Metformin Decreases Food Consumption and Induces Weight Loss in Subjects with Obesity with Type II Non-Insulin-Dependent Diabetes

Metformin often promotes weight loss in patients with obesity with non-insulin-dependent diabetes mellitus (NIDDM). The mechanism may be attributed to decreased food intake. This study has tested the effect of metformin on satiety and its efficacy in inducing weight loss. Twelve diet-treated NIDDM women with obesity were randomly given two dose levels (850 mg or 1700 mg) of metformin or placebo at 0800 for three consecutive days followed by a meal test on the third day on three occasions using a 3times3 Latin square design. The number of sandwich canapes eaten in three consecutive 10-minute periods beginning at 1400 hours was used to quantitate food intake, and the level of subjective hunger was rated just before the sandwich meal with a linear analogue hunger rating scale at 1400 after a 6-hour fast. The prior administration of metformin produced a reduction in calorie intake after each of the two doses of metformin treatment. The 1700-mg metformin dose had the most marked appetite suppressant action. Similarly, hunger ratings were significantly lowered after metformin, and the effect was most pronounced after the administration of 1700 mg of metformin. To assess the efficacy of metformin in reducing bodyweight, 48 diet-treated NIDDM women with obesity who had failed to lose weight by diet therapy were first placed on a 1200-kcal ADA (American Diabetes Association) diet before being randomized to receive either metformin (850 mg) or placebo twice daily in a double-blind fashion for 24 weeks. A 4-week single-blind placebo lead-in period preceded and a 6-week single-blind placebo period followed the 24-week double-blind treatment period. Subjects treated with metformin continued to lose weight throughout 24 weeks of treatment; their mean maximum weight loss was 8 kg greater than that of the placebo group, with corresponding lower HbA1C and fasting blood glucose levels at the end of the active treatment period. These results indicate that metformin decreases calorie intake in a dose-dependent manner and leads to a reduction in bodyweight in NIDDM patients with obesity.     

Treatment of Gross Obesity by Jejunal Bypass

Jejunal bypass operations were performed on 47 grossly obese patients. The results were disappointing in three patients who had a standard “14 in/4 in” Payne and DeWind procedure and therefore a more radical operation was performed, joining four inches (10·2 cm) of proximal jejunum to 10 inches (24·4 cm) of terminal ileum. Two years after the modified operation a mean of 44·2 kg had been lost and the weight tended to stabilize. This weight loss was due mainly to inadequate calorie intake. The appetite became more controlled so that if weight was regained this was small in amount. Metabolic sequelae and their symptoms also settled by two years. The physical, psychological, and social outcome was good. The postoperative period was stormy and required close medical and psychiatric supervision. There were two deaths.     

Clinical Management of Patients Presenting with Non-Adjustable Gastric Band (NAGB) Complications

Background: A number of bariatric surgical procedures have been developed to manage morbid obesity and related co-morbidities. The non-adjustable gastric band (NAGB) was one such procedure that created restriction to food intake by gastric segmentation. Benefits of the procedure included a low risk of perioperative complications and substantial early weight loss. Unfortunately, the long term results of NAGB include a high incidence of complications and failure to maintain weight loss. The purpose of this study was to examine the presentation, workup, and treatment of patients presenting with complications following NAGB placement.Methods: A retrospective review of the diagnosis and management of 11 patients who presented with complications related to NAGB placement.Results: All patients presented with some degree of proximal gastric outlet obstruction. The majority of patients (8/11) presented with vomiting as the main complaint. Other complaints included intolerance to solids, liquids, and reflux. Only 2/11 patients presented with weight loss since undergoing NAGB placement, while the remainder had weight regain to their pre-NAGB level and above. Depending on clinical presentation, desire for additional weight loss and co-morbid conditions, patients underwent a variety of treatments. This included NAGB removal (endoscopic, laparo-endoscopic, and laparoscopic) as well as conversion to another bariatric procedure (sleeve gastrectomy, Roux-en-Y gastric bypass).Conclusion: Patients with NAGB complications present with symptoms related to a proximal gastric outlet obstruction, related to constriction imposed by the band. This may result in severe food and liquid intolerance and subsequent weight loss, but more likely results in maladaptive eating and subsequent weight gain. Optimal therapy involves removal of the NAGB. Laparoscopic conversion to another bariatric procedure, optimally a Roux-en-Y gastric bypass, is warranted to treat morbid obesity and associated co-morbidities.     

Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys

We generated three fully human monoclonal antibody antagonists against fibroblast growth factor receptor-1 (FGFR1) that potently block FGF signaling. We found that antibodies targeting the c-splice form of the receptor (FGFR1c) were anorexigenic when administered intraperitoneally three times weekly to mice, resulting in rapid, dose-dependent weight loss that plateaued (for doses>4 mg/kg) at 35-40% in 2 wk. Animals appeared healthy during treatment and regained their normal body weights and growth trajectories upon clearance of the antibodies from the bloodstream. Measurements of food consumption and energy expenditure indicated that the rapid weight loss was induced primarily by decreased energy intake and not by increased energy expenditure or cachexia and was accompanied by a greater reduction in fat than lean body mass. Hypophagia was not caused through malaise or illness, as indicated by absence of conditioned taste aversion, pica behavior, and decreased need-induced salt intake in rats. In support of a hypothalamic site of action, we found that, after intraperitoneal injections, anti-FGFR1c (IMC-A1), but not a control antibody, accumulated in the median eminence and adjacent mediobasal hypothalamus and that FGFR1c is enriched in the hypothalamus of mice. Furthermore, a single intracerebroventricular administration of 3 microg of IMC-A1 via the 3rd ventricle to mice caused an approximately 36% reduction in food intake and an approximately 6% weight loss within the ensuing 24 h. Our data suggest that FGF signaling through FGFR1c may play a physiological role in hypothalamic feeding circuit and that blocking it leads to hypophagia and weight loss.     

A Primary Care Intervention for Weight Loss: Results of a Randomized Controlled Pilot Study

Most primary care providers (PCPs), constrained by time and resources, cannot provide intensive behavioral counseling for obesity. This study evaluated the effect of using medical assistants (MAs) as weight loss counselors. The study was a randomized controlled trial conducted in two primary care offices at an academic medical center. Patients (n = 50) had a BMI of 27–50 kg/m² and no contraindications to weight loss. They were randomized to quarterly PCP visits and weight loss materials (Control group) or to the same approach combined with eight visits with a MA over 6 months (Brief Counseling). Outcomes included change in weight and cardiovascular risk factors (glucose, lipids, blood pressure, and waist circumference). Patients in the Brief Counseling and Control groups lost 4.4 ± 0.6 kg (5.1 ± 0.7% of initial weight) and 0.9 ± 0.6 kg (1.0 ± 0.7%), respectively, at month 6 (P < 0.001). There were no significant differences between groups for changes in cardiovascular risk factors. Brief Counseling patients regained weight between month 6 and month 12, when MA visits were discontinued. Attrition was 10% after 6 months and 6% after 12 months. Brief Counseling by MAs induced significant weight loss during 6 months. Office‐based obesity treatment should be tested in larger trials and should include weight loss maintenance counseling.     

A new experimental model of human cachexia

A hypernephroma removed from a male patient who had lost 30 kg in weight in the two months preceding surgery was grown as a non-metastasizing transplantable xenograft in immune-suppressed mice. The tumour produced a considerable weight loss (greater than 25 per cent) in the mice at a stage when it comprised less than 5 per cent of the total body weight. A slight fall in food intake of the tumour-bearing mice was noted, but animals bearing other non-cachectic mouse and human tumours had much lower food intakes without accompanying weight loss. No obvious defects in gastrointestinal absorption were detected nor was any gross increase in basal metabolic rate observed. The precise mechanism producing the severe cachexia remains to be established, but elaboration of humoral factors by the tumour seems probable. This model of cachexia bears a closer relation to the clinical situation than do other experimental animal tumour models currently available.     

Comparison of Obese NIDDM and Nondiabetic Women: Short- and Long-Term Weight Loss

Previous research suggests that overweight patients with diabetes lose less weight than non diabetics. We compared the response of obese women with NIDDM to non diabetic controls, matched for age and weight, to a behavior weight loss program. Forty-three overweight women (20 NIDDM, 23 non diabetic) participated in the study. NIDDM and non diabetic subjects were treated together and received the same 16-week behavioral weight loss program. Dependent measures included weight, 3-day food records, physical activity, fasting plasma glucose, and questionnaires assessing eating behavior and depressive symptomatology. Weight loss of NIDDM and non diabetic subjects at posttreatment was comparable (-7.4 ± 5.3 kg vs. ?6.4 ± 3.8 kg, respectively). Changes in caloric intake, eating behavior, exercise and depressive symptomatology were also similar between the two groups. However, during the 1-year follow-up period, NIDDM subjects regained 5.4 ± 6.1 kg compared to 1.0 ± 6.7 kg for nondiabetics (p=.058). These data indicate that NIDDM subjects can lose as much weight as their nondiabetic peers during active treatment Once treatment terminated, however, NIDDM subjects demonstrated poor weight loss maintenance. Thus the added motivation that comes from having diabetes and seeing improvements in glycemic control with weight loss were not sufficient to improve long term weight loss in diabetic subjects. A continuous care model of weight control may be particularly necessary for overweight patients with type II diabetes.     

