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Background: The worldwide prevalence of obesity, a major risk factor for numerous debilitating chronic disorders, is increasing rapidly. Although a substantial amount of the variation in body mass index (BMI) is estimated to be heritable, the largest meta-analysis of genome-wide association studies (GWAS) to date explained only ~2.7% of the variation. To tackle this 'missing heritability' problem of obesity, here we focused on the contribution of DNA repeat length polymorphisms which are not detectable by GWAS., Subjects and Methods: We determined the cytosine-adenine-guanine (CAG) repeat length in the nine known polyglutamine disease-associated genes (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1 and AR) in two large cohorts consisting of 12,457 individuals and analyzed their association with BMI, using generalized linear mixed-effect models., Results: We found a significant association between BMI and the length of CAG repeats in seven polyglutamine disease-associated genes (including ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP and AR). Importantly, these repeat variations could account for 0.75% of the total BMI variation., Conclusions: Our findings incriminate repeat polymorphisms as an important novel class of genetic risk factors of obesity and highlight the role of the brain in its pathophysiology.

Background: Excessive consumption of sugar-sweetened beverages (SSBs) has been associated with obesity and related diseases. SSBs are often consumed cold, and both the energy content and temperature might influence the consumption behavior for SSBs., Objective: The main aim of this study was to elucidate whether consumption temperature and energy (i.e., glucose) content modulate homeostatic (hypothalamus) and reward [ventral tegmental area (VTA)] responses., Design: Sixteen healthy men participated in our study [aged 18-25 y; body mass index (kg/m2): 20-23]. High-resolution functional magnetic resonance imaging data were collected after ingestion of 4 different study stimuli: plain tap water at room temperature (22°C), plain tap water at 0°C, a glucose-containing beverage (75 g glucose dissolved in 300 mL water) at 22°C, and a similar glucose drink at 0°C. Blood oxygen level-dependent (BOLD) changes from baseline (7 min preingestion) were analyzed over time in the hypothalamus and VTA for individual stimulus effects and for effects between stimuli., Results: In the hypothalamus, water at 22°C led to a significantly increased BOLD response; all other stimuli resulted in a direct, significant decrease in BOLD response compared with baseline. In the VTA, a significantly decreased BOLD response compared with baseline was found after the ingestion of stimuli containing glucose at 0°C and 22°C. These responses were not significantly modulated by consumption temperature. The consumption of plain water did not have a significant VTA BOLD effect., Conclusions: Our data show that glucose at 22°C, glucose at 0°C, and water at 0°C lowered hypothalamic activity, which is associated with increased satiation. On the contrary, the consumption of water at room temperature increased activity. All stimuli led to a similar VTA response, which suggests that all drinks elicited a similar hedonic response. Our results indicate that, in addition to glucose, the low temperature at which SSBs are often consumed also leads to a response from the hypothalamus and might strengthen the response of the VTA. This trial was registered at www.clinicaltrials.gov as NCT03181217., (© 2018 American Society for Nutrition. All rights reserved.)

Aims/hypothesis: Elevated levels of lipoprotein(a) [Lp(a)] are an independent risk factor for cardiovascular disease (CVD), particularly in individuals with type 2 diabetes. Although weight loss improves conventional risk factors for CVD in type 2 diabetes, the effects on Lp(a) are unknown and may influence the long-term outcome of CVD after diet-induced weight loss. The aim of this clinical study was to determine the effect of diet-induced weight loss on Lp(a) levels in obese individuals with type 2 diabetes., Methods: Plasma Lp(a) levels were determined by immunoturbidimetry in plasma obtained before and after 3-4 months of an energy-restricted diet in four independent study cohorts. The primary cohort consisted of 131 predominantly obese patients with type 2 diabetes (cohort 1), all participants of the Prevention Of Weight Regain in diabetes type 2 (POWER) trial. The secondary cohorts consisted of 30 obese patients with type 2 diabetes (cohort 2), 37 obese individuals without type 2 diabetes (cohort 3) and 26 obese individuals without type 2 diabetes who underwent bariatric surgery (cohort 4)., Results: In the primary cohort, the energy-restricted diet resulted in a weight loss of 9.9% (95% CI 8.9, 10.8) and improved conventional CVD risk factors such as LDL-cholesterol levels. Lp(a) levels increased by 14.8 nmol/l (95% CI 10.2, 20.6). In univariate analysis, the change in Lp(a) correlated with baseline Lp(a) levels (r = 0.38, p < 0.001) and change in LDL-cholesterol (r = 0.19, p = 0.033). In cohorts 2 and 3, the weight loss of 8.5% (95% CI 6.5, 10.6) and 6.5% (95% CI 5.7, 7.2) was accompanied by a median increase in Lp(a) of 13.5 nmol/l (95% CI 2.3, 30.0) and 11.9 nmol/l (95% CI 5.7, 19.0), respectively (all p < 0.05). When cohorts 1-3 were combined, the diet-induced increase in Lp(a) correlated with weight loss (r = 0.178, p = 0.012). In cohort 4, no significant change in Lp(a) was found (-7.0 nmol/l; 95% CI -18.8, 5.3) despite considerable weight loss (14.0%; 95% CI 12.2, 15.7)., Conclusions/interpretation: Diet-induced weight loss was accompanied by an increase in Lp(a) levels in obese individuals with and without type 2 diabetes while conventional CVD risk factors for CVD improved. This increase in Lp(a) levels may potentially antagonise the beneficial cardiometabolic effects of diet-induced weight reduction.

Aims/hypothesis: Dicarbonyl compounds are formed as byproducts of glycolysis and are key mediators of diabetic complications. However, evidence of postprandial α-dicarbonyl formation in humans is lacking, and interventions to reduce α-dicarbonyls have not yet been investigated. Therefore, we investigated postprandial α-dicarbonyl levels in obese women without and with type 2 diabetes. Furthermore, we evaluated whether a diet very low in energy (very low calorie diet [VLCD]) or Roux-en-Y gastric bypass (RYGB) reduces α-dicarbonyl stress in obese women with type 2 diabetes., Methods: In lean (n = 12) and obese women without (n = 27) or with type 2 diabetes (n = 27), we measured the α-dicarbonyls, methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG), and glucose in fasting and postprandial plasma samples obtained during a mixed meal test. Obese women with type 2 diabetes underwent either a VLCD or RYGB. Three weeks after the intervention, individuals underwent a second mixed meal test., Results: Obese women with type 2 diabetes had higher fasting and particularly higher postprandial plasma α-dicarbonyl levels, compared with those without diabetes. After three weeks of a VLCD, postprandial α-dicarbonyl levels in diabetic women were significantly reduced (AUC MGO -14%, GO -16%, 3-DG -25%), mainly through reduction of fasting plasma α-dicarbonyls (MGO -13%, GO -13%, 3-DG -33%). Similar results were found after RYGB., Conclusions/interpretation: This study shows that type 2 diabetes is characterised by increased fasting and postprandial plasma α-dicarbonyl stress, which can be reduced by improving glucose metabolism through a VLCD or RYGB. These data highlight the potential to reduce reactive α-dicarbonyls in obese individuals with type 2 diabetes., Trial Registration: ClinicalTrials.gov NCT01167959.

