Neurobiologic changes in the hypothalamus associated with weight loss after gastric bypass.

BACKGROUND: Effects of Roux-en-Y gastric bypass (RYGB) on hypothalamic food intake regulation have not been investigated. The hypothalamic arcuate nucleus (ARC) and the magnocellular (m) and parvocellular (p) parts of the paraventricular nucleus (PVN) regulate hunger and satiety, and are under control of the orexigenic neuropeptide Y (NPY), and the anorexigenic alpha-melanocyte stimulating hormone (alpha-MSH) and serotonin (5-HT). We hypothesized that after RYGB, weight loss is associated with hypothalamic down regulation of NPY and up regulation of 5-HT and alpha-MSH. STUDY DESIGN: obesity was induced in 12 Sprague Dawley rats using a high-energy diet for 7 weeks, and then the rats were divided into three groups (n = 4/group): RYGB, sham-operated pair-fed (PF), and sham-operated ad libitum (obese control). Ten days after operation, immunohistochemical quantification of NPY, alpha-MSH, and 5-HT(1B)-receptors in ARC and PVN was performed. Data were analyzed using ANOVA and Tukey's test. RESULTS: Body weight decreased in RYGB (417 +/- 21 g; mean +/- SE) and in PF (436 +/- 14 g) rats 10 days after operation compared with obese control rats (484 +/- 15 g; p < 0.05 for each comparison). NPY in ARC, pPVN, and mPVN decreased by 43%, 43%, and 61%, respectively in RYGB and by 55%, 42%, and 71% in PF, respectively, compared with obese controls (p < 0.05 for each pairwise comparison). RYGB versus PF did not show differences. alpha-MSH in ARC, pPVN and mPVN increased by 35%, 175%, and 67%, respectively in RYGB and by 29%, 162%, and 116% in PF, respectively, compared with obese controls (each p < 0.05). In mPVN, alpha-MSH significantly decreased by 23% in RYGB versus PF (p < 0.05). 5-HT-(1B)-receptor in pPVN increased by 58% in RYGB and by 26% in PF, compared with obese controls (p < 0.05). Compared with obese controls, 5HT-(1B)-receptor in mPVN increased by 39% in RYGB (p < 0.05) and by 9% in PF (p > 0.05). An increase of 5-HT-(1B)-receptor in pPVN and mPVN occurred in RYGB versus PF (p < 0.05). CONCLUSIONS: Obese rats that undergo weight loss after RYGB demonstrate changes in hypothalamic down regulation of NPY and up regulation of alpha-MSH and serotonin.

Intensive lifestyle intervention combined with the choice of pharmacotherapy improves weight loss and cardiac risk factors in the obese.

BACKGROUND: obesity is on the increase yet within the National Health Service (NHS) treatment approaches differ greatly and service is patchy. Our aim was to compare current practice within a general dietetic clinic with a new clinic developed specifically for patients of higher morbidity risk. METHODS: Locally referred patients to the dietitians from within or without Hammersmith Hospitals NHS Trust of higher morbidity risk were invited to attend a new Lifestyle Clinic. Treatment was of a contractual nature and included more time with the dietitian, the offer of pharmacotherapy if appropriate and an emphasis on achieving a realistic weight loss of 10% within a 6-month period. Cognitive behavioural strategies were utilized focusing on achieving changes in dietary intake and physical activity levels. RESULTS: A total of 103 patients have been enrolled of whom 34 have been discharged before completion of the clinic programme. Twenty-six patients have completed (18 started pharmocotherapy with Orlistat ( Xenical ) and eight remained on lifestyle advice only), with the remainder still attending the Lifestyle Clinic. The results for these 26 patients demonstrate clinically significant benefits with regard to exercise tolerance 390.8 +/- 37.5 m vs. 473 +/- 46.6 m (P < 0.001), waist measurement 121.5 +/- 4.4 cm vs. 110.9 +/- 3.6 cm (P < 0.001), and total cholesterol : HDL ratio 1.17 +/- 0.05 mmol L-1 vs. 1.27 +/- 0.07 mmol L-1 (P < 0.05). A weight loss comparison with historical data collected in the general dietetic clinic achieves a 7.8 +/- 0.7 kg reduction in weight (with pharmocotherapy 8.96 +/- 0.98 kg, with lifestyle only 5.23 +/- 0.657) vs. 1.7 +/- 0.4 kg (P < 0.05). CONCLUSION: Lifestyle clinics facilitate beneficial lifestyle changes which impact positively on morbidity risk factors demonstrating an improvement on current service offered within the NHS. There is an obvious resource implication of offering an intensive management package. There is need for a randomized control trial with analysis to evaluate whether there is cost benefit from this type of intervention.

C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity.

