BACKGROUND: Previous studies have indicated that the secretion of the intestinal satiety hormone glucagon-like peptide-1 (GLP-1) is attenuated in obese subjects. OBJECTIVE: To compare meal-induced response of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in obese and lean male subjects, to investigate the effect of a major weight reduction in the obese subjects, and to look for an association between these hormones and ad libitum food intake. METHOD: Plasma concentrations of intestinal hormones and appetite sensations were measured prior to, and every 30 min for 180 min after, ingestion of a 2.5 MJ solid test meal. Gastric emptying was estimated scintigraphically. An ad libitum lunch was served 3 h after the test meal. SUBJECTS: Nineteen non-diabetic obese (body mass index (BMI) 34.1 ± 43.8 kgam 2 ) and 12 lean (BMI 20.4 ± 24.7 kgam 2 ) males. All obese subjects were re-examined after a mean stabilised weight loss of 18.8 kg (95% CI 14.4 ± 23.2). RESULTS: Total area under the GLP-1 response curve (AUC total, GLP-1 ) was lower in obese before and after the weight loss compared to lean subjects (P`0.05), although weight loss improved the response from 80 to 88% of that of the lean subjects (P 0.003). The GIP response was similar in obese and lean subjects. However, after the weight loss both AUC total, GIP and AUC incremental, GIP were lowered (P`0.05). An inverse correlation was observed between AUC incremental, GIP and energy intake at the subsequent ad libitum meal in all groups. In lean subjects ad libitum energy intake was largely predicted by the insulin response to the preceding meal (r 2 0.67, P 0.001). CONCLUSION: Our study con®rmed previous ®ndings of a reduced postprandial GLP-1 response in severely obese subjects. Following weight reduction, GLP-1 response in the obese subjects apparently rose to a level between that of obese and lean subjects. The data suggests that postprandial insulin and GIP responses are key players in short-term appetite regulation.

Formerly obese subjects had a 3-5% lower mean relative RMR than control subjects; the difference could be explained by a low RMR being more frequent among the formerly obese subjects than among the control subjects. Whether the cause of the low RMR is genetic or acquired, the existence of a low RMR is likely to contribute to the high rate of weight regain in formerly obese persons.

. Abdominal visceral fat is associated with a BclI restriction fragment length polymorphism at the glucocorticoid receptor gene locus. Obes Res. 1997;5: 186-192. Several investigations have suggested that body fat distribution is influenced by nonpathologic variations in the responsiveness to cortisol. Genetic variations in the glucocorticoid receptor (GRL) could therefore potentially have an impact on the level of abdominal fat. A restriction fragment length polymorphism (RFLP) has previously been detected with the BcZI restriction enzyme in the GRL gene identifying two alleles with fragment lengths of 4.5 and 2.3 kb. This study investigates whether abdominal fat areas measured by computerized tomography (CT) are associated with this polymorphism in 152 middle-aged men and women. The less frequent 4.5-kb allele was found to be associated with a higher abdominal visceral fat (AVF) area independently of total body fat mass (4.514.5 vs. 2.312.3 kb genotype; men: 190.7 f 30.1 vs. 150.7 2 33.3 cm', p=0.04; women: 132.7 f 37.3 vs. 101.3 34.5 cm' , p=0.06). However, the association with AVF was seen only in subjects of the lower tertile of the percent body fat level. In these subjects, the polymorphism was found to account for 41% @=0.003) and 35% @=0.007), in men and women, respectively, of the total variance in AVF area. The consistent association between the GRL polymorphism detected with BcZI and AVF area suggests that this gene or a locus in linkage disequilibrium with the BcZI restriction site may contribute to the accumulation of AVF.

The effect of an increase in dietary fat content on fat and carbohydrate balances and energy expenditure (EE) was studied in nine formerly obese women with genetic predisposition to obesity (postobese) and a closely matched control group. Isocaloric low- (20% fat energy) and high-fat diets (50%) were consumed for 3 days preceding and during a 24-h respiratory chamber stay, whereas a medium-fat diet (30%) was consumed only on the day of measurement. After adjustment for 24-h energy intake to equal 24-h EE, 24-h fat balance was increased when the dietary fat content increased (P < 0.0002). No differences in macronutrient balances were found on the low-fat and medium-fat diets, but on the high-fat diet the postobese women failed to increase ratio of fat to carbohydrate oxidation appropriately (0.59 g/g, 95% confidence interval 0.47-0.67 vs. controls 1.02 g/g, 0.88-1.12; P = 0.002). This caused a positive adjusted fat balance (+11.0 g/day, 2.3-19.6 vs. controls -8.9 g/day, -17.5 to -0.2; P < 0.001) and a negative carbohydrate balance (-41.8 g/day, -69.5 to -14.0 vs. controls +23.2 g/day, -4.6 to +50.9; P < 0.001). Decreasing the dietary fat content increased 24-h EE in the postobese women (P = 0.02), whereas it was unaffected in the control group. Independent of energy balance, an increase in dietary fat content to 50% fat energy results in preferential fat storage, impaired suppression of carbohydrate oxidation, and reduction of 24-h EE in postobese women.

