Pa Tataranni

Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance.

Aims/hypothesis. Cross-sectional studies indicate that enlarged subcutaneous abdominal adipocyte size is associated with hyperinsulinaemia, insulin resistance and glucose intolerance. To further explore the pathophysiological significance of these associations, we examined prospectively whether enlarged subcutaneous abdominal adipocyte size predicts Type II (non-insulin-dependent) diabetes mellitus. Methods. Body composition (hydrodensitometry), mean subcutaneous abdominal adipocyte size (fat biopsy), insulin sensitivity (hyperinsulinaemic clamp) and the acute insulin secretory response (25-g i. v. GTT) were assessed in 280 Pima Indians with either normal (NGT), impaired (IGT) or diabetic glucose tolerance (75-g OGTT). Subjects with NGT were then followed prospectively. Results. After adjusting for age, sex and per cent body fat, mean subcutaneous abdominal adipocyte size was 19 % and 11 % higher in subjects with diabetes and IGT, compared with those with NGT (p < 0.001). Insulin sensitivity was inversely correlated with mean subcutaneous abdominal adipocyte size (r = –0.53, p < 0.0001), even after adjusting for per cent body fat (r = –0.31, p < 0.001). In 108 NGT subjects followed over 9.3 ± 4.1 years (33 of whom developed diabetes), enlarged mean subcutaneous abdominal adipocyte size but not high per cent body fat, was an independent predictor of diabetes, in addition to a low insulin sensitivity and acute insulin secretory response [relative hazard 10th vs 90th centile (95 % CI): 5.8 (1.7–19.6), p < 0.005]. In 28 NGT subjects with a 9 % weight gain over 2.7 ± 1.3 years, changes in insulin sensitivity were inversely and independently related to changes in mean subcutaneous abdominal adipocyte size and per cent body fat. Conclusion/interpretation. Although enlarged mean subcutaneous abdominal adipocyte size is associated with insulin resistance cross-sectionally, prospectively, both abnormalities are independent and additive predictors of Type II diabetes. [Diabetologia (2000) 43: 1498–1506]

Brain abnormalities in human obesity: A voxel-based morphometric study

Obesity is accompanied by damage to several tissues. Overweight is a risk factor for Alzheimers disease and other neurodegenerative disorders. Whether structural abnormalities associated with excess body fat may also occur in the brain is unknown. We sought to determine to what extent excess body fat is associated with regional alterations in brain structure using voxel-based morphometry (VBM), a whole-brain unbiased technique based upon high-definition 3D magnetic resonance imaging (MRI) scans normalized into a common standard space and allowing for an objective assessment of neuroanatomical differences throughout the brain. We studied 24 obese (11 male, 13 female; age: 32 +/- 8 years; body mass index [BMI]: 39.4 +/- 4.7 kg/m2) and 36 lean (25 male, 11 female; mean age: 33 +/- 9 years; BMI: 22.7 +/- 2.2 kg/m2) non-diabetic Caucasians. In comparison with the group of lean subjects, the group of obese individuals had significantly lower gray matter density in the post-central gyrus, frontal operculum, putamen, and middle frontal gyrus (P < 0.01 after adjustment for sex, age, handedness, global tissue density, and multiple comparisons). BMI was negatively associated with GM density of the left post-central gyrus in obese but not lean subjects. This study identified structural brain differences in human obesity in several brain areas previously involved in the regulation of taste, reward, and behavioral control. These alterations may either precede obesity, representing a neural marker of increased propensity to gaining weight, or occur as a consequence of obesity, indicating that also the brain is affected by increased adiposity.

A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM

SummaryTo assess the role of fasting plasma non-esterified fatty acids (NEFA) in the development of non-insulin-dependent diabetes mellitus (NIDDM), data were analysed from annual examinations of 190 non-diabetic Pima Indians. Glucose tolerance was measured by a 75-g oral glucose tolerance test, insulin action by a euglycaemic hyperinsulinaemic (40 mU · m−2 · min−1) clamp and in vitro lipolysis using isolated abdominal fat cells. After a mean follow-up period of 4.0±2.4 years (mean ± SD), 47 subjects developed NIDDM. Risk factors for NIDDM were estimated by proportional-hazards analysis and risk ratios (RR) with 95% confidence intervals (95% CI) calculated at the 90th and 10th percentile of the predictor variables. A large average fat-cell volume was predictive of NIDDM (RR=2.4; 95% CI=1.2–4.8) independent of age, sex, percent body fat and body fat distribution. A high fasting plasma NEFA concentration was also a risk factor for NIDDM (RR=2.3; 95% CI=1.1–4.7) independent of sex, percent body fat, waist/thigh ratio, insulin-mediated glucose uptake and fasting triglyceride concentration. We conclude that large fat cells and the resulting increased plasma NEFA concentrations are risk factors for the development of NIDDM.