We hypothesized that brain circuits involved in reward and salience respond differently to fasting in obese versus lean individuals. We compared functional connectivity networks related to food reward and saliency after an overnight fast (baseline) and after a prolonged fast of 48 h in lean versus obese subjects. We included 13 obese (2 males, 11 females, BMI 35.4 ± 1.2 kg/m(2), age 31 ± 3 years) and 11 lean subjects (2 males, 9 females, BMI 23.2 ± 0.5 kg/m(2), age 28 ± 3 years). Resting-state functional magnetic resonance imaging scans were made after an overnight fast (baseline) and after a prolonged 48 h fast. Functional connectivity of the amygdala, hypothalamus and posterior cingulate cortex (default-mode) networks was assessed using seed-based correlations. At baseline, we found a stronger connectivity between hypothalamus and left insula in the obese subjects. This effect diminished upon the prolonged fast. After prolonged fasting, connectivity of the hypothalamus with the dorsal anterior cingulate cortex (dACC) increased in lean subjects and decreased in obese subjects. Amygdala connectivity with the ventromedial prefrontal cortex was stronger in lean subjects at baseline, which did not change upon the prolonged fast. No differences in posterior cingulate cortex connectivity were observed. In conclusion, obesity is marked by alterations in functional connectivity networks involved in food reward and salience. Prolonged fasting differentially affected hypothalamic connections with the dACC and the insula between obese and lean subjects. Our data support the idea that food reward and nutrient deprivation are differently perceived and/or processed in obesity., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Obesity and type 2 diabetes mellitus (T2DM) have been associated with increased levels of circulating branched-chain amino acids (BCAAs) that may be involved in the pathogenesis of insulin resistance. However, weight loss has not been consistently associated with the reduction of BCAA levels., Research Design and Methods: We included 30 obese normal glucose-tolerant (NGT) subjects, 32 obese subjects with T2DM, and 12 lean female subjects. Obese subjects underwent either a restrictive procedure (gastric banding [GB], a very low-calorie diet [VLCD]), or a restrictive/bypass procedure (Roux-en-Y gastric bypass [RYGB] surgery). Fasting blood samples were taken for the determination of amine group containing metabolites 4 weeks before, as well as 3 weeks and 3 months after the intervention., Results: BCAA levels were higher in T2DM subjects, but not in NGT subjects, compared with lean subjects. Principal component (PC) analysis revealed a concise PC consisting of all BCAAs, which showed a correlation with measures of insulin sensitivity and glucose tolerance. Only after the RYGB procedure, and at both 3 weeks and 3 months, were circulating BCAA levels reduced., Conclusions: Our data confirm an association between deregulation of BCAA metabolism in plasma and insulin resistance and glucose intolerance. Three weeks after undergoing RYGB surgery, a significant decrease in BCAAs in both NGT as well as T2DM subjects was observed. After 3 months, despite inducing significant weight loss, neither GB nor VLCD induced a reduction in BCAA levels. Our results indicate that the bypass procedure of RYGB surgery, independent of weight loss or the presence of T2DM, reduces BCAA levels in obese subjects., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aims/hypothesis: Not all obese individuals develop type 2 diabetes. Why some obese individuals retain normal glucose tolerance (NGT) is not well understood. We hypothesise that the biochemical mechanisms that underlie the function of adipose tissue can help explain the difference between obese individuals with NGT and those with type 2 diabetes., Methods: RNA sequencing was used to analyse the transcriptome of samples extracted from visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of obese women with NGT or type 2 diabetes who were undergoing bariatric surgery. The gene expression data was analysed by bioinformatic visualisation and statistical analyses techniques., Results: A network-based approach to distinguish obese individuals with NGT from obese individuals with type 2 diabetes identified acetyl-CoA metabolic network downregulation as an important feature in the pathophysiology of type 2 diabetes in obese individuals. In general, genes within two reaction steps of acetyl-CoA were found to be downregulated in the VAT and SAT of individuals with type 2 diabetes. Upon weight loss and amelioration of metabolic abnormalities three months following bariatric surgery, the expression level of these genes recovered to levels seen in individuals with NGT. We report four novel genes associated with type 2 diabetes and recovery upon weight loss: ACAT1 (encoding acetyl-CoA acetyltransferase 1), ACACA (encoding acetyl-CoA carboxylase α), ALDH6A1 (encoding aldehyde dehydrogenase 6 family, member A1) and MTHFD1 (encoding methylenetetrahydrofolate dehydrogenase)., Conclusions/interpretation: Downregulation of the acetyl-CoA network in VAT and SAT is an important feature in the pathophysiology of type 2 diabetes in obese individuals. ACAT1, ACACA, ALDH6A1 and MTHFD1 represent novel biomarkers in adipose tissue associated with type 2 diabetes in obese individuals.

Background: The brain is crucial for the control of food intake, reward, and energy homeostasis., Objective: We hypothesized that 1) brain circuits involved in energy homeostasis and reward show different functional connectivity patterns between obese and lean individuals and 2) food intake affects functional connectivity differentially in obese and lean individuals. Therefore, we compared the connectivity of the hypothalamus, amygdala, and posterior cingulate cortex, each probing a distinct network related to energy homeostasis and reward, between obese subjects and lean subjects in the fasting state and after meal ingestion., Design: We acquired 3 Tesla resting-state functional magnetic resonance imaging scans after an overnight fast and after ingestion of a liquid mixed meal in 46 obese female participants [19 with normal glucose tolerance and 27 with type 2 diabetes mellitus (T2DM)] and 12 lean subjects. Functional connectivity of our regions of interest was assessed by using a seed-based correlation approach., Results: No significant differences between normal-glucose-tolerant and T2DM subjects were observed. In the fasting state, the total obese group had stronger hypothalamic connectivity with the medial prefrontal cortex and the dorsal striatum than did the lean subjects. The amygdala was differentially connected to the right insula in obese compared with lean subjects. Food intake dampened hypothalamic connectivity with the frontal regions in lean subjects, whereas these connections were barely affected in obese subjects., Conclusions: Our results indicate that functional connectivity in several brain networks, particularly the homeostatic and cognitive control network and the reward network, was different between obese and lean subjects. In the fasting state, obesity appears to be associated with stronger functional connectivity between brain areas involved in cognitive control, motivation, and reward, whereas these connections are largely unaffected by food intake in obese compared with lean subjects., (© 2014 American Society for Nutrition.)

Objective: Roux-en-Y gastric bypass (RYGB) and restrictive weight loss interventions, such as gastric banding (GB) and very-low-calorie diets (VLCD) directly impact glucose metabolism, possibly by calorie restriction and/or altered secretion of gut hormones. We aimed to establish the direct endocrine and metabolic effects of RYGB compared to restrictive interventions in obese glucose-tolerant (NGT) subjects and subjects with type 2 diabetes (T2DM)., Design: Controlled, nonrandomized observational trial., Patients and Measurements: Four groups of obese females received a mixed meal at baseline and 3 weeks after intervention; NGT-GB (n = 11), NGT-RYGB (n = 16), T2DM-RYGB (n = 15) and T2DM-VLCD (n = 12). Normal weight controls (n = 12) were studied once., Results: At baseline, all obese subjects were hyperinsulinemic. T2DM was associated with hyperglycaemia and decreased GLP-1 levels. RYGB and VLCD reduced glucose levels to a similar extent in T2DM, insulin levels decreased only after VLCD. Comparison of restrictive intervention vs RYGB showed a more pronounced decrease in glucose and insulin AUC after restriction. In NGT and T2DM subjects, RYGB increased GLP-1 and PYY levels and decreased ghrelin levels, whereas VLCD and GB only increased GIP levels., Conclusions: These data indicate that deterioration of glucose metabolism in T2DM is associated with a decline of GLP-1 levels. Calorie restriction facilitates glucose metabolism and blunts hyperinsulinemia in obese (diabetic) humans. Additional duodenal exclusion through RYGB induces gut hormone release and hyperinsulinemia but does not improve postprandial glucose levels any further. Our data thus strongly suggest that calorie restriction underlies the short-term metabolic benefits of RYGB in obese T2DM patients., (© 2013 John Wiley & Sons Ltd.)

Introduction: Obesity is strongly related to type-2 diabetes (T2DM), but there is a subset of obese individuals that remains relatively insulin sensitive and metabolically healthy. This study determined to what extent differences in metabolic health in obese women are associated with differences in adipose tissue and/or systemic inflammation., Methods: The subject group consisted of age comparable lean (n=12) and obese women either with T2DM (n=28) or normal glucose tolerance (NGT; n=26). Number of crown like structures (CLS) and adipocyte size were measured in subcutaneous and visceral adipose tissue of the obese women. Circulating cytokine and free fatty acid (FFA) levels, as well as number and activation status of peripheral leukocytes were determined., Results: Obese T2DM subjects showed higher circulating levels of IL-6, FFA and glycerol as compared to obese NGT subjects. Obese T2DM subjects had higher absolute numbers of peripheral leukocytes which were mainly due to an increase of T helper cells. Activation status of circulating cytotoxic T (CD8+CD25+) and B (CD19+CD38+) cells was significantly increased in obese NGT subjects as compared to lean but was not different between the two obese groups. Subcutaneous adipose tissue of obese T2DM subjects contained more CLS than adipose tissue of obese NGT subjects., Conclusion: Obese T2DM subjects show higher FFA levels and adipose tissue macrophage infiltration in addition to higher levels of circulating IL-6 and numbers of CD4+ T cells than obese NGT subjects. Hence, obese T2DM subjects show a higher extent of inflammation at both the systemic and adipose tissue level., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Heart rate variability (HRV) reflects the balance of activities of sympathetic and parasympathetic components of the autonomic nervous system. We compared HRV parameters in response to a prolonged fast in obese versus normal weight humans. In addition, the effect of weight-loss was evaluated in obese individuals., Design: Intervention study., Patients: The study subjects included 14 nondiabetic obese (12 females/2 males, aged 30 ± 3 years, Body Mass Index (BMI) 35·2 ± 1·2 kg/m(2) ) and 12 lean subjects (10 females/2 males, aged 27 ± 3 years, BMI 23·3 ± 0·5 kg/m(2) )., Measurements: HRV was examined 75 min after standardized breakfast and after a 48-h fast in 14 nondiabetic obese and 12 lean subjects. The postprandial measurement was repeated in 12 obese subjects after weight-loss., Results: In lean subjects, fasting decreased high-frequency (HF) power by 43% (P < 0·05) and decreased low-frequency (LF) power by 37% (P = 0·1), leaving the LF/HF ratio unchanged (P = 0·7). In the obese group, autonomic nervous system tone shifted to sympathetic dominance as the LF/HF increased from 0·61 to 1·14 (P = 0·03). After an average weight-loss of 13·8 kg in obese subjects, a trend for sympathetic dominance was found; the LF/HF ratio increased by 56% (P = 0·06)., Conclusion: Our data show that a 48-h fast leaves autonomic nervous system balance unaltered in lean subjects. In contrast, a 48-h fast, as well as weight-loss, induces sympathetic dominance in obese humans., (© 2012 John Wiley & Sons Ltd.)