C75, a known inhibitor of fatty acid synthase is postulated to cause significant weight loss through decreased hypothalamic neuropeptide Y (NPY) production. Peripherally, C75, an alpha-methylene-gamma-butyrolactone, reduces adipose tissue and fatty liver, despite high levels of malonyl-CoA. To investigate this paradox, we studied the effect of C75 on fatty acid oxidation and energy production in diet-induced obese (DIO) mice and cellular models. Whole-animal calorimetry showed that C75-treated DIO mice had a 50% greater weight loss, and a 32.9% increased production of energy because of fatty acid oxidation, compared with paired-fed controls. Etomoxir, an inhibitor of carnitine O-palmitoyltransferase-1 (CPT-1), reversed the increased energy expenditure in DIO mice by inhibiting fatty acid oxidation. C75 treatment of rodent adipocytes and hepatocytes and human breast cancer cells increased fatty acid oxidation and ATP levels by increasing CPT-1 activity, even in the presence of elevated concentrations of malonyl-CoA. Studies in human cancer cells showed that C75 competed with malonyl-CoA, as measured by CPT-1 activity assays. Thus, C75 acts both centrally to reduce food intake and peripherally to increase fatty acid oxidation, leading to rapid and profound weight loss, loss of adipose mass, and resolution of fatty liver. The pharmacological stimulation of CPT-1 activity is a novel finding. The dual action of the C75 class of compounds as fatty acid synthase inhibitors and CPT-1 agonists has therapeutic implications in the treatment of obesity and type II diabetes.

Effects of short-term modest weight loss on fasting and post-prandial lipoprotein sub-fractions in type 2 diabetes mellitus patients.

OBJECTIVE: We assessed the efficacy of a modest weight loss (1.5 +/- 0.3 kg) and simultaneous rapid improvement in glycemic control on fasting an post-prandial lipoprotein sub-fractions in nine overweight (BMI=28 +/- 1.7 kg/m(2)) well controlled Type 2 diabetic patients (HbA(1c)=7.3 +/- 0.1%). MATERIAL AND METHODS: They followed a non-drastical hypocaloric balanced diet (1 561 +/- 39 kcal/day) over ten days in hospital. The fat content of the diet was significantly lowered from 96 +/- 12 g/day to 62 +/- 4 g/day (p<0.03). Plasma lipid and lipoprotein levels were measured in fasting and four hours after standard breakfast and four hours after standard lunch twice before and after ten days of hospitalization. The sub-fractions of very low density and low density lipoprotein were obtained by cumulative flotation ultracentrifugation. RESULTS: This weight loss reduced two well known independent cardiovascular risk factors such as the post-prandial glycemic excursions (p<0.05) and the post-prandial lipemia (p<0.05). Multiple linear regression analyses identified weight loss as an independent variable accounting for the ability to predict post-prandial capillary triglyceride clearance (p<0.05). Improvements in post-prandial glycemic excursions which was also entered as a parameter did not appear as a variable being able to predict these changes (p=0.4). In addition to the 23% improvement in post-prandial capillary triglyceride clearance (p<0.02), a decrement in post-prandial VLDL-2 triglyceride enrichment was found (p<0.05). Finally, fasting and post-prandial LDL-3 cholesterol levels were diminished (p<0.05) and the LDL-2/LDL-3 mass ratio post-prandial kinetics were improved (p<0.05). CONCLUSIONS: Even a modest weight loss in overweight, average controlled type 2 diabetic patients can achieve a significant improvement in two cardiovascular risk factors, namely post-prandial triglyceride excursions and the LDL-2/LDL-3 mass ratio kinetics independently from glycemic control improvements.

A receptor promoter polymorphism (HTR2C - 759C/T) is associated with obesity in women, and with resistance to weight loss in heterozygotes.

The serotonin receptor (HTR2C) helps regulate appetite and body weight. An HTR2C promoter polymorphism (-759C/T) has been associated with obesity and with weight gain in response to antipsychotic (neuroleptic) drugs. We studied this polymorphism in 120 obese women (BMI > or = 30) and 104 non-obese (BMI < or = 25) women. The C allele was commoner in the obese group (OR = 1.72 [95% CI, 1.13-2.64], P = 0.008). Ninety-five of the obese women participated in a randomized trial of psychological treatments for weight loss. Among these women, heterozygotes lost less weight during the trial than did homozygotes (6.8 vs. 9.7 kg; P = 0.047) and weighed more 6 months (90.1 vs. 83.6 kg; P = 0.006) and 12 months (91.8 vs. 84.6 kg; P = 0.009) later. Heterozygotes also had higher triglyceride levels than homozygotes. C/C subjects in the obesity trial did not differ from T/T subjects in terms of weight loss or triglycerides. In a separate RT-PCR study of 43 subjects, we found that HTR2C mRNA abundance in frontal cortex was unaffected by -759C/T status. Our data extend the evidence that HTR2C promoter variation may be a risk factor for obesity and, perhaps through heterosis, influences weight loss by obese women. Pharmacogenetic testing of HTR2C promoter variants may be valuable when evaluating anti-obesity drugs which act directly or indirectly on the receptor. Copyright 2003 Wiley-Liss, Inc.