Sibutramine Treatment in Obesity: Predictors of Weight Loss Including Rorschach Personality Data

Objective: To study personality and clinical factors in weight loss by sibutramine (Meridia and Reductil), an anti‐obesity drug enhancing satiety. Research Methods and Procedures: The subjects were 30 obese patients [43 ± 12 years (mean ± SD), BMI 40 ± 4 kg/m²]. The treatment comprised 15 mg of sibutramine administered daily and monthly dietary advice. Weight loss after 6 months of treatment was evaluated. For psychological assessment, the Rorschach method (Comprehensive System) and the Beck Depression Inventory were used. Results: A multiple linear regression model including the Rorschach predictors’ physical demand states (animal movement, designated as FM) being intrusive or difficult to hold and a dependency orientation (food contents) could explain 47% of 6 months of weight loss. A model including initial weight loss in addition to the Rorschach predictors explained 58% of the 6‐month weight loss. Discussion: The personality factors predicted greater weight loss. In particular, patients with difficulties concerning physical demand states, which would include hunger, could have reduced their eating behavior with enhanced satiety, resulting in greater weight loss. Enhanced satiety could also have helped patients with a dependent need for food to limit food intake. Being enrolled in a treatment program could also have provided essential support for patients with dependency needs. Furthermore, initial weight loss was a predictor of greater weight loss in sibutramine treatment, in accordance with prior research.     

Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents

Objective: To characterize a model of atypical antipsychotic drug‐induced obesity and evaluate its mechanism. Research Methods and Procedures: Chronically, olanzapine or clozapine was self‐administered via cookie dough to rodents (Sprague‐Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance. Results: Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting ～24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted. Discussion: A model of olanzapine‐induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug‐induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine‐induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge.     

Lifestyle intervention leading to moderate weight loss normalizes postprandial triacylglycerolemia despite persisting obesity

Obesity is associated with impaired postprandial triacylglycerolemia, an independent risk factor for cardiovascular disease. Given that obesity is hard to treat, efforts should focus on treating its comorbidities. We aimed to investigate whether moderate weight loss normalizes postprandial triacylglycerol (TAG) concentrations, in the absence of the acute effects of negative energy balance. For this purpose, postprandial lipemia was investigated in eight obese but otherwise healthy, sedentary men (age: 41.3 ± 4.1 years, BMI: 36.5 ± 1.6 kg·m(-2)), once before and again after a 10% weight loss followed by ≥4 weeks of weight maintenance, and was compared with that of eight age-matched healthy lean men (BMI: 24.7 ± 0.6 kg·m(-2)). Dietary intervention consisted of reduced carbohydrate and saturated fat intake and increased monounsaturated fat intake. Obese volunteers were advised to increase physical activity using pedometers to record daily activity. Postprandial triacylglycerolemia after weight loss was reduced by 27-46% (P < 0.05), and became similar to that of lean men despite persisting obesity (BMI after weight loss: 32.9 ± 1.5 kg·m(-2)). Reduction in postprandial TAG responses was inversely correlated with the decrease in postprandial insulin sensitivity index (ISI) after weight loss (r = -0.714, P = 0.047). We conclude that moderate weight loss induced by a low-carbohydrate and saturated fat diet and a slight increase in daily physical activity normalizes postprandial triacylglycerolemia in obese men, independently of acute diet-induced negative energy balance, and possibly through enhancement of insulin action.     

Anti-obesity effect of SR141716, a CB1 receptor antagonist,in diet-induced obese mice

Because the CB1 receptor antagonist SR141716 was previously reported to modulate food intake in rodents, we studied its efficacy in reducing obesity in a diet-induced obesity (DIO) model widely used for research on the human obesity syndrome. During a 5-wk treatment, SR141716 (10 mg. kg(-1). day(-1) orally) induced a transient reduction of food intake (-48% on week 1) and a marked but sustained reduction of body weight (-20%) and adiposity (-50%) of DIO mice. Furthermore, SR141716 corrected the insulin resistance and lowered plasma leptin, insulin, and free fatty acid levels. Most of these effects were present, but less pronounced at 3 mg. kg(-1). day(-1). In addition to its hypophagic action, SR141716 may influence metabolic processes as the body weight loss of SR141716-treated mice was significantly higher during 24-h fasting compared with vehicle-treated animals, and when a 3-day treatment was compared with a pair feeding. SR141716 had no effect in CB1 receptor knockout mice, which confirmed the implication of CB1 receptors in the activity of the compound. These findings suggest that SR141716 has a potential as a novel anti-obesity treatment.     