Successful dieters have increased neural activity in cortical areas involved in the control of behavior

Objective:To investigate whether dietary restraint, a landmark of successful dieting, is associated with specific patterns of brain responses to the sensory experience of food and meal consumption.Design and subjects:Cross-sectional study of the brains response to the sensory experience of food and meal consumption in nine successful dieters (age: 38±7 years, body fat (%): 28±3) and 20 non-dieters (age: 31±9 years, body fat (%): 33±9), all women.Measurements:Changes in brain activity in response to the sensory experience of food and meal consumption were assessed by using positron emission tomography and 15O water as a radiotracer. Body fatness was assessed by dual X-ray absorptiometry. Subjective ratings of hunger and fullness were measured by visual analogue scale. Dietary restraint, disinhibition and hunger were assessed by the Three Factor Eating Questionnaire.Results:Successful dieters had a significantly higher level of dietary restraint compared to non-dieters. In response to meal consumption, successful dieters had a greater activation in the dorsal prefrontal cortex (DPFC), dorsal striatum and anterior cerebellar lobe as compared to non-dieters. In response to the same stimulation, the orbitofrontal cortex (OFC) was significantly more activated in non-dieters as compared to successful dieters. Dietary restraint was positively correlated with the response in the DPFC and negatively with the response in the OFC. The responses in the DPFC and OFC were negatively intercorrelated.Conclusion:Cortical areas involved in controlling inappropriate behavioral responses, such as the DPFC, are particularly activated in successful dieters in response to meal consumption. The association between the degree of dietary restraint and the coordinated neural changes in the DPFC and OFC raises the possibility that cognitive control of food intake is achieved by modulating neural circuits controlling food reward.

Persistence of abnormal neural responses to a meal in postobese individuals

OBJECTIVE: To determine whether abnormal obese-like neural responses to a meal persist in postobese individuals, who achieved and maintained a normal body weight despite a past history of severe obesity.DESIGN AND SUBJECTS: Cross-sectional study of the brains response to tasting and consuming a satiating meal in 11 postobese (age: 40±6 y, body mass index (BMI): 23.6±1.9 kg/m2), 23 obese (age: 29±6 y, BMI: 39.6±3.8 kg/m2) and 21 lean (age: 33±9 y, BMI: 22.8±2.1 kg/m2) subjects.MEASUREMENTS: Regional cerebral blood flow (rCBF, a marker of neural activity) at baseline (after a 36-h fast), after tasting and after consuming a satiating liquid meal was assessed using positron emission tomography and state-dependent changes (taste-baseline; satiation-baseline), and compared across groups. Subjective ratings of hunger and fullness were measured by a visual analogue scale and body fatness by dual-energy X-ray absorptiometry.RESULTS: In response to tasting the liquid meal, changes in rCBF were different in the obese as compared to the lean individuals (P<0.05, corrected for multiple comparisons) in the middle insula (peak voxel, x=−41, y=1, z=8; Montreal Neurological Institute coordinates) and posterior cingulate cortex (peak voxel, x=17, y=−47, z=40). The middle insular cortex exhibited a similar increase of neural activity in the obese and postobese subjects, whereas in the lean subjects the regional activity did not change. In the posterior cingulate cortex, the changes in rCBF in the postobese subjects were not different from those in the other groups. In response to a satiating amount of the same liquid meal, changes in rCBF were different in the obese as compared to the lean individuals (P<0.05, corrected for multiple comparisons) in the posterior hippocampus (peak voxel, x=21, y=−45, x=4), posterior cingulate cortex (peak voxel, x=17, y=−47, z=40), and amygdala (peak voxel, x=27, y=1, z=−24). The posterior hippocampus exhibited a similar decrease of neural activity in the obese and postobese subjects, whereas in the lean subjects the regional activity increased. In the posterior cingulate cortex and amygdala, the changes in rCBF were not different between the postobese and lean individuals. None of the changes in neural activity were correlated with the age of the individuals, the subjective ratings of hunger and fullness, or the meal induced-changes in plasma glucose, insulin, or serum free fatty acids.CONCLUSION: Persistence of abnormal neural responses to a meal in the postobese individuals, a group at high risk for relapse, indicates that a predisposition to obesity may involve areas of the brain that control complex aspects of eating behavior including anticipation and reward, chemosensory perception, and autonomic control of digestion (insular cortex), as well as enteroception and learning/memory (hippocampus).

