Obesity-news.com THE LATEST IN OBESITY RESEARCH AND WEIGHTLOSS DRUG DEVELOPMENT     Join our list More information      Volume 4, Issue 11 November 2000 SPECIAL ISSUE ON THE NAASO ANNUAL MEETING Access to full-text is available with a subscription to Obesity-news. To subscribe please fill out our subscription information form. Subscribing is easy using your American Express, Discover, VISA or Mastercard on our secure server. We also take credit card orders by fax at 703/960-7462. To order by mail, send your subscription information form to PO Box 19316, Alexandria, VA 22320-0316 with your check, money order, or credit card information. LETTER FROM THE EDITOR It has now been more than a year since scientists finished sequencing the human genome. And as expected, this new resource, along with better drug development methods, have resulted in the discovery of new obesity genes and anti-obesity compounds at a break-neck pace. In this year's coverage of the North American Association for the Study of Obesity annual meeting, Obesity-news concentrates on "news you can use" including the latest research on drugs in current use which are now being tested for obesity, over-the-counter supplements and foods shown to have an effect on weight, and anti-obesity drugs currently in development. As the discovery of obesity genes continues, the most likely culprit in the world-wide increase in overweight and obesity remains the interaction between genetics and environment. And for that reason, in this issue we feature animal research that reveals the effect of environmental factors on susceptibility genes which normally have little impact on body weight. Whether these specific genes will be found to produce a gene-diet interaction in humans remains to be seen, but other still to be discovered genetic factors predispose Pima Indians and former "hunter gatherer" populations to obesity and diabetes in an environment of readily available high-calorie food. For any of you who have ever attended the NAASO meeting or another medical conference, you are already aware that sessions run concurrently, making attendance at each one of interest impossible. In cases where Obesity-news attended the session, or spoke with a presenter, you will find a summary of the session or poster. A blue icon appears to the left of these titles in the table of contents. Where we have no additional information but think you will still be interested in the research, we have reproduced the abstract for you. A white icon appears to the left of these titles in the table of contents. Contents CURRENTLY USED MEDICATIONS Acipimox and insulin resistance. Bupropion SR and lifestyle intervention. Phentermine vs. phen/fen. Orlistat studies. Sibutramine studies. Topiramate and weight loss. DIET STUDIES Amylose and lipids. CCK, hunger and energy consumption. Nisin and weight loss. Oolong tea and weight loss. DRUGS IN DEVELOPMENT Corticotropin releasing hormone and energy expenditure. Is L-796,568 a selective beta-agonist in humans? NGD 95-1, an NPY antagonist, and body weight. P57 and food intake. OBESITY AND GENETICS Diet-gene interactions in obesity. OTC SUPPLEMENTS Calcium, vitamin D and body weight. Chitosan and fat absorption. Chitosan vs. orlistat redux. Conjugated linoleic acid and fat deposition. Ephedra supplements and weight loss. Ephedrine and caffeine and the β-3 receptor. SUBCRIPTION INFORMATION A one year on-line subscription to Obesity-news is $104.00. Send check or money order, in US currency to: Obesity-news, PO Box 19316, Alexandria, VA 22320-0316. Or subscribe or renew on-line using American Express, Discover, VISA or Mastercard through our secure server. Currently used medications Acipimox and insulin resistance. Acipimox is a nicotinic analog, used to treat high-cholesterol that works by decreasing the release of fatty acids from adipose tissue and reducing blood concentrations of LDL cholesterol. Patients who are obese have increased levels of free fatty acids (FFAs) in the blood which can result in insulin resistance and hyperinsulinemia. In a study on type-2 diabetics, acipimox increased leptin levels, decreased body