Objective: Obesity and type 2 diabetes mellitus (T2DM) are reported to be associated with relative overactivity of the sympathetic nervous system (SNS), which is reversible by weight loss. However, direct effects of weight loss by calorie restriction vs Roux-en-Y gastric bypass (RYGB) on SNS overactivity were not studied in parallel. This study compared the effects of RYGB vs restrictive weight loss in obese patients with normal glucose tolerance (NGT) and with T2DM on SNS function as measured by heart rate variability (HRV)., Design and Methods: Lean (n=12), obese NGT (n=27) and T2DM (n=27) subjects were included in this study. Weight reduction in NGT subjects was achieved by gastric banding (GB) or RYGB and in T2DM subjects by RYGB or high-protein very-low-calorie diet (VLCD). HRV analysis was performed and blood samples were taken at baseline, 3 weeks and 3 months after intervention., Results: At baseline, T2DM subjects showed SNS overactivity and NGT subjects showed similar, but non-significant, findings when compared with lean controls. Weight loss after 3 weeks was comparable in all treatment groups, whereas after 3 months, weight loss was most in VLCD and RYGB subjects. RYGB and VLCD treatment reduced SNS activity within 3 weeks in T2DM patients. After 3 months, restoration to normal autonomic nervous system activity was evident for all groups, except for the NGT-GB group., Conclusion: We can conclude that SNS overactivity is more pronounced in obese T2DM subjects when compared with NGT subjects. Reduction of SNS overactivity coincides with weight loss with the time-course of reduction dependent on the type of intervention. Surgery or caloric restriction may transiently induce SNS overactivity but do not prevent a direct restoration of sympathovagal balance.

Obesity in humans is often associated with metabolic inflexibility, but the underlying molecular mechanisms remain incompletely understood. The aim of the present study was to investigate how adaptation to prolonged fasting affects energy/nutrient-sensing pathways and metabolic gene expression in skeletal muscle from lean and obese individuals. Twelve lean and 14 nondiabetic obese subjects were fasted for 48 h. Whole body glucose/lipid oxidation rates were determined by indirect calorimetry, and blood and skeletal muscle biopsies were collected and analyzed. In response to fasting, body weight loss was similar in both groups, but the decrease in plasma insulin and leptin and the concomitant increase in growth hormone were significantly attenuated in obese subjects. The fasting-induced shift from glucose toward lipid oxidation was also severely blunted. At the molecular level, the expression of insulin receptor-β (IRβ) was lower in skeletal muscle from obese subjects at baseline, whereas the fasting-induced reductions in insulin signaling were similar in both groups. The protein expression of mitochondrial respiratory chain components, although not modified by fasting, was significantly reduced in obese subjects. Some minor differences in metabolic gene expression were observed at baseline and in response to fasting. Surprisingly, fasting reduced AMPK activity in lean but not in obese subjects, whereas the expression of AMPK subunits was not affected. We conclude that whole body metabolic inflexibility in response to prolonged fasting in obese humans is associated with lower skeletal muscle IRβ and mitochondrial respiratory chain content as well as a blunted decline of AMPK activity.

Objective: Long-term treatment with topiramate reduces body weight and improves insulin sensitivity in obese humans. Our aim was to evaluate the effect of topiramate treatment for 4 weeks on insulin sensitivity and secretion, independent of weight loss., Design: Randomized, double-blind, crossover, placebo-controlled study., Methods: Thirteen obese (BMI 36.6 ± 1.3 kg/m(2) (mean ± s.e.m.)), insulin-resistant (homeostasis model of assessment-insulin resistance 2.0 ± 0.2) women received topiramate (T, maximum dose of 75 mg) and placebo (P) for 4 weeks, separated by a 4-week washout period. Insulin sensitivity and β-cell function were assessed using a two-step hyperinsulinemic euglycemic clamp with stable isotopes and a hyperglycemic clamp., Results: Hepatic and peripheral insulin sensitivities were not affected by topiramate treatment (glucose disposal rate (step 1 (insulin infusion rate 10 MU/M(2) per min) T: 17.5 ± 0.8 vs P: 18.5 ± 1.0 μmol/kg(LBM) per min, t=1.016, P=0.33; step 2 (insulin infusion rate 40 mU/m(2) per min) T: 27.9 ± 3.2 vs P: 28.8 ± 1.9 μmol/kg(LBM) per min, t=0.418, P=0.68)). Subjects lost a small amount of weight during the topiramate period (T: -1.0 ± 0.2 vs P: -0.1 ± 0.2 kg, t=2842, P=0.15). There were no changes in body fat mass, blood pressure, and fasting glucose. β-Cell function was not affected by topiramate as evidenced by an unaltered area under the curve of early (0-10 min; T: 1929.6 ± 265.7 vs P: 2024.7 ± 333.6 pmol/l, t=-0.357, P=0.73) and late (80-120 min; T: 28,017.7 ± 5029.9 vs P: 31,567.7 ± 5376.2 pmol/l, t=-1.481, P=0.16) phase insulin levels during hyperglycemia. The use of topiramate was associated with significant side effects such as paresthesia, nausea, dizziness, and concentration problems., Conclusions: Low-dose topiramate treatment for 4 weeks, relative to placebo, had no significant effect on insulin sensitivity in overweight/obese adult females without established diabetes.

Background: The ACTH-cortisol axis in women is activated and associated with decreased ACTH potency, estimated by relating ACTH and cortisol pulse masses. Recently, a new accurate method for constructing the endogenous dose-response relationship was introduced, which is based on the relation between ACTH concentrations and associated cortisol secretion rates within cortisol bursts., Hypothesis: The endogenous dose-response relation between ACTH and cortisol in obesity is changed, leading to diminished responsiveness., Subjects: Twenty-five obese premenopausal women and 16 normal weight premenopausal women were studied by 10-min blood sampling for 24 h., Outcomes: ACTH and cortisol secretion rates, analytical dose-response estimates of endogenous ACTH efficacy (maximal cortisol secretion), dynamic ACTH potency, and adrenal sensitivity (slope term) from 24-h ACTH-cortisol profiles were quantified., Results: The initial potency (negative logarithm) was -7.83 ± 0.75 (mean ± s.e.m.) in obese women and -10.14 ± 1.08 in lean women (P=0.10), and the corresponding values for the recovery phase were -26.62 ± 2.21 and -36.67 ± 1.66 (P=0.004). The sensitivity (curve slope) amounted to 0.468 ± 0.05 in obese women and 0.784 ± 0.09 in normal weight women (P=0.004). The efficacy (maximal value) was 17.6 ± 4.9 nmol/l per min in obese women and 26.3 ± 3.8 nmol/l per min in normal weight women (P=0.009). Basal secretion rate, inflection point, and EC(50) values were not different. Bromocriptine or acipimox did not change the dose-response curve., Conclusion: The ACTH-cortisol relation in obesity in women is characterized by decreased sensitivity and efficacy, thus explaining non-elevated serum cortisol concentrations despite increased plasma ACTH levels.

Purpose: To evaluate the effect of multidisciplinary treatment on obesity and health-related quality of life (HRQOL)., Methods: Obese children were randomized to a multidisciplinary lifestyle treatment, including medical, nutritional, physical, and psychological counseling during 3 months, (n = 40, BMI-SDS; 4.2 ± 0.7, age; 13.3 ± 2.0) or standard care, including an initial advice on nutrition and physical activity by the pediatrician (n = 39, BMI-SDS; 4.3 ± 0.7, age; 13.1 ± 1.9). At baseline, after 3 months of treatment and at 12 months follow-up, data were collected for BMI-SDS and a European validated questionnaire for assessing HRQOL (DISABKIDS)., Results: A significantly reduced BMI-SDS was found for the intervention group after 3 months treatment (4.0 ± 0.9 vs. 4.2 ± 0.7, P = 0.02) and at 12 months follow-up (3.8 ± 1.1 vs. 4.2 ± 0.7, P = 0.03). HRQOL in the intervention group was significantly improved at 12 months follow-up and unchanged in the obese control group. Agreement between child and parent report was moderate (67-85%), with parents reporting a lower HRQOL for their obese children than children themselves in both groups., Conclusion: Multidisciplinary treatment is effective in reducing BMI-SDS and improving HRQOL after 12 months follow-up.