Body weight gain in free-living Pima Indians: effect of energy intake vs expenditure.

BACKGROUND: Obesity results from a chronic imbalance between energy intake and energy expenditure. However, experimental evidence of the relative contribution of interindividual differences in energy intake and expenditure (resting or due to physical activity) to weight gain is limited.OBJECTIVE: To assess prospectively the association between baseline measurements of daily energy metabolism and weight changes by studying free-living adult Pima Indians, one of the most obese populations in the world.DESIGN: A study of the pathogenesis of obesity in the Pima Indians living in Southwestern Arizona. The participants were 92 nondiabetic Pima Indians (64M/28F, 35±12 y, 35±9% body fat; mean±s.d.). At baseline, free-living daily energy metabolism was assessed by doubly labeled water and resting metabolic rate (RMR) by indirect calorimetry. Data on changes in body weight (5.8±6.5 kg) over a follow-up period of 4±3 y were available in 74 (49M/25F) of the 92 subjects.RESULTS: The baseline calculated total energy intake (r=0.25, P=0.028) and RMR (r=−0.28, P=0.016) were significantly associated with changes in body weight. The baseline energy expenditure due to physical activity was not associated with changes in body weight.CONCLUSION: Using state-of-the-art methods to assess energy intake and expenditure in free-living conditions, we show for the first time that the baseline calculated total energy intake is a determinant of changes in body weight in Pima Indians. These data also confirm that a low RMR is a risk factor for weight gain in this population.

Thermic effect of food in humans: methods and results from use of a respiratory chamber.

During the past two decades, many investigators have measured the thermic effect of food (TEF) in humans and have speculated on its role in the development of obesity. In this study we compared different ways of computing TEF from daily energy expenditure measurements in a respiratory chamber, evaluated the determinants of TEF, and more importantly assessed for the first time the relation between TEF and change in body weight. In 471 subjects, TEF was 1697 +/- 857 kJ/d (mean +/- SD), ie, 18 +/- 9% of energy intake. In 114 subjects studied more than once, intraindividual TEF variability was very high (CV = 48%). TEF correlated positively with the level of spontaneous physical activity (SPA) and negatively with fasting plasma glucose and insulin concentrations. TEF correlated inversely with age (males only) and body weight, percent body fat, and waist-to-hip ratio (females only). The level of SPA and fasting plasma glucose concentration were the only significant determinants of TEF, explaining 15% of its variance. In 137 subjects in whom body weight was measured > or = 6 mo after TEF measurement (mean follow-up duration of 2.9 +/- 1.7 y), a low TEF was not predictive of body weight gain. We conclude that, despite the low reproducibility of TEF from use of a respiratory chamber, data in a large number of subjects suggest that TEF is increased by higher SPAs and that insulin resistance is associated with a low TEF. More important, longitudinal data indicate that the variability in TEF is not associated with changes in body weight.