weight and maintained the diurnal variations in leptin which flatten out during dieting. The increased leptin concentrations are thought to increase glucose uptake in skeletal muscle. The β-3 agonist CL-316,243 also normalizes glycemia, decreases plasma free fatty acids (FFA) concentration, improves insulin responsiveness and increases glucose uptake, not only in brown and white adipose tissues, but also in skeletal muscle. Since muscles do not express typical β-3 adrenoceptors, researchers at Laval University postulated that effect of acipimox in muscle was indirect and possibly mediated by an activation of the glucose fatty acid cycle. To test this hypothesis, they investigated the effects of acipimox in obese diabetic Zucker rats. Methods. Obese diabetic Zucker rats (ZDF) rats were given 150 mg/kg acipimox or CL-316,243. Results. A glucose clamp test showed acipimox improved insulin responsiveness and significantly increase glucose uptake in the diaphragm, the heart and skeletal muscle. But unlike CL-316,243, acipimox did not increase glucose utilization in brown or white adipose tissue, demonstrating that it is possible to improve diabetes without necessary stimulating thermogenesis in fat cells. While both drugs lower plasma FFAs, acipimox does so through inhibition of lipolysis, and CL-316,243 does it through chronic stimulation of FFA oxidation. Conclusions. Acipimox decreases plasma FFAs, glucose and insulin and improved glucose tolerance while reducing the insulin response in obese ZDF rats. Plasma FFAs were significantly correlated with plasma glucose and insulin. The glucose clamp test revealed that acipimox markedly improved insulin responsiveness and increased glucose uptake in various muscles, but not in BAT or WAT. These results suggest that the glucose fatty acid cycle is operative in obese ZDF rats. Abstract. Objective: To investigate the effect of acipimox on lipolysis rate in subcutaneous adipose of obese subjects. Methods: Sixteen obese females (age 22.8 ± 10.3, range 18-47 yrs) were studied. Before beginning of the experiments, subjects were given 250 mg. acipimox. Venous blood samples were drawn every 30 min. Glycerol release was measured in abdominal subcutaneous adipose tissue with microdialysis technique (cuprohane membranes, 30 x 0.3 mm). Adipose tissue blood flow (ATBF) was assessed with the ethanol escape technique. Perfusion solution was saline containing 100 mM ethanol, perfusion rate was 2.5 ml/min (for 4 hours). Glycerol concentration was measured by bioluminescense and ethanol by gas-chromatography. One membrane was perfused with saline only. In another membrane after three hours of basal measurement, norepinephrine (10-3 M) was added to the perfusate for 1 hour. Results: Serum glycerol concentrations decreased from 160 ± 11.1 to 113.8 ± 7.5 µM (p >0.0001). Glycerol concentration in the dialysate from 53.0 ± 16.4 to 15.0 ± 2.0 µM (p > 0.0001). ATBF increased during the last hour of the experiment (p=0.023). When norepinephrine was added to the perfusate, a significant elevation of glycerol output was observed (p > 0.0001). Conclusions: Acipimox exerts an antilipolytic effect in subcutaneous adipose tissue in situ in subjects with severe obesity. In the large body fat mass of obese subjects, a reduction of lipolysis in adipose tissue may play an important role in lowering of insulin resistance. Acipimox inhibits basal lipolysis in subcutaneous adipose tissue of subjects with severe obesity. Flechtner-Mors M, et al. Obes Res 2000 Oct:8:65s. (Suppl. 