Obesity-news.com THE LATEST IN OBESITY RESEARCH AND WEIGHTLOSS DRUG DEVELOPMENT     Join our list More information      Volume 5, Issue 3 March 2001 CANNABINOIDS AND BODY WEIGHT 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. Contents Obesity and genetics Melanocortin and wasting syndrome. Nutrition studies Sugar and obesity in children. Leptin studies Dietary fat and leptin resistance. More on fat and leptin. Review article Mini-review: Cannabinoids and body weight. Drug development P57 CCK-A promoter β-3 adrengeric receptor agonist R-fluoxetine. 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. Leptin studies Dietary fat and leptin resistance. Diet-induced obesity in both animals and humans is associated with leptin resistance -- caused by an increase in body fat and the resulting rise in serum leptin. It is theorized that elevated serum leptin desensitizes obese patients to the hormone's effects, much like obesity results in increased insulin levels and eventually insulin resistance. Studies showing that obese subjects have elevated levels of leptin in the blood, but not in cerebral spinal fluid support that leptin resistance may result from high serum leptin levels overloading the transport system resulting in smaller amounts crossing the blood brain barrier. The blood brain barrier protects the brain from toxins, but also prevents useful therapy from crossing into the brain. Does dietary fat cause leptin resistance independent of obesity? More recent experiments have investigated the role of dietary fat in the development of leptin resistance. Mice, and a variety of laboratory rat species develop peripheral resistance to leptin after habituation to a high-fat diet, indicating that impaired leptin transport contributes to the development of obesity. But other research suggests that dietary fat may induce leptin resistance regardless of body fat mass changes. In one set of experiments Sprague-Dawley rats became resistant to both peripheral and central leptin injection 1-week after switching to a high-fat diet, despite no change in body weight. To investigate whether the weight gain accompanied by a high-fat diet, or dietary fat itself is responsible for the altered response to leptin, scientists at Pennington Biomedical Research Center compared the response to peripheral leptin administration in rats adapted to either a high-fat or a low fat diet. They also looked at the effects of the diets on serum insulin, corticosterone, neuropetide Y (NPY), and the serotonin 2C receptor (5-HT2C). Experiments. 50 Male Osborne-Mendel rats with a starting weight of 250 ± 2 grams were adapted to either a high-fat diet (56 percent fat, 4.78 kcal/g) or a low fat diet (10 percent fat, 3.66 kcal/g) for a minimum of 2 weeks, and then switched to the alternate diet. High-fat/low-fat. The first group was adapted to a high-fat diet for 14 days and then tested for its response to either leptin or saline. The rats were then switched to a low-fat diet and were tested again for leptin sensitivity. Low-fat/high-fat. The second group was adapted to a high-fat diet for 14 days and then tested for its response to either leptin or saline. The rats remained on the high-fat diet and were tested again for leptin sensitivity. Results and discussion. The major finding of the study was that dietary fat, rather than obesity, induced peripheral leptin resistance within a short period of time. In all cases a high-fat diet prevented the hypophagic effects of leptin. When low-fat fed rats were tested with a high-fat diet the appetite suppressant effects of leptin were present on day 1, but disappeared by day 5. When high-fat fed rats were subsequently given a low fat-diet, the feeding reduction was evident immediately on day 1 and persisted through day 15. The speed of onset after introduction of a high-fat diet and its disappearance upon implementation of a low-fat diet, makes it unlikely that leptin resistance is caused by changes in body fat mass. Dietary fat, rather than obesity, may induce peripheral leptin resistance. This study used a feeding regimen that adapted the rats to one diet, and then tested them on a diet that differed in fat and carbohydrate composition. This approach allows the differentiation between a chronic signal related to adaptation to a diet from an acute signal related to a diet being consumed during the test period. The results show that there is an adaptive response to increasing the dietary fat that blocks the response to leptin. Leptin and serum hormone concentrations. Rats maintained on the high-fat diet had significantly higher body weight (483 ± 13.1 grams vs. 437 ± 6.3 grams) and serum leptin (approx. 30 ng/ml vs. approx. 