11β-Hydroxysteroid dehydrogenase Type 1: genetic polymorphisms are associated with Type 2 diabetes in Pima Indians independently of obesity and expression in adipocyte and muscle

Aims/hypothesisThe enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) modulates tissue-specific glucocorticoid concentrations by generating active cortisol. We have shown that adipose tissue 11β-HSD1 mRNA levels were associated with adiposity and insulinaemia. Here we conducted further expression and genetic association studies in Pima Indians.MethodsThe 11β-HSD1 mRNA concentrations were measured in abdominal subcutaneous adipocytes (n=61) and skeletal muscle tissues (n=64). Single nucleotide polymorphisms in the HSD11B1 gene were genotyped in a larger group of full-blooded Pima Indians.ResultsTwo representative SNPs (SNP1, n=706; SNP5, n=839) were associated with Type 2 diabetes mellitus (p=0.01), although neither SNP was associated with obesity. Among subjects with normal glucose tolerance, SNP1 (n=127) and SNP5 (n=159) were associated with insulin-mediated glucose uptake rates (p=0.03 and p=0.04), and SNP1 was further associated with fasting, 30-min, and 2-h plasma insulin concentrations (p=0.002, p=0.002 and p=0.03). Adipocyte 11β-HSD1 mRNA concentrations were correlated positively with adiposity and insulinaemia, and were additionally negatively correlated with insulin-mediated glucose uptake rates; nevertheless, the adipocyte 11β-HSD1 expression did not correlate with genotypes of the donors. The muscle 11β-HSD1 mRNA concentrations did not correlate with any anthropometric or metabolic variables.Conclusions/interpretationWe confirmed that adipocyte 11β-HSD1 mRNA concentrations were associated with adiposity, and showed that genetic variations in the HSD11B1 gene were associated with Type 2 diabetes mellitus, plasma insulin concentrations and insulin action, independent of obesity. The variable adipose expression might not be a primary consequence of these HSD11B1 SNPs. Therefore, it is possible that the HSD11B1 gene is under tissue-specific regulation, and has tissue-specific consequences.

The Gln223Arg polymorphism of the leptin receptor in Pima Indians: influence on energy expenditure, physical activity and lipid metabolism

Leptin regulates body weight by its receptor-mediated anorectic, thermogenic and antisteatotic effects. Recently, lower leptin binding to the soluble form of the leptin receptor (LEPR) was shown in carriers of the Arg223-encoding allele of the Gln223Arg polymorphism of the LEPR. To investigate whether this variant influences energy metabolism and adiposity in Pima Indians, we genotyped non-diabetic Pima Indians in whom we had measured body composition and 24 h energy expenditure (24 h EE), physical activity level (PAL) and 24 h respiratory quotient (24 h RQ) in a respiratory chamber (n=268) and who had undergone percutaneous fat biopsies from the periumbilical region (n=184). Genotype was not associated with percent body fat (P>0.39), but was associated with 24 h EE, PAL and mean subcutaneous abdominal adipocyte size (SAAS all P<0.05). Homozygotes for the Arg223-encoding allele had lower 24 h EE (P=0.04) and PAL (P=0.007), but larger SAAS (P=0.01) than Gln homozygotes. These findings are consistent with a role of the Gln223Arg polymorphism in reducing peripheral and central leptin binding to the LEPR in humans. However, these effects do not seem to have a major impact on adiposity in this population.

Postprandial glucagon-like peptide-1 (GLP-1) response is positively associated with changes in neuronal activity of brain areas implicated in satiety and food intake regulation in humans.

Postprandial glucagon-like peptide-1 (GLP-1) secretion can act as a meal termination signal in animals and humans. We tested the hypothesis that the postprandial changes in plasma GLP-1 concentrations are associated with changes in the human brain activity in response to satiety by performing a post-hoc analysis of a cross-sectional study of neuroanatomical correlates of hunger and satiation using (15)O-water positron-emission tomography (PET). Forty-two subjects (22M/20F, age 31+/-8 years) spanning a wide range of adiposity (body fat: 7-44%) were included in this analysis. Outcome measures included changes in PET-measured regional cerebral blood flow (rCBF) and plasma concentrations of GLP-1, glucose, insulin, and free-fatty acids (FFA), elicited by the administration of a satiating amount of a liquid formula meal. The peak postprandial increases in plasma GLP-1 concentrations were correlated with increases in rCBF in the left dorsolateral prefrontal cortex (including the left middle and inferior frontal gyri), previously implicated in PET studies of human satiation, and the hypothalamus, previously implicated in the regulation of food intake in animal and human studies, both before and after adjustment for sex, age, body fat, and changes in plasma glucose, insulin, and serum FFA concentrations. The postprandial GLP-1 response is associated with activation of areas of the human brain previously implicated in satiation and food intake regulation.