1: abstr. PA10) Abstract. We previously reported that chronic treatment of Zucker diabetic fatty (ZDF) rats with the selective β3-agonist CL-316,243 normalizes glycemia, decreases plasma free fatty acids (FFA) concentration, improves insulin responsiveness and increases glucose uptake, not only in brown and white adipose tissues, but also in skeletal muscle (Am J Physiol 1998 May;274(5 Pt 2):R1212-9). Since muscles do not express typical β3-adrenoceptors, we postulated the muscle effect was indirect and that it was possibly mediated by an activation of the glucose fatty acid cycle. To test this hypothesis, we investigated the effects of Acipimox, a potent inhibitor of lipolysis in adipose tissue. Similarly to CL-316,243, Acipimox (150 mg/kg, po) markedly decreased plasma FFA, glucose and insulin concentrations and improved glucose tolerance while reducing the insulin response in obese (350-400g) ZDF rats. Remarkably plasma FFA concentrations were significantly correlated with plasma glucose and insulin concentrations (r=0.72-0.83, respectively, p > 0.01), indicating strong metabolic relationships between these parameters. Euglycemic-hyperinsulinemic clamps combined with the 2-(3H)deoxyglucose method revealed that Acipimox markedly improved insulin responsiveness and significantly increased glucose uptake in the diaphragm, the heart and various skeletal muscles. Contrary to CL-316,243, Acipimox did not increase glucose utilization in brown or white adipose tissues. This selectivity demonstrates that it is possible to improve diabetes in obese ZDF rats without necessarily stimulating thermogenesis in adipose tissues. Thus, lowering of plasma FFA with two drugs (Acipimox or CL-316,243) acting via different mechanisms (acute inhibition of lipolysis or chronic stimulation of FFA oxidation) is associated with increased glucose uptake in muscles and enhanced insulin responsiveness. These observations strongly suggest that the glucose-fatty acid cycle is operative in muscles of obese ZDF rats. They also support the hypothesis that CL-316,243 may indirectly stimulate glucose uptake in muscles of type 2 diabetic rats by first stimulating brown adipose tissue (increasing uncoupling protein content and fatty acid oxidation) and progressively decreasing the levels of circulating FFAs, resulting in an activation of the glucose-fatty acid cycle. (Supported by the MRC and the CDA). Lowering plasma free fatty acids with Acipimox mimics the anti-diabetic effects of the beta 3-adrenergic agonist CL-316243 in obese Zucker diabetic fatty rats: evidence for the operation of the glucose-fatty acid cycle. Blachere JC, et al. Obes Res 2000 Oct:8:117s. (Suppl. 1: abstr. PF6) See also: The nicotinic acid analogue acipimox increases plasma leptin and decreases free fatty acids in type 2 diabetic patients. Worm D, et al. (medline) Eur J Endocrinol 2000 Sep;143(3):389-95. Diet studies CCK, hunger and energy consumption. Cholecystokinin (CCK) is a gut peptide that has been shown to slow gastric emptying and decrease appetite when administered during a meal. The premeal beverage Satietrol, available over the counter in health food stores, is a potato-derived appetite-suppressant powder which is mixed with water and taken 15 minutes before a meal. The product, which contains a combination of whey protein enriched with glycomacropeptide, oleic acid, calcium, and fiber, was designed to activate CCK before eating and prevent the breakdown of CCK after a meal, thus increasing satiety. Several manufacturer supported studies indicate that Satietrol reduces hunger, assisting overweight women in maintaining a reduced calorie diet. Satietrol is a premeal beverage, available in health food stores, that may increase CCK release. subjects. Fifteen women (BMI 28.1, mean age 1, mean weight 80 kg). Methods. On separate days subjects were given Satietrol or a placebo beverage 15 minutes before a 380 calorie meal. They then rated their feelings of fullness every fifteen minutes over the following 3 1/2 hours. Later in the day subjects were fed an open-ended meal. Results. Hunger ratings following Satietrol were significantly lower throughout the post meal period compared to the control beverage. In addition, subjects ate 34 percent fewer calories in the subsequent open-ended meal. Other studies. Other longer trials indicate that Satietrol curbs hunger and assists weight loss. In a six-week trial, 113 subjects lost an average of 8.82 lbs and showed a significant decrease in food cravings and overall appetite when compared to pre-study ratings. In a four-week trial, subjects were placed on a reduced calorie diet during which they ingested Satietrol twice daily 15 minutes before lunch and dinner. At the end of the trial period