Pericardial fat accumulation has been associated with an increased cardiovascular risk. A very low calorie diet (VLCD) improves the cardiovascular risk profile in patients with type 2 diabetes mellitus (T2DM), by improving the metabolic profile, heart function, and triglyceride (TG) stores in (non)adipose tissues. However, long-term effects of a VLCD on pericardial fat volume and tissue-specific TG accumulation have not been documented. The aim of this study was therefore to assess the effects of a 16-week VLCD and of subsequent 14 months follow-up on a regular diet on pericardial fat in relation to other TG stores in obese T2DM patients. We included 14 obese patients with insulin-treated T2DM (mean ± s.e.m.: age 53 ± 2 years; BMI 35 ± 1 kg/m(2)). Pericardial fat and other (non)adipose TG stores were measured using magnetic resonance (MR) imaging and proton spectroscopy before and after a 16-week VLCD and after a 14-month follow-up without dietary interventions. A 16-week VLCD reduced body weight, pericardial fat, hepatic TG content, visceral and subcutaneous abdominal fat volumes to 78, 83, 16, 40, and 53% of baseline values respectively, (all P < 0.05). After an additional 14 months of follow-up on a regular diet, the reduction in pericardial fat volume sustained, despite a substantial regain in body weight, visceral abdominal fat, and hepatic TG content (respectively 90, 83 and 73% of baseline values). In conclusion, VLCD-induced weight loss in obese T2DM patients is accompanied by a substantial decrease in pericardial fat volume, which is sustained even after subsequent weight regain.

Context: Reduction of 50% excess body weight, using a very low-calorie diet (VLCD; 450 kcal/d) improves insulin sensitivity in obese type 2 diabetes mellitus patients., Objective: The objective of the study was to evaluate whether adding exercise to the VLCD has additional benefits., Design: This was a randomized intervention study., Setting: The study was conducted at a clinical research center in an academic medical center., Subjects: Twenty-seven obese [body mass index 37.2 ± 0.9 kg/m(2) (mean ± sem)] insulin-treated type 2 diabetes mellitus patients., Intervention: Patients followed a 16-wk VLCD. Thirteen of them simultaneously participated in an exercise program (E) consisting of 1-h, in-hospital training and four 30-min training sessions on a cycloergometer weekly., Outcome Measures: Insulin resistance was measured by a hyperinsulinemic euglycemic clamp. Insulin signaling, mitochondrial DNA (mtDNA) content, and intramyocellular lipid content was measured in skeletal muscle biopsies., Results: Baseline characteristics were identical in both groups. Substantial weight loss occurred (-23.7 ± 1.7 kg VLCD-only vs. -27.2 ± 1.9 kg VLCD+E, P = NS within groups). The exercise group lost more fat mass. Insulin-stimulated glucose disposal increased similarly in both study groups [15.0 ± 0.9 to 39.2 ± 4.7 μmol/min(-1) · kg lean body mass (LBM(-1)) VLCD-only vs. 17.0 ± 1.0 to 37.5 ± 3.5 μmol/min(-1) · kg LBM(-1) in VLCD+E], as did phosphorylation of the phosphatidylinositol 3-kinase-protein kinase B/AKT insulin signaling pathway. In contrast, skeletal muscle mtDNA content increased only in the VLCD+E group (1211 ± 185 to 2288 ± 358, arbitrary units, P = 0.016 vs. 1397 ± 240 to 1196 ± 179, P = NS, VLCD-only group). Maximum aerobic capacity also only increased significantly in the VLCD+E group (+6.6 ± 1.7 ml/min(-1) · kg LBM(-1) vs. +0.7 ± 1.5 ml/min(-1) · kg LBM(-1) VLCD-only, P = 0.017)., Conclusion: Addition of exercise to a 16-wk VLCD induces more fat loss. Exercise augments maximum aerobic capacity and skeletal muscle mtDNA content. These changes are, however, not reflected in a higher insulin-stimulated glucose disposal rate.

Objective: To assess the short- and long-term effects of addition of exercise to a very low calorie diet (VLCD) on low-grade inflammation in obese patients with type 2 diabetes mellitus (T2DM)., Methods: Twenty seven obese, insulin-dependent T2DM patients followed a 4-month VLCD with (n=13) or without (n=14) exercise and were followed up to 18 months. Anthropometric measurements, metabolic and inflammatory parameters were assessed before, directly after the intervention and at 6 and 18 months follow-up. The same measurements were performed only once in 56 healthy lean and 56 healthy obese controls., Results: At baseline hsCRP, IL10 and IL8 were significantly elevated in obese T2DM compared to lean healthy controls. After 4 months, despite substantial weight loss (-25.4 ± 1.3 kg), neither the VLCD nor VLCD+exercise had an effect on plasma cytokines. At 6 months, in the weight-stabilizing period, measures of low-grade inflammation had decreased substantially and equally in both intervention groups. Despite subsequent weight regain, beneficial effect was sustained up to 18 months in both groups, except for IL1 and hsCRP which had returned to baseline in the VLCD-only group., Conclusion: Our findings suggest that severe caloric restriction increases cytokine production by adipose tissue macrophages and that the beneficial effects of weight loss become apparent only in the eucaloric state., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Luteinizing hormone (LH) concentrations and pulsatility are increased in obese women with polycystic ovary syndrome (PCOS). In addition, patients have hyperandrogenemia and insulin resistance. The mechanisms involved in aberrant hormone regulation in PCOS are still unclear. We investigated 15 obese PCOS women with a body mass index between 30 and 54 kg/m(2) and 9 healthy obese controls (body mass index, 31-60 kg/m(2)) with regular menstrual cycles. Subjects underwent 24-hour blood sampling at 10-minute intervals for later measurements of LH, leptin, testosterone, and insulin concentrations. Data were analyzed with a new deconvolution program, approximate entropy (and bivariate approximate entropy), and a cross-correlation network. Patients had increased LH pulse frequency and more than 2-fold greater daily LH secretion, with diminished pattern regularity. Testosterone secretion was increased 2-fold, but pattern regularity was similar to that in controls. In the network construct, insulin was correlated positively with LH, whereas leptin and testosterone were correlated negatively with LH. Bivariate synchrony of LH with insulin was decreased. Short-term caloric restriction paradoxically increased LH secretion by 1.5-fold and pattern irregularity, and reduced interpulse variability. Testosterone secretion and fasting concentrations of estradiol and sex hormone-binding globulin levels remained unchanged. Correlations between LH and insulin, leptin, and calculated free testosterone decreased. This study demonstrates marked alterations in the control of LH secretion in PCOS in the fed and calorie-restricted states. The ensemble results point to abnormal feedback control of not only the GnRH-gonadotrope complex, but also LH's relationships with leptin, insulin, and testosterone., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The prevalence of childhood obesity has increased rapidly during the last three decades in the Netherlands. It is assumed that mainly environmental factors have contributed to this trend. Parental overweight and low social economic status are risk factors for childhood obesity. Childhood obesity affects self-esteem and has negative consequences on cognitive and social development. Obese children tend to become obese adults, which increases the risk for developing cardiovascular complications, type 2 diabetes mellitus, and psychosocial problems. Additionally, the secretion of several gastrointestinal hormones, responsible for appetite and food intake, is impaired in obese subjects. Weight reduction through lifestyle changes in order to change health risks is, until now, suggested as the preferred treatment for childhood obesity.The objective of this study is the effect evaluation of a family-based cognitive behavioral multidisciplinary lifestyle treatment. The intervention aims to establish long-term weight reduction and stabilization, reduction of obesity-related health consequences and improvement of self-image by change of lifestyle and learning cognitive behavioral techniques., Study Design/methods: In this randomized clinical trial newly presented children with obesity (8-17 years old) are divided, by randomization, in an intervention and control group, both consisting of 40 obese children. The intervention is carried out in groups of 8-11 children, and consists of respectively 7 and 5 separate group meetings for the children and their parents and 1 joint group meeting of 2 ½ hours. Main topics are education on nutrition, self-control techniques, social skills, physical activity and improvement of self-esteem. The control group is given advice on physical activity and nutrition. For normal data comparison, data were collected of 40 normal-weight children, 8-17 years old., Discussion: Because of the increasing prevalence of childhood obesity and the impact on the individual as well as on society, prevention and treatment of obesity in children is of great importance. For evaluation of short- and long-term effects of the treatment, measurements are taken before and after 3 months of treatment, and after 12 and 24 months follow-up. During these visits clinical and biochemical data are determined, cardiovascular fitness tests are performed and quality of life questionnaires are completed., Trial Registration: International Standard Randomised Controlled Trial Number Register ISRCTN36146436

This paper delineates the evolutionary background of the unprecedented epidemic of obesity that has evolved over the last century. Some two million years ago, a change of climate in the habitat of our primate ancestors triggered dietary adaptations which allowed our brain to grow. A shift from principally carbohydrate-based to fish- and meat-based eating habits provided sufficient fuel and building blocks to facilitate encephalisation. Insulin resistance may have evolved simultaneously as a means to avert the danger of hypoglycaemia to the brain (in view of the reduction of carbohydrate intake). Ensuing cognitive capacities enabled the control of fire and the manufacturing of tools, which increased energy yield from food even further and eased the defence against predators. The latter development relieved the selective pressure to maintain an upper level of bodyweight (driven by predation of overweight ndividuals). Since then, random mutations allowing bodyweight to increase spread in the human gene pool by genetic drift. Also, (seasonal) food insecurity in hunter-gatherer societies spurred the evolution of thrifty genes to maximise nutrient intake and energy storage when food was available. The agricultural and industrial revolutions rapidly changed our habitat: virtually unlimited stocks of (refined) foodstuffs and mechanical substitutes of physical efforts push up energy balance, particularly in those of us who are still adapted to former environmental conditions: i.e. who carry thrifty genes and lack (genetic) protection against weight gain. Intrauterine epigenetic mechanisms potentially reinforce the impact of these genes on the propensity to grow obese.

