Obesity-news.com THE LATEST IN OBESITY RESEARCH AND WEIGHTLOSS DRUG DEVELOPMENT     Join our list More information      Volume 5, Issue 2 February 2001 METABOLISM AND OBESITY 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. A lower body weight and caloric restriction have long been associated with longevity whereas obesity and caloric excess is known to promote a number of related diseases and a shorter life span. As discussed in July 2000 Obesity-news, the process of metabolizing food puts wear and tear on the body, and as we age, a small number of genes that control critical biological tasks begin to break down. This results in increased oxidative damage, the production of free radicals, inflammation, and eventually disease. While calorie restriction increases longevity, overeating and obesity result an in a condition that mimics the aging process. And as research progresses, we learn more about how body weight and fat mass cause disease. This month in Obesity-news we bring you the latest studies on how oxidative damage leads to obesity related comorbidities. Research at the University of Buffalo shows us how chronic overeating results in the production of free radicals which can lead to heart disease. And two new studies discuss how excess adipose tissue and inflammation trigger genes that cause diabetes. Experiments at Harvard University have found that obese individuals have elevated levels of inflammatory cytokines, which lead to heart disease, diabetes and other obesity related conditions, and a study by Danish researchers shows that even overweight children have signs of inflammatory disease which may lead to illnesses later on, even if they become normal weight adults. At first glance, all this research centered on how bad it is to be overweight can seem depressing. After all, we already know that being fat is bad for us. But understanding the molecular and genetic basis for obesity, and obesity related conditions, is the first step in developing effective treatments, and hopefully one day a cure. And this better understanding of obesity, combined with more effective drug discovery methods have already started to bear fruit. After the disappointing results of the recombinant leptin trials, early data on the drug Axokine, which will begin phase 3 testing this year, look much more promising. The human growth hormone fragment AOD-9604 is scheduled to begin phase 1 trials this month, and it looks like Famoxin will begin human testing later this year. Contents Obesity and genetics Dopamine and obesity. Obesity and diabetes New gene explains the link between obesity and diabetes. Fat cell defect may trigger insulin resistance. Obesity and metabolism Chronic overeating and free radicals. Pregnancy and long-term weight gain. Body weight and inflammation Obesity and chronic low-grade inflammation. Raised inflammatory cytokines in obese patients. Leptin studies Obesity, aging and leptin resistance. Effect of diet and exercise on leptin. Drug studies Ephedrine/caffeine and weight loss in teenagers. Famoxin. Orlistat and body composition. 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. Obesity and genetics. Dopamine and obesity. A new study published in The Lancet, suggests that obese people may eat more to try to stimulate the dopamine "pleasure" circuits in their brains, just as addicts do by taking drugs. Investigators at Brookhaven National Laboratory found that availability of the dopamine D-2 receptor is decreased in obese individuals in proportion to their BMI and hypothesize that obese individuals eat more to improve dopamine function. Obese subjects had a significant decrease in D-2 receptors compared to normal controls. subjects. Ten severely obese individuals (5 men and five women), age 38.9 (range 26-54), BMI 51.2 (range 42-60) were selected for the study. Three women and seven men, age 37.5 (range 25-45), BMI 24.7 (range 21-28) were used as controls. Subjects were excluded for psychiatric or neurological diseases, head injury, hypertension, diabetes or other medication conditions that might alter cerebral function, anorexic medications within 6 months, prescription medications in the past 4 weeks, or a history of alcohol or drug abuse. Methods. To test their hypothesis, scientists measured the number of dopamine receptors in the brains of both the obese subjects and normal weight controls. Each volunteer was given an injection containing a radiotracer, a radioactive chemical "tag" designed to bind to dopamine receptors in the brain. Then, the researchers scanned the subjects' brains using a positron emission tomography (PET) camera. The PET camera picks up the radioactive signal of the tracer and shows where it is bound to dopamine receptors in the brain. The strength of the signal indicates the number of receptors. Results and discussion. The obese subjects had lower dopamine D-2 receptor availability in the striatum compared to the normal controls, and this measure declined as BMI increased. Similar results have been found in individuals addicted to drugs like cocaine, alcohol and opiates. The results suggest that a reduction in D-2 receptors is associated with addictive behavior irrespective of whether it is to food, drugs or alcohol. It is possible that the downregulation of D-2 receptors in obese individuals is compensating for the overstimulation which occurs with chronic overeating. However, it is also possible that individuals with low numbers of D-2 receptors are just more vulnerable to addictive behaviors, including compulsive food intake. Nonetheless, investigators speculate that obese individuals overeat as a means to compensate for the decreased activation of reward circuits, which are modulated by dopamine. Further studies assessing D-2 receptor levels both before and after weight loss may help determine if the low levels are secondary to the obese state. The