subjects lost an average of 4.4 lbs. The effect of Satietrol on hunger ratings was measured before the diet began and again in the fourth week. In the fourth week of the diet, subjects who were given Satietrol, followed by a fixed calorie meal, were 32 percent less hungry 3 1/2 hours later, when compared to placebo. Study results indicate that Satietrol reduces appetite and energy consumption, thus helping overweight women adhere to a reduced calorie diet. The results indicate that the product may be useful as part of a weight management program. Abstract. Cholecystokinin (CCK) decreases food intake in man when administered during an open-ended meal (Gut 1996 Nov;39(5):661-7). Certain fibers bind bile salts (J Nutr 1976 Sep;106(9):1292-4) and may, therefore, prevent the inhibition of CCK release. AIM: To measure the effect of an 80 kcal premeal beverage designed to stimulate CCK release on postmeal satiety and subsequent energy intake in overweight females. METHODS: The premeal beverage (Satietrol, Pacific Health Labs) contained whey protein enriched with glycomacropeptide, oleic acid, calcium and various fibers (guar, glucomannan, potato fiber and mean alfalfa). Fifteen female subjects (mean BMI=28.1, mean age=41., mean wt=80 kg) were randomized in a double-blind cross over design. On separate days subjects ingested either the premeal beverage or a maltodextrin control beverage matched for volume, flavor and energy 15 minutes before consuming a 380 kcal meal. Subjects rated hunger and fullness on visual analog scales every 15 minutes for 3.5 hours. After 3.75 hours subjects were offered an open ended meal of macaroni and cheese (Kraft). Energy consumption was calculated for both treatment groups. RESULTS: Hunger rating following ingestion of the premeal beverage were significantly lower throughout the post meal period compared to the control beverage, and were 36 percent lower at 195 minutes (p > 0.05). Subjects receiving the premeal beverage consumed 34 percent fewer calories (p > 0.05) in the subsequent open ended meal compared to the control beverage. Conclusions: These results indicate that the premeal beverage reduces appetite and in a subsequent meal reduces energy consumption in overweight women. The premeal beverage may, therefore, be a valuable adjunct to a weight management program. Study funded by PacificHealth Laboratories, Inc. Ingestion of a premeal beverage designed to release CCK reduces hunger and energy consumption in overweight females. Portman R, et al. Obes Res 2000 Oct:8:82s. (Suppl. 1: abstr. PB59) PacificHealth Laboratories, Inc. announces positive results in six-week home trial with Satietrol®, new weight loss product. PacificHealth Labs press release, February 11, 2000. PacificHealth Laboratories, Inc. announces results of second clinical trial confirming new Satietrol®, weight loss product, decreases hunger. PacificHealth Labs press release, July 7, 1999. PacificHealth Laboratories, Inc. announces preliminary clinical results showing Satietrol, new weight loss product decreases hunger by 30 percent. PacificHealth Labs press release, July 7, 1999. Drugs in development Corticotropin releasing hormone and energy expenditure. Corticotropin releasing factor (CRH) functions as a neurotransmitter in the brain and plays a critical role in coordinating psychological and behavioral responses to stress, including eating behavior. Studies indicate that leptin modulates the secretion of CRH from the hypothalamus and that an imbalance between leptin and CRH may contribute to obesity. CRH, which decreases feeding, is found primarily in the paraventricular nucleus (PVN). CRH binding protein (CRH-BP) binds to and inactivates CRH. Central administration of CRH increases energy expenditure and decreases food intake in rodents, however this is not a viable method for administering medication to humans. But humans have a peripherally circulating binding protein and measurable levels of CRH in the blood, which suggests that CRH injection would increase energy expenditure (EE) and reduce food intake. In a pilot study investigators from Pennington Biomedical Research Center and