leptin did not change with training in either group (10.4 +/- 1.6 v 9.2 +/- 1.0 ng/mL). These findings suggest that exercise does not independently affect the fasting plasma leptin concentration and the improvement in insulin action with exercise is not associated with an alteration in fasting leptin in healthy sedentary lean and relatively lean subjects.     

Predictors of adipose tissue lipoprotein lipase in middle-aged and older men: relationship to leptin and obesity, but not cardiovascular fitness

The effects of long-term endurance exercise training, body composition, and cardiovascular fitness (VO2max) on the activity of adipose tissue lipoprotein lipase (AT-LPL) and lipoprotein lipids were examined in 66 healthy age-matched middle-aged and older men (mean +/- SE, 61 +/- 1 years). We compared subcutaneous abdominal (ABD) and gluteal (GLT) heparin-elutable AT-LPL activity in 19 master athletes (VO2max > 40 mL/kg/min) and 20 lean sedentary men (VO2max < 40 mL/kg/min) versus 27 obese sedentary men (VO2max < 40 mL/kg/min; body fat > 27%). Fasting insulin and leptin levels were similar in master athletes and lean sedentary men, but were lower than in obese sedentary men. There were no differences in fasting values for total cholesterol or low-density lipoprotein cholesterol (LDL-C) among the groups, but master athletes had lower triglyceride (TG) values (P < .05) and higher high-density lipoprotein cholesterol (HDL-C) and HDL2-C (P < .05) than obese and lean sedentary men. There were no regional (ABD v GLT) differences in the activity of AT-LPL in these groups, but obese sedentary men had higher levels of ABD AT-LPL (2.1 +/- 0.3 nmol/10(6) cells x min) than lean sedentary men (0.8 +/- 0.2) and master athletes (0.5 +/- 0.1, P = .01). Similar results were observed for GLT AT-LPL. Both ABD and GLT AT-LPL activity correlated positively with percent body fat (r = .46 to .54, P < .001), fasting insulin (r = .37 to .45, P < .001), and leptin (r = .61 to .65, P < .0001), but not with VO2max. In stepwise multiple regression analysis, leptin was the main independent predictor of ABD (R2 = .43, P < .0001) and GLT (R2 = .40, P < .0001) AT-LPL activity. Plasma TG correlated positively (r = .32, P < .01) and HDL-C correlated negatively (r = -.32, P = .02) with ABD AT-LPL activity, but these relationships were not significant after controlling for percent body fat or leptin. The results of this study indicate that in healthy middle-aged and older men, the major determinants of AT-LPL activity are obesity and its major associated hormones, leptin and insulin, not cardiovascular fitness, and also suggest that the higher HDL-C levels observed in endurance-trained men are not associated with increased AT-LPL activity.     

Gender differences in relation to leptin concentration and insulin sensitivity in nondiabetic Chinese subjects.

OBJECTIVE: To investigate the relationship between fasting plasma leptin concentrations and insulin resistance in Chinese men and women. DESIGN: Cross-sectional study design. SUBJECTS: Ninety-six nondiabetic Chinese (51 men and 45 women) with body mass index (BMI) between 18.4-35.8 kg/m2 were studied. MEASUREMENTS: Plasma glucose and insulin concentrations were measured every 30 min for 2 h after a 75 g oral glucose load. The degree of insulin resistance was assessed using a modified insulin suppression test. Plasma leptin values were determined by radioimmunoassay. RESULTS: Fasting plasma glucose, glucose areas, fasting insulin, insulin areas, most of the lipoprotein concentrations and steady state plasma glucose (SSPG) concentrations were relatively similar between men and women. Despite the fact that men had higher BMI values (26.1 +/- 0.5 vs 24.7 +/- 0.5 kg/m2, P < 0.05), fasting plasma leptin concentrations were significantly lower in men than in women (4.9 +/- 0.5 vs 9.0 +/- 0.8 ng/ml, P < 0.001). Fasting leptin values were positively related to SSPG concentrations by simple correlation analysis in both sexes. However, this relationship persisted in men (r = 0.513, P < 0.01) but not in women (r = 0.119, P = NS) after adjustment for BMI. Multiple regression analysis showed that SSPG concentrations, BMI, glucose and insulin responses together accounted for 62.5% and 52.2% of the variation in plasma leptin concentrations in Chinese men and women respectively. CONCLUSION: Fasting plasma leptin concentrations were lower in Chinese men than in Chinese women despite the higher BMI observed in men. After adjustment for BMI, plasma leptin values correlated with the degree of insulin resistance in men but not in women.     