Calorie restriction is the most effective way of expanding life-span and decreasing morbidity. It improves insulin sensitivity and delays the age-related loss of dopamine receptor D(2) (DRD2) expression in the brain. Conversely, high-fat feeding is associated with obesity, insulin resistance and a reduced number of DRD2 binding sites. We hypothesised that the metabolic benefit of calorie restriction involves the preservation of appropriate DRD2 transmission. The food intake of wild-type C57Bl6 male mice was restricted to 60% of ad lib. intake while they were treated with the DRD2 antagonist haloperidol or vehicle using s.c. implanted pellets. Mice with ad lib. access to food receiving vehicle treatment served as controls. All mice received high-fat food throughout the experiment. After 10 weeks, an i.p. glucose tolerance test was performed and, after 12 weeks, a hyperinsulinaemic euglycaemic clamp. Hypothalamic DRD2 binding was also determined after 12 weeks of treatment. Calorie-restricted (CR) vehicle mice were glucose tolerant and insulin sensitive compared to ad lib. (AL) fed vehicle mice. CR mice treated with haloperidol were slightly heavier than vehicle treated CR mice. Haloperidol completely abolished the beneficial impact of calorie restriction on glucose tolerance and partly reduced the insulin sensitivity observed in CR vehicle mice. The metabolic differences between AL and CR vehicle mice were not accompanied by alterations in hypothalamic DRD2 binding. In conclusion, blocking DRD2 curtails the metabolic effects of calorie restriction. Although this suggests that the dopaminergic system could be involved in the metabolic benefits of calorie restriction, restricting access to high-fat food does not increase (hypothalamic) DRD2 binding capacity, which argues against this inference., (© 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.)

High fat feeding induces a variety of obese and lean phenotypes in inbred rodents. Compared to Diet Resistant (DR) rodents, Diet Induced Obese (DIO) rodents are insulin resistant and have a reduced dopamine receptor D2 (DRD2) mediated tone. We hypothesized that this differing dopaminergic tone contributes to the distinct metabolic profiles of these animals. C57Bl6 mice were classified as DIO or DR based on their weight gain during 10 weeks of high fat feeding. Subsequently DIO mice were treated with the DRD2 agonist bromocriptine and DR mice with the DRD2 antagonist haloperidol for 2 weeks. Compared to DR mice, the bodyweight of DIO mice was higher and their insulin sensitivity decreased. Haloperidol treatment reduced the voluntary activity and energy expenditure of DR mice and induced insulin resistance in these mice. Conversely, bromocriptine treatment tended to reduce bodyweight and voluntary activity, and reinforce insulin action in DIO mice. These results show that DRD2 activation partly redirects high fat diet induced metabolic anomalies in obesity-prone mice. Conversely, blocking DRD2 induces an adverse metabolic profile in mice that are inherently resistant to the deleterious effects of high fat food. This suggests that dopaminergic neurotransmission is involved in the control of metabolic phenotype.

Context: Melanocortin receptor 4 (MC4R) deficiency is characterized by increased linear growth greater than expected for the degree of obesity., Objective: The objective of the investigation was to study the somatotroph axis in obese MC4R-deficient patients and equally obese controls., Patients and Methods: We obtained anthropometric measurements and insulin concentrations in 153 MC4R-deficient subjects and 1392 controls matched for age and severity of obesity. We measured fasting IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit levels in a subset of 33 MC4R-deficient patients and 36 control subjects. We examined pulsatile GH secretion in six adult MC4R-deficient subjects and six obese controls., Results: Height sd score was significantly greater in MC4R-deficient children under 5 yr of age compared with controls (mean ± SEM: 2.3 ± 0.06 vs. 1.8 ± 0.04, P < 0.001), an effect that persisted throughout childhood. Final height (cm) was greater in MC4R-deficient men (mean ± SEM 173 ± 2.5 vs. 168 ± 2.1, P < 0.001) and women (mean 165 ± 2.1 vs. 158 ± 1.9, P < 0.001). Fasting IGF-I, IGF-II, acid-labile subunit, and IGFBP-3 concentrations were similar in the two groups. GH levels were markedly suppressed in obese controls, but pulsatile GH secretion was retained in MC4R deficiency. The mean maximal GH secretion rate per burst (P < 0.05) and mass per burst (P < 0.05) were increased in MC4R deficiency, consistent with increased pulsatile and total GH secretion. Fasting insulin levels were markedly elevated in MC4R-deficient children., Conclusions: In MC4R deficiency, increased linear growth in childhood leads to increased adult final height, greater than predicted by obesity alone. GH pulsatility is maintained in MC4R deficiency, a finding consistent with animal studies, suggesting a role for MC4R in controlling hypothalamic somatostatinergic tone. Fasting insulin levels are significantly higher in children carrying MC4R mutations. Both of these factors may contribute to the accelerated growth phenotype characteristic of MC4R deficiency.

Background/aims: The usefulness of the concept of the metabolic syndrome (MS) in its current form has recently been questioned, and its association with insulin resistance is unknown. We assessed whether a multivariate model based on all components of MS expressed on a continuous scale would be a better predictor of a common marker of insulin resistance than the current dichotomous MS definitions., Methods: Data from 78 obese Dutch teenagers (age 13.0 ± 2.1 years) were used for model development, and the model was validated in 40 obese Hindustani children (age 12.6 ± 2.0 years). MS components and homeostasis model assessment-insulin resistance (HOMA-IR) were expressed as standard deviation scores (SDSs), based on gender- and age-specific reference values., Results: Using the three dichotomous models, the prevalence of MS was found to be 36, 65 and 18%, with low mutual agreement. None of these dichotomous models was a significant predictor for increased HOMA-IR SDS. The multivariate model incorporating MS components expressed as SDSs explained 58% of the variance of increased HOMA-IR SDS. In the validation group, the predicted and observed HOMA-IR SDS (2.4 ± 1.2 vs. 2.6 ± 2.2) did not differ significantly., Conclusion: A multivariate prediction model based on MS components expressed as SDSs has a good predictive value for increased HOMA-IR SDS., (Copyright © 2011 S. Karger AG, Basel.)

Context: The pituitary-adrenal axis in obesity and polycystic ovary syndrome (PCOS) is marked by increased urinary excretion of cortisol and its metabolites. It is not as yet clear whether the increased cortisol production in PCOS is related to obesity per se., Intervention and Methods: We investigated 15 obese PCOS women with a body mass index of 30-54 kg/m(2) and 15 healthy obese controls (body mass index 31-60 kg/m(2)) with a regular menstrual cycle. Patients and control women underwent 24-h blood sampling at 20-min intervals. Cortisol concentrations were measured with a sensitive assay. Data were analyzed with a new deconvolution program, approximate entropy, and cosinor regression., Outcome: Basal, pulsatile, and total cortisol production expressed per liter distribution volume, per square meter body surface, and as absolute amount per 24 h was similar in PCOS patients and matched healthy control women. In addition, the regularity of cortisol secretion and the diurnal properties were identical. Compared with 10 lean control women, mean cortisol production per liter distribution volume was similar in the three groups, but the total 24-h cortisol production was increased in obese control women and PCOS women., Conclusion: This study demonstrates equally increased cortisol production in PCOS women and obese healthy control women.

Context: The pituitary-adrenal ensemble of obese humans is marked by increased urinary excretion of cortisol and its metabolites in the face of normal circulating cortisol levels. For better understanding of the (patho) physiological meaning of these changes, the mechanistic underpinnings need to be clarified., Intervention and Methods: We investigated 17 obese women [body mass index (BMI) 30-39.4 kg/m(2)] and 14 normal women (BMI, 18.3-24.8 kg/m(2)) who underwent 24-h blood sampling at 10-min intervals, and plasma ACTH and cortisol concentrations were measured with sensitive assays. Data were analyzed with a new deconvolution program, approximate entropy (ApEn) analyses, and cosinor regression., Outcome: ACTH and cortisol production rates were higher in obese women than in controls and correlated with BMI. Secretion of ACTH correlated with leptin (R = 0.63; P = 0.0001) and insulin (R = 0.67; P = 0.0001). ACTH ApEn and forward ACTH-cortisol cross-ApEn were diminished in obese women. The half-maximal effective concentration (ED(50)) of ACTH pulses vs. cortisol pulses was higher in obese women (38.3 +/- 4.9 vs. 25.1 +/- 3.7 ng/liter; P = 0.03), indicating decreased potency of ACTH. The diurnal properties of ACTH and cortisol secretion were unchanged in obese females., Conclusion: Obese women exhibit enhanced ACTH and cortisol 24-h production compared with lean controls. The amplified ACTH drive is accompanied by decreased secretory regularity and diminished forward coupling between ACTH and cortisol. In addition, the potency of ACTH is decreased in obesity.