Neurocrine Biosciences looked at the effect of human CRH (hCRH), ovine CRH (oCRH) or placebo on 8 subjects. Methods. Four men and 4 women, ages 19-39 were given hCRH, oCRH or placebo at progressively increasing doses (0.5, 1.0 and 2.0 µg/kg/hour) over a 6 hour period. Resting energy expenditure (REE) was then measured by indirect calorimetry. Subjects were subsequently crossed over to the other treatments on two separate days. EFFECT OF hCRH VERSUS oCRH ON ENERGY EXPENDITURE hCRH 2.0 µg oCRH 2.0 µg 13.3% 4.3% Results. hCRH increased resting energy expenditure by 13.3 percent versus 4.3 percent for oCRH at the 2.0 µg dose. hCRH also increased EE at 1.0 µg. Respiratory quotient (RQ), the ratio of carbohydrates to fat oxidized, fell from 0.828 to 0.768 during the hCRH infusion. In addition heart rate increased from 5.6 ± 3.4 beats per minute to 78.5 ± 5.4 beats per minute after 2.0 µg/kg/hour hCRH. There was no effect on hunger or food intake. Conclusions. Short term hCRH increased resting energy expenditure, and CRH binding protein did not inhibit the effect. These results indicate that peripherally administered CRH may be useful in increasing REE and thus decreasing body weight. Abstract. Introduction: Central administration of CRH increases energy expenditure and decreases food intake in rodents. Humans, but not rodents, have a peripherally circulating binding protein and measurable levels of CRH in blood. The source of this circulating CRH is unknown. Human CRH (hCRH), but not ovine CRH (oCRH) binds to the circulating binding protein (CRH-BP). We proposed the hypothesis that peripheral administration of CRH would increase energy expenditure and decrease food intake in human subjects. Methods: Four men and four women (age 19-39) enrolled in a three period, cross-over, double blind trial to test the effect of hCRH, oCRH, and placebo (PL) on resting energy expenditure (REE) as measured by indirect calorimetry (Deltatrac II). CRH was administered by primed continuous infusion at progressively increasing doses of 0.5, 1.0 and 2.0 µg/kg/hour (2h each). Results: hCRH, but not oCRH, increased REE (percent increase above PL: 13.3 percent and 4.3 percent respectively at the 2.0 µg/kg/hr dose, p > 0.05 for hCRH vs. placebo). hCRH increased EE at the 1.0 µg/kg/hr dose, with a larger increase in energy expenditure at the 2.0 µg/kg/hr dose. RQ fell from 0.828 to 0.768 during the hCRH infusion, from 0.843 to 0.794 during oCRH, and from 0.836 to 0.807 during PL. Heart rate increased from 56.3 ± 3.4 bpm to 78.5 ± 5.4 bpm after 2.0 µg/kg/hr hCRH. There were no effects on hunger ratings or food intake. Conclusions: Short-term peripheral infusion of hCRH increases REE. Since hCRH, which binds to CRH-BP was able to increase REE, CRH-BP does not inhibit this effect. Activation of peripheral CRH receptors may offer a novel strategy to increase REE. Peripheral administration of human CRH Increases energy expenditure and decreases respiratory quotient in-vivo in humans. Smith SR, et al. Obes Res 2000 Oct:8:44s. (Suppl. 1: abstr. O121) OTC supplements Chitosan and fat absorption. A new study shows that the dietary supplement chitosan is not an over-the-counter substitute for Xenical, as claimed by many manufacturers. At last year's NAASO conference, Roche Pharmaceuticals, the manufacturers of Xenical, sponsored a study, showing that chitosan had no effect on fat absorption. Now an independent study has come to the same conclusion. Chitosan is a substance made from the shells of shrimp and other marine exoskeletons, which is sold by various vendors as a dietary supplement that "traps fat" and helps individuals lose weight. Claims include that chitosan can block the absorption of as much as 120 grams of dietary fat daily and that it promotes weight loss. To evaluate the strength of these assertions, Judith Stern and colleagues at the Department of Nutrition, University of California at Davis, tested the efficacy of a chitosan supplement on fat excretion in 7 healthy male subjects in a 12 day study. subjects. The 7 male subjects were between 23-30 years of age, BMI 23-31. Methods. Subjects ate a high-fat