15 ng/ml), insulin and corticosterone levels compared to low-fat fed rats. But the response to leptin injection was blunted in the high-fat fed animals. Although leptin levels were approximately 2 fold higher in high-fat fed animals, it rose to approximately the same level (30.7 ± 3.3 ng/ml vs. 31.9 ± 10.2 ng/ml) in both groups after injection, irrespective of the diet. Leptin treatment significantly increased the corticosterone level in low-fat fed rats, but not high-fat fed rats. Leptin administration did not affect the insulin level of rats in either dietary group. Leptin and NPY and 5-HT2C. Rats fed the low-fat diet had higher hypothalamic NPY levels than rats fed the high-fat diet, and leptin treatment reduced NPY levels in low-fat fed rats but not in the high-fat fed rats. 5-HT2C receptor levels were not affected by leptin administration, but were decreased in rats fed the high-fat diet. The absence of any effect of leptin on NPY in rats adapted to a high-fat diet suggests that the resulting leptin resistance is caused by either an impairment in leptin transport into the central nervous system, or lack of activation of the JAK-STAT pathway (a pathway involved in leptin signaling) however further research is necessary. Other possible mechanisms of leptin resistance could include the presence of a circulating antagonist or binding protein, alterations in clearance, activation of SOCS-3 or other cytokine signal inhibitors. Acute changes in the response to peripheral leptin with alteration in the diet composition. Lin L, et al. (medline) Am J Physiol Regul Integr Comp Physiol. 2001 Feb;280(2):R504-R509. More on fat and leptin. Rodents are more susceptible to dietary-induced obesity from a high-fat diet than humans. Humans who eat high-fat diets do not always become obese, and there is at least some evidence that high-fat low-carb diets can produce weight loss. (See June 1999 Obesity-news for the results of one such study). Whether or not a high-fat diet will make humans leptin resistant is unknown, but at least one study has shown that a high-fat diet does increase leptin levels in individuals with the same body weight. Researchers hypothesize that the higher levels of serum leptin may provide protection against weight gain. CHARACTERISTICS OF SUBJECTS   HF LF Age 23.6 ± 1.1 22.7 ± 0.6 Percent body fat 12.6 ± 1.6 10.6 ± 1.1 Fat mass 9.5 ± 1.5 7.1 ± 1.0 BMI 22.4 ± 0.6 22.6 ± 0.4 Calories/day 2734 ± 115 2217 ± 190 Fat (grams/day) 138 ± 6.5 78.7 ± 7.7 Carbs (grams/day) 297 ± 12.3 319 ± 27.7 Protein 105 ± 4.9 83.4 ± 7.0 subjects. Ten habitual high-fat (HF) consumers and ten habitual low-fat (LF) consumers recruited from the staff-student population at Leeds University. HF and LF subjects were defined as consuming >44 percent and <35 percent of energy from fat, respectively. Dietary content was evaluated from a food frequency questionnaire. All volunteers were male, ranging in age from 18-25 years, and had a body mass index (BMI) <25. Methods. Body fat was measured by bioelectric impedance, and a blood sample was taken to measure leptin, triglycerides and glucose. Results and discussion. Plasma leptin correlated significantly with BMI, fat mass and percentage of body fat. However, this was a group effect as leptin correlated with BMI highly significantly in the HF group but not at all in the LF group. There was also a positive correlation between the percentage of dietary fat intake and leptin levels, and a negative correlation between carbohydrate consumption and leptin. Although the groups of subjects differed dramatically in both the amount and the percentage of energy from fat, and total energy intake, the groups did not differ in BMI, body weight or fat mass. Therefore it can be concluded that some factor is protecting them against the weight inducing action of a HF, high-energy diet. LEPTIN, GLUCOSE & TRIGLYCERIDE LEVELS IN HF AND LF subjects.   HF LF Glucose (mmol/L) 4.88 ± 0.08 5.18 ± 0.11 Triglyceride (mmol/L) 0.91 ± 0.10 0.87 ± 0.08 Leptin (mmol/L) 2.92 ± 0.43 1.79 ± 0.15 Investigators found no differences in physical activity levels between the groups, but the HF subjects did have a higher basal metabolic rate (BMR) and also higher heart rates than LF subjects As shown in the table on the right, HF and LF subjects differed significantly in plasma leptin and glucose concentrations, and showed a tendency to differ in plasma triglycerides. The difference in glucose and triglycerides is consistent with the diets. However, the difference in plasma leptin concentrations was not expected. Although it is not possible to identify a cause for the difference in leptin levels based on this study, some mechanism must be preventing the HF subjects from gaining weight. One possible interpretation is that the higher plasma leptin in HF subjects protects them from weight gain, and may explain the increased BMR in the HF group. It is possible that this protective effect only occurs in young males and may not be present in older men or in women. The high-fat phenotype: Is leptin involved in the adaptive response to a high fat (high energy) diet? Cooling J, et al. (medline) Int J Obes Relat Metab Disord. 1998 Nov;22(11):1132-5. 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. 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