Context: Diurnal TSH secretion is enhanced in obese premenopausal women. Dopamine inhibits TSH secretion through activation of dopamine D(2) receptors (D(2)R). Dopamine D(2)R availability in the brain is reduced in obese humans in proportion to body adiposity. We hypothesized that deficient dopamine D(2)R signaling is involved in the enhanced TSH secretion associated with obesity., Objective: The effect of short-term bromocriptine treatment on spontaneous TSH secretion in obese women was studied while body weight and caloric intake remained constant., Design and Setting: We conducted a prospective, fixed-order, crossover study in a Clinical Research Center., Participants: Seventeen obese women (body mass index, 33.2 +/- 0.6 kg/m(2)) were studied twice in the early follicular phase of their menstrual cycle., Intervention: Subjects were treated for 8 d with placebo and bromocriptine., Main Outcome Measure(s): Blood was collected for 24 h at 10-min intervals, and TSH and leptin were analyzed with deconvolution and correlation techniques, approximate entropy, and cosine regression., Results: Bromocriptine reduced 24-h TSH secretion (placebo, 29.8 +/- 4.6 mU/liter . 24 h, vs. bromocriptine, 22.4 +/- 3.7 mU/liter . 24 h; P = 0.001), whereas free T(4) and total T(3) concentrations did not change. Bromocriptine administration reduced the mesor and amplitude of the 24-h rhythm without resetting the phase. The regularity of the subordinate TSH pattern and synchrony between leptin and TSH were unaffected by bromocriptine., Conclusion: Activation of dopamine D(2)R by bromocriptine reverses enhanced diurnal TSH secretion in obese women. Thus, reduced dopaminergic neuronal signaling might be involved in the perturbation of the thyrotrope hormonal axis in obese premenopausal women.

Objectives: This study sought to assess the effects of prolonged caloric restriction in obese patients with type 2 diabetes mellitus (T2DM) on myocardial triglyceride (TG) content and myocardial function., Background: Myocardial TG content is increased in patients with T2DM and may reflect altered myocardial function. It is unknown whether myocardial TG content is influenced during a therapeutic intervention., Methods: Myocardial TG content (magnetic resonance [MR] spectroscopy), myocardial function (MR imaging), plasma hemoglobin A1c, and body mass index (BMI) were measured in 12 obese, insulin-treated T2DM patients before and after a 16-week very-low-calorie diet (VLCD) (450 kcal/day) to achieve substantial weight loss. Insulin was stopped during the VLCD., Results: The BMI decreased from 35.6 +/- 1.2 kg/m(2) (baseline, mean +/- SEM) to 27.5 +/- 1.3 kg/m(2) (after the VLCD, p < 0.001) and was associated with an improvement in hemoglobin A1c from 7.9 +/- 0.4% (baseline) to 6.3 +/- 0.3% (after the VLCD, p = 0.006). Myocardial TG content decreased from 0.88 +/- 0.12% to 0.64 +/- 0.14%, respectively (p = 0.019), and was associated with improved diastolic function (reflected by the ratio between the early and atrial filling phase) from 1.02 +/- 0.08 to 1.18 +/- 0.06, respectively (p = 0.019)., Conclusions: Prolonged caloric restriction in obese T2DM patients decreases BMI and improves glucoregulation associated with decreased myocardial TG content and improved diastolic heart function. Therefore, myocardial TG stores in obese patients with T2DM are flexible and amendable to therapeutic intervention by caloric restriction.

Context: A profound reduction of spontaneous as well as stimulated GH secretion has been consistently observed in obesity. Dopamine promotes GH release through activation of dopamine D2 receptors (D2Rs). Dopamine D2R availability in the brain is reduced in obese humans in proportion to body adiposity. We hypothesized that impaired dopamine D2R signaling is mechanistically involved in the deficient GH secretion associated with obesity., Objective: To test this hypothesis, we studied the effect of short-term bromocriptine (B) (a D2R agonist) treatment on spontaneous 24-h GH secretion in obese women, while body weight and caloric intake remained constant., Design: This was a prospective, fixed order, cross-over study., Setting: The study was performed in the Clinical Research Center at Leiden University Medical Center., Participants: There were 18 healthy obese women (body mass index 33.2 +/- 0.6 kg/m2) studied twice in the early follicular phase of their menstrual cycle., Intervention(s): Eight days of treatment with B and placebo (Pl) was performed., Main Outcome Measure(s): Blood was collected during 24 h at 10-min intervals for determination of GH concentrations. GH secretion parameters were calculated using deconvolution analysis., Results: Short-term treatment with B significantly enhanced diurnal GH secretion (Pl 121.4 +/- 16.4 vs. B 155.4 +/- 15.2 microg/liter(volume of distribution).24 h; P = 0.01), whereas IGF-I concentrations remained constant (Pl 22.4 +/- 2.4 vs. B 21.8 +/- 1.6 nmol/liter; P = 0.928)., Conclusions: Activation of dopamine D2Rs by B favorably affects impaired nyctohemeral GH secretion in obese women. Reduced dopaminergic neuronal signaling might be involved in the pathogenesis of obesity associated hyposomatotropism.

Aims/hypothesis: Both energy restriction (ER) per se and weight loss improve glucose metabolism in obese insulin-treated type 2 diabetic patients. Short-term ER decreases basal endogenous glucose production (EGP) but not glucose disposal. In contrast the blood glucose-lowering mechanism of long-term ER with substantial weight loss has not been fully elucidated. The aim of this study was to investigate the effect of loss of 50% of excess weight [50% excess weight reduction (EWR)] on EGP, whole-body insulin sensitivity and the disturbed myocellular insulin-signalling pathway in ten obese insulin-treated type 2 diabetic patients., Methods: A euglycaemic-hyperinsulinaemic clamp with stable isotopes ([6,6-(2)H2]glucose and [2H5]glycerol) combined with skeletal muscle biopsies was performed during a very low energy diet (VLED; 1,883 kJ/day) on day 2 and again after 50% EWR. Oral blood glucose-lowering agents and insulin were discontinued 3 weeks prior to the VLED and at the start of the VLED, respectively., Results: Loss of 50% EWR (20.3+/-2.2 kg from day 2 to day of 50% EWR) normalised basal EGP and improved insulin sensitivity, especially insulin-stimulated glucose disposal (18.8+/-2.0 to 39.1+/-2.8 micromol kg fat-free mass(-1) min(-1), p=0.001). The latter was accompanied by improved insulin signalling at the level of the recently discovered protein kinase B/Akt substrates AS160 and PRAS40 along with a decrease in intramyocellular lipid (IMCL) content., Conclusions/interpretation: Considerable weight loss in obese, insulin-treated type 2 diabetic patients normalises basal EGP and improves insulin sensitivity resulting from an improvement in insulin signal transduction in skeletal muscle. The decrease in IMCL might contribute to this effect.

The endocannabinoid system controls the regulation of food intake and appetite in the brain and lipogenesis in adipose tissue. Rimonabant belongs to the new drug class of cannabinoid-1 receptor antagonists. It can decrease appetite and food intake and thus stimulate weight loss. Rimonabant is indicated for severe obesity and as an adjunct to lifestyle modifications for obese patients with type 2 diabetes or hyperlipidaemia. Safety concerns limit the clinical applicability of the drug. The drug has not been approved in the US due to its neurological and psychiatric adverse effects. Rimonabant is approved in Europe but is contraindicated in patients with major depression and those taking antidepressants.

The metabolic syndrome comprises a cluster of metabolic anomalies including insulin resistance, abdominal obesity, dyslipidemia, and hypertension. Previous studies suggest that impaired dopamine D2 receptor (D2R) signaling is involved in its pathogenesis. We studied the acute effects of bromocriptine (a D2R agonist) on energy metabolism in obese women; body weight and caloric intake remained constant. Eighteen healthy, obese women (BMI 33.2 +/- 0.6 kg/m(2), mean age 37.5 +/- 1.7, range 22-51 yr) were studied twice in the follicular phase of their menstrual cycle in a prospective, single-blind, crossover design. Subjects received both placebo (P; always first occasion) and bromocriptine (B; always second occasion) on separate occasions for 8 days. At each occasion blood glucose and insulin were assessed every 10 min for 24 h, and circadian plasma free fatty acid (FFA) and triglyceride (TG) levels were measured hourly. Fuel oxidation was determined by indirect calorimetry. Body weight and composition were not affected by the drug. Mean 24-h blood glucose (P < 0.01) and insulin (P < 0.01) were significantly reduced by bromocriptine, whereas mean 24 h FFA levels were increased (P < 0.01), suggesting that lipolysis was stimulated. Bromocriptine increased oxygen consumption (P = 0.03) and resting energy expenditure (by 50 kcal/day, P = 0.03). Systolic blood pressure was significantly reduced by bromocriptine. Thus these results imply that short-term bromocriptine treatment ameliorates various components of the metabolic syndrome while it shifts energy balance away from lipogenesis in obese humans.