Expansion of the fat stores has been proposed as a prerequisite for increasing fat oxidation in response to a high-fat diet in individuals with a predisposition to obesity. In a cross-sectional design we measured 24-h substrate oxidations on a standardized diet in 38 overweight or obese and 35 nonobese women. Fat oxidation (g/d) was mainly a function of total energy requirements (r = 0.71, P < 0.0001). To account for this we used for further analysis oxidative fat energy (%), a counterpart to dietary fat energy (%). After differences in fat energy of consumed food (%), age, and 24-h energy balance were adjusted for, obese women had higher oxidative fat energy than did nonobese women [40.2% (37.8-42.6) vs 36.0% (33.6-38.5), P < 0.02]. Adjusted oxidative fat energy (%) increased with increasing size of fat mass (r = 0.31, P < 0.01). This relation suggests that a 10-kg change in fat mass may be caused by a change in dietary fat energy of > or = 1.6% (0.4-2.7%). The study supports the concept that in susceptible individuals the expansion of fat stores is a prerequisite to increase the oxidative fat energy to an amount commensurate with a high percentage of dietary fat energy.

BACKGROUND: An enhanced gastric emptying rate might reduce the satiating effect of food and thereby promote obesity. Gastric emptying rate has previously been compared between obese and lean subjects with con¯icting outcome. OBJECTIVE: Comparison of gastric emptying rate in lean and obese subjects before and after a major weight reduction. DESIGN: The study was designed as a case ± control study comparing obese and lean subjects and a subsequent comparison of obese subjects before and after a dietary induced major weight reduction. METHOD: Gastric emptying rate following a solid test meal was estimated scintigraphically for 3 h using the left anterior oblique projection. SUBJECTS: Nineteen non-diabetic obese (mean BMI 38.7 kgam 2 ) and 12 lean (mean BMI 23.1 kgam 2 ) males matched for age and height. All obese subjects were re-examined after a mean weight loss of 18.8 kg (95% CI, 14.4 ± 23.2) achieved by 16 weeks of dietary intervention followed by 8 weeks of weight stability. RESULTS: When comparing obese and lean subjects no differences were seen in overall 3 h emptying rate (30.3% per hour vs 30.5% per hour). However, a trend towards a higher percentage gastric emptying during the initial 30 min was seen in the obese when compared to lean subjects (24.0% vs 17.8% of the test meal; P 0.08). Weight loss was associated with a reduction in percentage gastric emptying during the initial 30 min (from 24.0% to 18.3% of the testmeal; P`0.02), whereas the overall 3 h emptying rate was unaffected (30.3% vs 30.9% per hour). Neither initial or overall emptying rate differed between reduced-obese and lean subjects. CONCLUSION: Overall 3 h gastric emptying rate was similar in obese and normal weight males, and unaffected by a major weight loss. However, percentage gastric emptying during the initial 30 min for a solid meal appeared to be increased in obese males and was normalized after a major weight reduction.

Generation of reactive oxygen species from mitochondrial respiration has been proposed as an important determinant of longevity and cumulative cancer risk. Interspecies correlations and animal calorie restriction studies of metabolic rate and oxidative DNA damage support this notion. In the present study we have demonstrated a close association between oxidative DNA damage as assessed by the urinary excretion of 8-oxo-7,8-dihdro-2'-deoxyguanosine (8-oxodG) and oxygen consumption in 33 healthy premenopausal women (r = 0.64; p = 0.00007). In the 12 women who smoked, 8-oxodG excretion was increased by 35%, although oxygen consumption increased only 10% compared with the 21 nonsmoking women. Apparently, the rate of oxidative DNA damage relates to mitochondrial respiration in humans and is aggravated by smoking.

BACKGROUND:Energy expenditure may partly be determined by genetic variations in uncoupling proteins. We have previously found an increased physical activity but a similar 24-h energy expenditure (EE) in subjects with the valaval-55 UCP2 genotype compared to those with the alaaala genotype which indicates that the val-55 allele is statistically associated with a higher metabolic ef®ciency. DESIGN: EE during bicycling was determined by indirect calorimetry at three different loads (30, 40 and 60% of VO 2max in eight subjects with the valaval-55 genotype (35 AE 6 y weight 76.8 AE 13.6 kg, VO 2max 2.79 AE 0.71 lamin) and eight subjects with the alaaala-55 genotype (37 AE 3 y, weight 78.3 AE 16.5 kg, VO 2max 2.66 AE 0.41 lamin). RESULTS: Incremental exercise ef®ciency across the three different work levels was higher in the valaval (25.3%, c.i. 24.2 ± 26.4%) than in the alaaala (23.6%, c.i. 22.5 ± 24.7%) genotype P`0.05. Gross exercise ef®ciency at 40% VO 2max was higher in the valaval (15.3 AE 0.6%) than in the alaaala (13.5 AE 0.4%) group. CONCLUSION: As the valaala-55 polymorphism is located in a domain of the protein without any known function, the different exercise ef®ciency between the two genotypes most likely re¯ects a linkage disequilibrium with a functionally signi®cant polymorphism in UCP2 or in the neighbouring UCP3 gene. The study suggests that variations in the UCP genes may affect not only basal metabolic rate but also in¯uence energy costs of exercise.