diet containing 135 grams of fat daily for 12 days. Feces were collected from day 2 to day 12. The chitosan supplement Fat Trapper Plus from Enforma Natural Products was used in the study. Subjects took a total of 15 capsules per day (1.2 grams) in divided doses 5 minutes before 3 high-fat meals and 2 snacks on days 6-9. Results. FAT EXCRETION WITH AND WITHOUT CHITOSAN Baseline Chitosan 6.9 ± 1.0 g 6.8 ± 0.4 g 5.1 ± 0.7% 5.0 ± 0.3% Daily fecal fat content did not significantly differ during the baseline and supplement periods whether expressed as grams or as percentage of fat intake. Key points. Chitosan had no effect on dietary fat absorption even though subjects consumed a high fat diet and a dose of chitosan exceeding suggested use. Based on this study, the claim that chitosan blocks the absorption of 120 grams of dietary fat per day is false and misleading. This illustrates the value of clinical research in evaluating the efficacy of dietary supplements. These results support an April 2000 FTC order, which prevents Enforma from making any claims that the "Fat Trapper" enables weight loss or prevents fat absorption. Abstract. Manufacturers and distributors of supplements marketed for weight loss often make claims that are unsubstantiated in humans. One example is seen in the marketing of the supplement chitosan. Chitosan is an N-deacetylated derivative of the polysaccharide chitin. Chitin supplements have been marketed as "fat blockers". Claims include that it can block the absorption of as much as 120g of dietary fat daily and that it promotes weight loss. We tested the efficacy of a chitosan supplement on fat excretion in 7 healthy male subjects (28 years old, range 23-30 years, BMI=26, range 23-21). Subjects ate 135 grams of fat daily for 12 days and all feces were collected from day 2 to day 12. A chitosan supplement (1.2g daily, 15 capsules, Fat Trapper Plus, Enforma Natural Products, Inc., Poincoima, CA) was taken on days 6-9 five minutes prior to 3 high fat meals and 2 snacks. A 10 percent charcoal solution (100 ml, Actidose-Aqua, Paddock Labs, Minneapolis, MN) was consumed prior to breakfast to visually identify feces associated with baseline (days 2-5) and supplement periods (days 6-9). Fecal fat was measured using a modification of the Van de Kamer method. During the study, subjects ate an average of 135 ± 3 grams of fat daily. Daily fecal fat content did not significantly differ during baseline and supplement periods whether expressed as grams (6.9 M 1.0 g/day vs. 6.8 ± 0.4 g/day, respectively) or as percentage of fat intake (5.1 ± 0.7 percent vs. 5.0 ± 0.3 percent, respectively). In conclusion, consumption of chitosan did not increase fecal fat content and therefore did not block fat absorption. These results are supportive of the April 2000 FTC Stipulated Final Order with Enforma Natural Products, Inc. which included that "the defendant not make any representation that "Fat Trapper" enables weight loss, prevents fat absorption or enables the consumption of foods high in fat unless these claims can be substantiated with reliable scientific evidence". Supported in part by the district Attorney's Office, Napa County, CA and DK 35747. Chitosan does not block fat absorption in men fed a high fat diet. Stern JS, et al. Obes Res 2000 Oct:8:91s. (Suppl. 1: abstr. PB94) Home|Subscribe|Archives|Drug info|Contact|Media & Links|Site index|FAQs|Doctors/meetings|Admin Obesity-news is a publication of Hirsch Communications. An on-line subscription is $104.00 per year, payable in advance by check, money order, American Express, Discover, VISA or Mastercard. Subscribing is simple using our secure on-line subscription form. Obesity-news also accepts fax orders at 703/960-7462 and mail orders at PO Box 19316, Alexandria, VA 22320-0316. Copyright 1997-2008, all rights reserved. IMPORTANT: All information in this publication is believed to be accurate and true. Publisher is not liable for omissions or inaccuracies. Information in this newsletter is for educational purposes only and should not be construed as medical advice, or be used in lieu of consultation with a health care provider.