Context: Leptin release is regulated by factors other than fat mass alone. Previous observations provide indirect evidence for an inhibitory effect of dopaminergic neurotransmission on leptin secretion. This study was done to establish the effect of bromocriptine treatment on circadian plasma leptin concentrations in obese humans., Objective: The objective of the study was to study the acute effects of bromocriptine (a D2R agonist) on circadian leptin levels in obese women, whereas body weight and caloric intake remained constant., Design: This was a prospective, single-blind, crossover study (2004)., Setting: The study was conducted at a clinical research center., Participants: Eighteen healthy obese women (body mass index 33.2 +/- 0.6 kg/m(2)) were studied twice in the early follicular phase of their menstrual cycle., Intervention(s): Treatment consisted of bromocriptine or placebo for 8 d., Main Outcome Measure(s): Blood was collected during 24 h at 20-min intervals for determination of leptin concentrations at the last day of medical treatment (bromocriptine or placebo). Mean 24-h serum concentrations were determined for insulin, glucose, free fatty acids, and triglycerides., Results: Short-term treatment with bromocriptine reduced leptin concentration (placebo 33.6 +/- 2.5 vs. bromocriptine 30.5 +/- 2.5 ng/liter, P = 0.03). Free fatty acid concentrations were increased by treatment with bromocriptine. The increase of free fatty acids was inversely related with the decline of leptin levels. The decline of glucose, insulin, or prolactin concentrations in response to bromocriptine was not correlated with the reduction of leptin., Conclusion: Activation of dopamine D2 receptors by bromocriptine lowers circulating leptin levels in obese women, which suggests that dopaminergic neurotransmission is involved in the control of leptin release in humans.

We recently showed that prolactin (PRL) release is considerably enhanced in obese women in proportion to the size of their visceral fat mass. PRL release is inhibited by dopamine 2 receptor (D2R) activation, and dietary restriction/weight loss are associated with increased dopaminergic signaling in animals. Therefore, we hypothesized that enhanced PRL release in obese humans would be reversed by weight loss. To evaluate this postulate, we measured 24-h plasma PRL concentrations at 10-min intervals in 11 obese premenopausal women (BMI 33.3 +/- 0.7 kg/m2) before and after weight loss (50% reduction of overweight/15% absolute weight loss, using a very low-calorie diet) in the follicular phase of their menstrual cycle. The 24-h PRL concentration profiles were analyzed by a peak detection program (Cluster) and a wave form-independent deconvolution technique (Pulse). Spontaneous 24-h PRL secretion was significantly reduced in obese women [mean daily release, before 128 +/- 24 vs. after weight loss 110 +/- 17 microg/liter distribution volume (Vdl)(-1) x 24 h, P = 0.05]. Body weight loss particularly blunted PRL secretory burst mass (Pulse area, before 230 +/- 28 vs. after weight loss 221 +/- 31 microg/Vdl(-1) x 24 h, P = 0.03), whereas burst frequency was unaffected (no. of pulses, before 11 +/- 1 vs. after weight loss 12 +/- 1 n/24 h, P = 0.69). Thus elevated PRL secretion rate in obese women is significantly reduced after loss of 50% of overweight. We speculate that amelioration of deficit D2R-mediated neurotransmission and/or diminutions of circulating leptin/estrogen levels might be involved in the physiology of this phenomenon.

This study investigates the molecular mechanisms underlying the blood glucose-lowering effect of a 2-day very low-energy diet (VLED, 1883 kJ/d) in 12 obese (body mass index, 36.3 +/- 1.0 kg/m2 [mean +/- SEM]) type 2 diabetic (HbA(1C) 7.3% +/- 0.4%) patients simultaneously taken off all glucose-lowering therapy, including insulin. Endogenous glucose production (EGP) and glucose disposal ([6,6-2H2]-glucose) were measured before and after the VLED in basal and hyperinsulinemic (40 mU/m2 per minute) euglycemic conditions. Insulin signaling and expression of GLUT-4, FAT/CD36, and triglycerides were assessed in muscle biopsies, obtained before the clamp and after 30 minutes of hyperinsulinemia. Fasting plasma glucose decreased from 11.3 +/- 1.3 to 10.3 +/- 1.0 mmol/L because of a decreased basal EGP (14.2 +/- 1.0 to 11.9 +/- 0.7 micromol/kg per minute, P = .009). Insulin-stimulated glucose disposal did not change. No diet effect was found on the expression of the insulin receptor and insulin receptor substrate-1 or on phosphatidylinositol 3'-kinase activity, or on FAT/CD36 expression pattern, GLUT-4 translocation, or triglyceride distribution in either the basal or insulin-stimulated situation. Unexpectedly, basal PKB/Akt phosphorylation on T308 and S473 increased after the diet, at equal protein expression. In conclusion, a 2-day VLED lowers fasting plasma glucose via a decreased basal EGP without an effect on glucose disposal. Accordingly, no changes in activation of phosphatidylinositol 3'-kinase, triglyceride distribution, FAT/CD36 expression, and GLUT-4 translocation were found in skeletal muscle biopsies.

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.

Context: Previous clinical studies concerning the impact of body weight loss on single plasma TSH concentration measurements or the TSH response to TRH in obese humans have shown variable results., Objective: The objective of this study was to investigate the effect of weight loss induced by caloric restriction on diurnal TSH concentrations and secretion in obese humans., Design: This was a clinical, prospective, crossover study., Setting: The study was conducted at the Clinical Research Center of Leiden University Medical Center., Participants: Eleven obese premenopausal women (body mass index, 33.3 +/- 0.7 kg/m2) were studied., Intervention: The study intervention was weight loss (50% reduction overweight by caloric restriction)., Main Outcome Measure(s): Twenty-four-hour plasma TSH concentrations (10-min intervals) and the 24-h TSH secretion rate, calculated by a waveform-independent deconvolution technique (Pulse), were determined., Results: The 24-h TSH secretion rate was significantly higher in obese women than in normal weight controls, and weight loss was accompanied by diminished TSH release (before weight loss, 43.4 +/- 6.4 mU/liter.24 h; after weight loss, 34.4 +/- 5.9 mU/liter.24 h; P = 0.02). Circulating free T3 levels decreased after weight loss from 4.3 +/- 0.19 to 3.8 +/- 0.14 pmol/liter (P = 0.04). Differences in 24-h TSH release correlated positively with the decline of circulating leptin (r2 = 0.62; P < 0.01)., Conclusions: Elevated TSH secretion in obese women is significantly reduced by diet-induced weight loss. Among various physiological cues, leptin may be involved in this phenomenon. The decreases in TSH and free T3 may blunt energy expenditure in response to long-term calorie restriction, thereby frustrating weight loss attempts of obese individuals.

The mechanism of the blood glucose-lowering effect of a 2-day very low calorie diet (VLCD; 1890 kJ/d) in combination with the cessation of all blood glucose-lowering agents was studied in 12 (7 women, 5 men) obese (body mass index, 36.3 +/- 1.0 kg/m 2 [mean +/- SEM]) type 2 diabetic patients (age, 55 +/- 4 years; HbA 1c , 7.3% +/- 0.4%) undergoing insulin therapy. Endogenous glucose production (EGP) and whole body glucose disposal (6,6 2 H 2 -glucose), lipolysis ( 2 H 5 -glycerol), and substrate oxidation (indirect calorimetry) rates were measured before and after the intervention in basal and hyperinsulinemic conditions. After 2 days of a VLCD and discontinuation of all blood glucose-lowering therapies, fasting plasma glucose levels did not increase (11.3 +/- 1.3 vs 10.3 +/- 1.0 mmol/L). Basal EGP significantly declined (14.2 +/- 1.0 to 11.9 +/- 0.7 mu mol/kg per minute; P = .009). Basal metabolic clearance rate of glucose and rate of basal lipolysis did not change. During hyperinsulinemia, EGP (5.5 +/- 0.8 to 5.2 +/- 0.5 mu mol/kg per minute), whole body glucose disposal (12.1 +/- 0.7 to 11.3 +/- 1.0 mu mol/kg per minute), the metabolic clearance rate of glucose, and the rate of lipolysis did not change after the 2-day intervention. Cessation of blood glucose-lowering therapy in combination with a 2-day VLCD does not lead to hyperglycemia and is associated with a reduction in basal EGP. Insulin-stimulated whole body glucose disposal did not improve, nor did insulin suppressibility of EGP and lipolysis.