Comparison of methods for assessing body composition changes during weight loss.

PURPOSE: Four cross-sectional studies have reported that percent body fat (%BF) measured by dual-energy x-ray absorptiometry (DXA) is significantly higher compared with values obtained with air displacement plethysmography (ADP) using the Bod Pod(R) in normal-weight individuals. This study was performed to confirm these findings in an overweight population and to assess whether DXA and ADP detected similar changes in body composition after moderate weight loss. METHODS: Twelve women (42 +/- 8 yr) and 10 men (40 +/- 11 yr) had their %BF, fat mass (FM), and fat-free mass (FFM) measured using DXA and ADP before and after an 8-wk weight-loss program involving moderate energy restriction and exercise. RESULTS: Body weight decreased significantly in women (-4.3 +/- 3.4 kg) and men (-4.7 +/- 3.1 kg). There were significant method (ADP vs DXA) and time (pre and post) effects but no method by time or gender interactions. Methods were significantly different in estimating %BF, FM, and FFM with ADP estimates of %BF and FM being lower and estimates of FFM higher than corresponding DXA values (P = 0.000). There were significant correlations accounting for a high degree of the shared variance between DXA and ADP (r = 0.98 to 0.99) for %BF, FM, and FFM and lower correlations for the changes in %BF (r = 0.66), FM (r = 0.86), and FFM (r = 0.34). In response to weight loss, the mean changes in %BF, FM, and FFM were not significantly different between methods (P > 0.05). CONCLUSION: Both DXA and ADP measure changes in body composition after small to moderate weight loss to the same extent and with similar sensitivity.

Laparoscopic mini-gastric bypass for failed vertical banded gastroplasty.

BACKGROUND: Bariatric surgery is the only method for sustained weight loss in morbid obesity. However, 10-25% of patients will require re-operation for unsatisfactory weight loss or weight regain after restrictive surgery. Re-operation is associated with higher morbidity and mortality. This study is to evaluate the s a fety and efficacy of laparoscopic mini-gastric bypass (LMGB) for failed vertical banded gastroplasty (VBG). METHODS: From May 2001 to March 2003, 29 consecutive patients underwent LMGB for failed VBG. Average age was 39.7 years (range 22 to 56), and average BMI before re-operation was 41.7 kg/m(2) (range 35.0-70.8). 8 patients had previous open VBG, and 21 had laparoscopic VBG. The re-operation was for regain of weight in 16 patients, inadequate weight loss in 10 patients, and severe reflux esophagitis in 3 patients. Re-operation was performed after an average of 58.5 months (range 14 to 180). RESULTS: All the re-operations were completed laparoscopically. Average operative time was 171.4 minutes (range 130 to 290). There was 1 mortality, due to leakage (3.4%). 1 re-operation was necessary, for incarceration of small bowel in a trocar wound 10 days after the LMGB (3.4%). 1 anastomotic site bleeding and 1 wound infection occurred. Average BMI 12 months after the LMGB was 32.1 kg/m(2) (range 26.4 to 42.7). The quality of life study was significantly improved. The revision operation had much more technical difficulty for those with previous open VBG than laparoscopic VBG. CONCLUSION: LMGB is an effective and safe revision operation for patients with failed VBG. A large series and long-term follow up is needed for confirmation.

Comparison of Yukon Women by weight loss Effort and Body Mass Index: Self-reported Nutrition and Exercise Practices and Beliefs and Self-rated Health.

The purpose of this study was to determine the prevalence of weight loss efforts among women in the Yukon Territory and to assess relationships between weight loss effort (not trying/trying to lose weight) or weight status and self-reported nutrition and exercise practices and self-rated health. Data were obtained from 711 nonpregnant, noninstitutionalized women aged >15 y participating in the Yukon Health Promotion Survey. Over 50% of women were trying to lose weight at the time of the survey. These women were more likely to believe they ate well enough to maintain health, to report following certain recommended nutrition practices and to feel they didn't exercise as much as they needed. Self-rated mental and emotional health and physical health, however, were lower than among women not trying to lose weight. Overweight (Body Mass Index (BMI) >27) and normal weight (BMI 20-25) women reported similar nutrition practices and beliefs, whereas underweight women (BMI <20) were less likely to report following certain recommended nutrition practices or to believe they ate well enough to maintain health. Overweight women reported lower overall quality of life, physical health and social relationships than women with BMI = 25. These results suggest that weight loss should not be emphasized as the primary benefit of sound nutrition and that dietitians should reinforce that eating well and being active are important to everyone, regardless of weight.