results of this study suggest that improving dopamine function would be beneficial in the treatment of obesity, but unfortunately psychostimulant drugs, like amphetamine and cocaine, which increase dopamine are also highly addictive. However, other strategies, such as exercise, have also been shown to increase dopamine release and raise D-2 receptor levels in animal studies. This suggests that obese people might be able to boost their dopamine response through exercise instead of eating - just one more reason to exercise if you are trying to lose weight. Brain dopamine and obesity. Wang GJ, et al. (article) Lancet 2001;357:354-357. Leptin studies Obesity, aging and leptin resistance. Leptin regulates triglyceride homeostasis in organs like the heart, lung and pancreas. But, cells other than fat cells have a very limited capacity to store excess fat. Researchers hypothesize that the inability of organs and other nonadipose cells to properly manage fat surpluses ultimately causes lipoapoptosis (fat related cell death), leading to a number of obesity related comorbidities. Obesity-induced diabetes involves an accumulation of triglycerides within pancreatic β-cells. This accumulation leads to apoptosis (cell death) of the islets by increasing ceramide formation and enhancing nitric oxide production. Lipoapoptosis occurs only in fat-laden β-cells while β-cells with lesser amounts are spared. Ceramide causes cell death by increasing nitric oxide production. Diabetes occurs in obesity because the reduced number of β-cells cannot meet the increased demands for insulin imposed by the elevated fat content of the target tissues. Identical abnormalities occur in nonadipose tissue throughout the body. In the heart this leads to congestive failure and dilatation, in the lungs, Pickwickian syndrome, in the gall bladder, bile stasis and gall stones, in coronary arteries, cardiac syndrome X. In a recent study published in the FASEB Journal, scientists at Southwestern Medical Center looked at the effects of aging and a high fat diet on the development of obesity related disease. They found that the anorexic and lipolytic actions of leptin decline with age, and this may account for the abnormalities of lipid metabolism in the elderly. Experiments. The effects of hyperleptinemia on 2 month-old (young rats) and 18 month-old (old rats) Zucker diabetic rats by adenovirus gene transfer were compared. Food intake, body fat, free fatty acids, triglycerides, and the effect of a high-fat diet were measured. Results. Food intake and body weight. Leptin treatment resulted in marked serum leptin elevations in both sets of rats, which averaged 48±16 ng/ml in the young rats and 44±10 ng/ml in the old rats. But leptin was much more effective in curbing food intake in young animals. In the 2 month-old rats food intake during the 7 post-treatment days decreased by 37.5 percent and body weight declined by 10.6 percent, compared to 9 percent and 5.3 percent in the 18 month-old rats. Plasma free fatty acids (FFAs) and triglycerides (TG) fell by 44 and 94 percent respectively in the young rats, but did not decline significantly in the older animals. Gene expression. Changes in white adipose tissue (WAT) gene expression as measured by an increase in preadipocyte factor-1 (PREF-1) and suppression of leptin mRNA was significantly attenuated in 18 month-old rats compared to young rats. The increased in PREF-1 messenger-RNA (mRNA) was only 1 percent and the suppression of leptin expression only 37 percent of the changes in young rats. While leptin did have a significant effect on older animals, the effect was small compared to the younger rats. Effect of high fat diet. Old rats ate more of the high fat diet, 132 calories per day compared to 96 calories per day in the young rats. Body fat increased by 46.7±4.3 grams in the young rats and 79.2±5.4 grams in the old rats. SOCS-3. The mean pretreatment level of suppressor of cytokine signaling-3 (SOCS-3) was almost 3 times greater in the hypothalamus of old vs. young rats with normal leptin levels. Discussion. This study confirms that age-related leptin resistance is a factor in the accumulation of fat in organs, and in the development of associated metabolic diseases. In 18-month old rats with adenovirus-induced hyperleptinemia the reduction in food intake and loss of body fat was only a fraction of that observed in 2 month-old rats. Plasma FFA and TG were unchanged in old rats, but declined dramatically in the young. In addition the TG content in the liver, heart and skeletal muscle was unchanged in old rats but was reduced in the young. In old rats marked hyperleptinemia failed to upregulate the enzymes of fatty acid oxidation (ACO and CPT-1) and their transcription factor peroxisome proliferator-activated receptor-alpha (PPAR-α), which explains why these changes failed to occur. Researchers hypothesize that leptin plays a role in protecting nonadipocytes from lipid overload and resulting conditions like diabetes and heart disease. In the young, leptin permits triglyceride stores to expand in fat without accumulation in sensitive cells like the heart, lungs and pancreas. In the elderly, this protection action declines and there is a tendency for increased overall body fat and a shift of lipids into nonadipocytes. The tendency of the elderly to gain weight may be explained by a decrease in leptin sensitivity. Despite greater leptin concentrations, the older rats ate more and gained approximately 60 percent more body fat. Thus if a role of leptin is to limit food intake, the older rats were leptin resistant. This leptin resistance may be explained by the higher levels of SOCS-3, an inhibitor of leptin action. The role of leptin resistance in the lipid abnormalities of aging. Wang ZW, et al. (medline) FASEB J. 2001 Jan 1;15(1):108-114. 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.