To evaluate the possible role of the kidney in the enhanced metabolic clearance rate (MCR) of GH in obesity, we studied the kinetics of GH and renal fractional extraction of GH (RFEGH) in 12 male hypertensive patients over a wide range of body weights (71.7-129 kg) while undergoing contrast angiography on suspicion of renal artery stenosis. A continuous infusion of recombinant human GH was administered during a continuous infusion of somatostatin to suppress endogenous GH secretion. After 2 h of GH infusion, when plasma GH had reached a steady state at concentrations that were still in the physiological range, blood was sampled from the left and right renal arteries and veins for determination of GH levels. Subsequently, the GH infusion was stopped, and GH kinetics were investigated with noncompartmental analysis. In none of the patients was hemodynamically significant renal artery stenosis present. Whole body MCR of GH averaged 375 +/- 142 ml/min. Average GH levels were significantly higher in arterial plasma than in simultaneously sampled renal venous plasma (P < 0.001). RFEGH was 8.6 +/- 6.8%. The MCRs of both GH and RFEGH correlated significantly with body weight, body fat mass, and endogenous creatinine clearance. Renal uptake of GH per 100 g kidney tissue correlated inversely with MCR. These results suggest that RFEGH rises with increasing adiposity, but per unit of renal mass, the capacity of the kidney to remove GH from the circulation falls at high MCR values.

Objective: To identify factors which predict the blood glucose lowering effect of monotherapy with a 30-day very low calorie diet (VLCD) in obese Type 2 diabetic patients. A responder was a priori defined as a patient with a fasting plasma glucose (FPG) level < 10 mmol/l on day 30., Research Design and Methods: In 17 obese patients (BMI 37.6 +/- 5.6 (mean +/- SD) kg/m(2)) with Type 2 diabetes, all blood glucose lowering medication (including insulin) was discontinued on day -1 followed by a 30-day VLCD. On day 2 and 30 of the VLCD an intravenous glucose tolerance test (IVGTT) was performed., Results: Of the 14 patients who completed the 30-day VLCD, eight qualified as responder. Responders and non-responders could be distinguished by day 2. Responders had a shorter duration of Type 2 diabetes and higher fasting serum insulin, C-peptide and HOMA-beta-values. In addition, responders displayed a more prominent second-phase insulin response following i.v. glucose loading and higher k-values. In a stepwise discriminant analysis, the change in FPG from day 0 to day 2 (responders +0.64 +/- 2.3, non-responders +4.15 +/- 3.3 mmol/l, P = 0.035) in combination with the area under the curve of insulin (AUC) above baseline during an IVGTT on day 2 (responders 571 +/- 236, non-responders 88 +/- 65 mU*50 min, P < 0.001), distinguished responders completely from non-responders., Conclusion: Preservation of the capacity of beta-cells to secrete insulin predicts a favourable metabolic response to a VLCD in obese Type 2 diabetic patients.

Several studies suggest that the hypothalamo-pituitary-adrenal (HPA) axis is exceedingly active in obese individuals. Experimental studies show that circulating free fatty acids (FFAs) promote the secretory activity of the HPA axis and that human obesity is associated with high circulating FFAs. We hypothesized that HPA axis activity is enhanced and that lowering of circulating FFAs by acipimox would reduce spontaneous secretion of the HPA hormonal ensemble in obese humans. To evaluate these hypotheses, diurnal ACTH and cortisol secretion was studied in 11 obese and 9 lean premenopausal women (body mass index: obese 33.5 +/- 0.9 vs. lean 21.2 +/- 0.6 kg/m(2), P < 0.001) in the early follicular stage of their menstrual cycle. Obese women were randomly assigned to treatment with either acipimox (inhibitor of lipolysis, 250 mg orally four times daily) or placebo in a double-blind crossover design, starting one day before admission until the end of the blood-sampling period. Blood samples were taken during 24 h with a sampling interval of 10 min for assessment of plasma ACTH and cortisol concentrations. ACTH and cortisol secretion rates were estimated by multiparameter deconvolution analysis. Daily ACTH secretion was substantially higher in obese than in lean women (7,950 +/- 1,212 vs. 2,808 +/- 329 ng/24 h, P = 0.002), whereas cortisol was not altered (obese 36,362 +/- 5,639 vs. lean 37,187 +/- 4,239 nmol/24 h, P = 0.912). Acipimox significantly reduced ACTH secretion in the obese subjects (acipimox 5,850 +/- 769 ng/24 h, P = 0.039 vs. placebo), whereas cortisol release did not change (acipimox 33,542 +/- 3,436 nmol/24 h, P = 0.484 vs. placebo). In conclusion, spontaneous ACTH secretion is enhanced in obese premenopausal women, whereas cortisol production is normal. Reduction of circulating FFA concentrations by acipimox blunts ACTH release in obese women, which suggests that FFAs are involved in the pathophysiology of this neuroendocrine anomaly.

Prolactin (PRL) promotes (visceral) fat accrual in a variety of animal models. The release of PRL by the pituitary is tonically inhibited by dopamine through activation of the dopamine D2 receptor (D2R) of lactotroph cells, and obese humans appear to have reduced D2R-binding sites in their brain. Therefore, we hypothesized that spontaneous PRL release is enhanced in obese humans. To evaluate this hypothesis, we measured 24-h plasma PRL concentrations at 10-min intervals in 11 obese premenopausal women [body mass index (BMI), 33.3 +/- 0.7 kg/m(2)] and 10 lean premenopausal women of similar age (BMI, 21.2 +/- 0.6 kg/m(2)). Total body fat was determined using dual energy x-ray absorptiometry, and sc and visceral fat area was measured by magnetic resonance imaging in 10 obese subjects. PRL secretion rate was estimated by deconvolution analysis. All subjects were studied in the early follicular stage of their menstrual cycle. PRL secretion was significantly enhanced in obese women (total daily release, 137 +/- 8; lean controls, 92 +/- 8 microg/liter.24 h; P = 0.001) in proportion to their BMI (r(2) = 0.55; P < 0.001). Interestingly, PRL release was particularly associated with the size of the visceral fat mass (total PRL secretion vs. visceral fat area, r(2) = 0.64; P = 0.006). These data show that spontaneous PRL release is considerably enhanced in obese women in proportion to the size of their visceral fat mass. Because PRL is inhibited by D2R activation we speculate that elevated PRL secretion may be due to reduced D2R availability in the brain.

It has been suggested that (abdominally) obese individuals are hypersensitive to growth hormone (GH) action. Because GH affects glucose metabolism, this may impact glucose homeostasis in abdominal obesity. Therefore, we studied the effect of GH on glucose metabolism in abdominally obese (OB) and normal-weight (NW) premenopausal women. A 1-h intravenous infusion of GH or placebo was randomly administered to six NW [body mass index (BMI) 21.1 +/- 1.9 kg/m(2)] and six OB (BMI 35.5 +/- 1.5 kg/m(2)) women in a crossover design. Insulin, glucagon, and GH secretion were suppressed by concomitant infusion of somatostatin. Glucose kinetics were measured using a 10-h infusion of [6,6-(2)H(2)]glucose. In both groups, similar physiological GH peaks were reached by infusion of GH. GH strongly stimulated endogenous glucose production (EGP) in both groups. The percent increase was significantly greater in OB than in NW women (29.8 +/- 11.3 vs. 13.3 +/- 7.4%, P = 0.014). Accordingly, GH responsiveness, defined as the maximum response of EGP per unit GH, was increased in OB vs. NW subjects (6.0 +/- 2.1 vs. 2.2 +/- 1.5 micromol.min(-1).mU(-1).l(-1), P = 0.006). These results suggest that the liver is hyperresponsive to GH action in abdominally obese women. The role of the somatotropic ensemble in the control of glucose homeostasis in abdominal obesity is discussed.

The present study tests the hypothesis that specific endocrine, metabolic, and anthropometric features distinguish obese women with polycystic ovary syndrome (PCOS) who resume ovulation in response to calorie restriction and weight loss from those who do not. Fifteen obese (body mass index 39 +/- 7 kg/m(2)) hyperandrogenemic oligoovulatory patients undertook a very low calorie diet (VLCD), wherein each lost > or =10% of body weight over a mean of 6.25 mo. Body fat distribution was quantitated by magnetic resonance imaging. Hormones were measured in the morning at baseline, after 1 wk of VLCD, and after 10% weight loss. To monitor LH release, blood was sampled for 24 h at 10-min intervals before intervention and after 7 days of VLCD. Responders were defined a priori as individuals exhibiting two or more ovulatory cycles in the course of intervention, as corroborated by serum progesterone concentrations > or =18 nmol/l followed by vaginal bleeding. At baseline, responders had a higher sex hormone-binding globulin (SHBG) concentration but were otherwise indistinguishable from nonresponders. Body weight, the size of body fat depots, and plasma insulin levels declined to a similar extent in responders and nonresponders. Also, SHBG increased, and the free testosterone index decreased comparably. However, responders exhibited a significant decline of circulating estradiol concentrations (from 191 +/- 82 to 158 +/- 77 pmol/l, means +/- SD, P = 0.037) and a concurrent increase in LH secretion (from 104 +/- 42 to 140 +/- 5 U.l(-1).day(-1), P = 0.006) in response to 7 days of VLCD, whereas neither parameter changed significantly in nonresponders. We infer that evidence of retention of estradiol-dependent negative feedback on LH secretion may forecast follicle maturation and ovulation in obese patients with PCOS under dietary restriction.