In vivo assessment of the mitochondrial response to caloric restriction in obese women by the 2-keto[1-C]isocaproate breath test

The 2-keto[1-(13)C]isocaproate breath test has been proposed as a tool to detect mitochondrial dysfunction in alcoholic liver disease. The aim of this study was to evaluate if the 2-keto[1-(13)C]isocaproate breath test could detect in vivo dynamic changes on mitochondrial activity due to caloric restriction in obese women. Fifteen obese women (body mass index [BMI] > 30 kg/m(2)) participated in the study at baseline. Ten of these women agreed to participate on a diet program to induce body weight loss. Fifteen lean women (BMI < 25 kg/m(2)) were included as a control group. The breath test was performed by the oral administration of the tracer measuring (13)CO(2) enrichment in breath before and after ingestion using isotope ratio mass spectrometry. Body composition, resting energy expenditure, and plasma levels of insulin and leptin were measured. There were no relationships observed between the 2-keto[1-(13)C]isocaproate breath test and the plasma insulin (before diet: P =.863; after diet: P =.879), or leptin (before diet: P =.500; after diet: P =.637). In obese women before treatment, kilograms of fat free mass (P =.108), resting energy expenditure adjusted for body composition (P =.312), and the 2-keto[1-(13)C]isocaproate breath test (P =.205) were similar in comparison to lean women. However, 2-keto[1-(13)C]isocaproate oxidation tended to increase after dieting and was significantly higher than in controls (P =.015). These data suggest that the 2-keto[1-(13)C]isocaproate breath test reflected the adaptive modifications in mitochondrial oxidation in response to caloric restriction in obese women.     

Effect of orlistat on plasma leptin levels and risk factors for the metabolic syndrome

Background: The aim of this research was to assess the impact of treatment with Orlistat 120 mg three times daily on serum leptin levels, weight loss, glycemic control, and cardiovascular risk factors involved in the metabolic syndrome. Methods: A 3-month open-labeled prospective study was conducted on 40 patients with the clinical features of the metabolic syndrome divided into two groups-with and without type 2 diabetes mellitus. Twenty type 2 diabetic obese patients (group A) were studied, with BMI of 35.4 +/- 0.9 kg/m(2), as were 20 obese patients without diabetes (group B), with BMI of 36.2 +/- 0.7 kg/m(2). Weight, serum leptin levels, insulin resistance, and cardiovascular risk factors were measured at baseline and at the end of each month. Results: Patients reduced weight at 8.5 +/- 2.3 kg for men and 5.7 +/- 2.6 kg for women in group A against 7.9 +/- 1.9 kg for men and 5.6 +/- 2.0 kg for women in group B. Plasma leptin levels decreased at 4.5 +/- 1.9 ng/mL for men and 1.9 +/- 0.9 ng/mL for women in group A against 3.8 +/- 2.0 ng/mL for men and 2.8 +/- 1.4 ng/mL for women in group B. The level of insulin resistance measured with HOMA-IR decreased from 4.54 +/- 2.35 to 2.69 +/- 0.86 in group A against 3.98 +/- 1.89 to 2.87 +/- 0.93 in group B. In the lipid parameters, the highest decrease was found in triglycerides levels: 6.1 +/- 2.3 mmol/L for men and 3.5 +/- 2.6 mmol/L for women in group A against 2.1 +/- 1.9 mmol/L for men and 1.8 +/- 0.7 mmol/L for women in group B (all p < 0.05). Conclusions: Orlistat beneficially enhances weight loss, contributing to a decrease of serum leptin, insulin resistance level, and cardiovascular risk factors in both groups. An additional beneficial pleotropic effect of Orlistat could be proposed through a reduction of plasma leptin and lipid levels.     

Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects

The effect of metformin on glucose metabolism was examined in eight obese (percent ideal body weight, 151 +/- 9%) and six lean (percent ideal body weight, 104 +/- 4%) noninsulin-dependent diabetic (NIDD) subjects before and after 3 months of metformin treatment (2.5 g/day). Fasting plasma glucose (11.5-8.8 mmol/L), hemoglobin-A1c (9.8-7.7%), oral glucose tolerance test response (20.0-17.0 mmol/L; peak glucose), total cholesterol (5.67-4.71 mmol/L), and triglycerides (2.77-1.52 mmol/L) uniformly decreased (P less than 0.05-0.001) after metformin treatment; fasting plasma lactate increased slightly from baseline (1.4 to 1.7 mmol/L; P = NS). Body weight decreased by 5 kg in obese NIDD subjects, but remained constant in lean NIDD. Basal hepatic glucose production declined in all diabetics from 83 to 61 mg/m2.min (P less than 0.01), and the decrease correlated (r = 0.80; P less than 0.01) closely with the fall in fasting glucose concentration. Fasting insulin (115 to 79 pmol/L) declined (P less than 0.05) after metformin. During a 6.9 mmol/L hyperglycemic clamp, glucose uptake increased in every NIDD subject (113 +/- 15 to 141 +/- 12 mg/m2.min; P less than 0.001) without a change in the plasma insulin response. During a euglycemic insulin clamp, total glucose uptake rose in obese NIDD subjects (121 +/- 10 to 146 +/- 9 mmol/m2.min; P less than 0.05), but decreased slightly in lean NIDD (121 +/- 10 to 146 +/- 0.5; P = NS). Hepatic glucose production was suppressed by more than 80-90% in all insulin clamp studies before and after metformin treatment. In conclusion, metformin lowers the fasting plasma glucose and insulin concentrations, improves oral glucose tolerance, and decreases plasma lipid levels independent of changes in body weight. The improvement in fasting glucose results from a reduction in basal hepatic glucose production. Metformin per se does not enhance tissue sensitivity to insulin in NIDD subjects. The improvement in glucose metabolism under hyperglycemic, but not euglycemic, conditions suggests that metformin augments glucose-mediated glucose uptake. Metformin has no stimulatory effect on insulin secretion.     

Relationship between serum resistin concentration and proinflammatory cytokines in obese women with impaired and normal glucose tolerance

The aim of this study was to investigate the possible role of resistin in obese women with and without insulin resistance. We compared serum concentrations of resistin with interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), soluble TNF receptors 1 and 2, and certain anthropometric and metabolic parameters in 26 obese women (body mass index [BMI], 35.8 +/- 4.12 kg/m2) and 15 healthy control women (BMI, 22.32 +/- 1.89 kg/m2). Fasting serum resistin and inflammatory cytokine levels were measured by enzyme immunoassay. Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-R) formula. Compared with lean controls, obese women showed higher HOMA-R values and levels of insulin and increased values of TNF-alpha, soluble TNF receptors, and IL-6. There was no significant difference in resistin levels between the investigated groups of obese women and lean subjects. The results showed that serum resistin concentrations did not correlate with BMI, HOMA, fasting plasma glucose level, or fasting plasma insulin level. Serum resistin correlated with fat mass and IL-6 in the group with impaired glucose tolerance (obese group) (r = 0.51, P < .05, and r = 0.37, P < .05, respectively) and with low-density lipoprotein cholesterol (r = -0.39, P < .05) in the same group. The groups we examined are relatively small; it is likely that with a larger number of subjects, the correlation in other obese women groups may achieve statistical significance. It seems that resistin may be linked with inflammation and obesity and, indirectly, with insulin resistance.