Relationship of Co-Morbidities of Obesity to Weight Loss and Four-Year Weight Maintenance/Rebound

This study examined the effect of weight loss (separate from energy restriction) and weight maintenance/rebound over time on blood pressure, serum lipids, and body composition in 24 obese (mean 137% ideal body weight (IEW)) females with mild to moderate hypertension. Weight loss was induced under tightly controlled General Clinical Research Center conditions until each subject had lost at least 10 kg (mean 13 kg) and attained normal body weight (<120% IBW). After 4 years subjects returned for repeat evaluation. Weight changes were compared with 24 pair-matched normal weight controls who were also followed for 4 years. With weight loss, significant improvements were seen in standing mean arterial pressure (MAP), serum total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Subjects regained 11 kg (87% of the weight lost) over the 4 year follow-up period while control subjects gained only 2 kg. Subjects who chose self-selected exercise gained less weight than nonexercisers (6 kg vs. 13 kg, P<0.05). With weight regain there were significant increases in standing and supine MAP, total cholesterol, and high-density lipoprotein (HDL) cholesterol. The amount of weight regained was significantly correlated with standing MAP (r=0.73), triglycerides (r=0.43), and HDL cholesterol (r=-0.47). The percentage fat of the weight regained was no greater than that of the weight previously lost. Weight loss, distinct from energy restriction, was associated with improvements in blood pressure and serum lipid levels. The ability to sustain these improvements in the co-morbidities of obesity was directly related to the persistence and magnitude of weight loss maintenance.     

Gastric Pacing for Morbid Obesity: Plasma Levels of Gastrointestinal Peptides and Leptin

Objective: A gastric pacemaker has been developed to treat morbid obesity. Patients experience increased satiety, the ability to reduce food intake, and a resultant weight loss. However, the mechanism behind the changed eating behavior in paced patients is still under investigation. Research Methods and Procedures: This study was performed on 11 morbidly obese patients (mean BMI, 46.0 kg/m²) treated with gastric pacing. The peripheral blood levels of satiety signals of cholecystokinin (CCK), somatostatin, glucagon‐like peptide‐1 (GLP‐1), and leptin were studied 1 month before gastric pacer implantation, 1 month after implantation, and 6 months after activation of electrical stimulation. Blood samples were drawn 12 hours after fasting and in response to a hypocaloric meal (270 kcal). Patients were followed monthly for vital signs and weight level. Results: Gastric pacing resulted in a significant weight loss of a mean of 10.4 kg (4.4 BMI units). No negative side effects or complications were observed during the treatment. After activation of the pacemaker, meal‐related response of CCK and somatostatin and basal levels of GLP‐1 and leptin were significantly reduced (p < 0.05) compared with the tests before gastric pacing. The weight loss correlated significantly with a decrease of leptin levels (R = 0.79, p < 0.01). Discussion: Gastric pacing is a novel and promising therapy for morbid obesity. Activation of the gastric pacer was associated with a decrease in plasma levels of CCK, somatostatin, GLP‐1, and leptin. More studies are necessary to elucidate the correlations between satiety, weight loss, and digestive neuro‐hormone changes.     

Amount of Food Group Variety Consumed in the Diet and Long‐Term Weight Loss Maintenance

Objective: Decreases in variety of foods consumed within high‐fat‐dense food groups and increases in variety of foods consumed within low‐fat‐dense food groups are associated with lower energy intake and greater weight loss during obesity treatment and may assist with weight loss maintenance. This study examined food group variety in 2237 weight loss maintainers in the National Weight Control Registry, who had lost 32.2 ± 18.0 kg (70.9 ± 39.5 lbs) and maintained a weight loss of at least 13.6 kg (30 lbs) for 6.1 ± 7.7 years. Research Methods and Procedures: At entry into the registry, registry members completed a food frequency questionnaire from which amount of variety consumed from different food groups was assessed. To provide a context for interpreting the level of variety occurring in the diet of registry participants, food group variety was compared between registry participants and 96 individuals who had recently participated in a behavioral weight loss program and had lost at least 7% of initial body weight. Results: Registry members reported consuming a diet with very low variety in all food groups, especially in those food groups higher in fat density. Registry participants consumed significantly (p < 0.001) less variety within all food groups, except fruit and combination foods, than recent weight losers after 6 months of weight loss treatment. Discussion: These results suggest that successful weight loss maintainers consume a diet with limited variety in all food groups. Restricting variety within all food groups may help with consuming a low‐energy diet and maintaining long‐term weight loss.     

Enhanced metabolic efficiency contributes to weight regain after weight loss in obesity-prone rats

Metabolic adjustments occur with weight loss that may contribute to a high rate of weight regain. We have previously observed in obesity-prone, obese rats that weight reduction is accompanied by a suppression in resting metabolic rate beyond what would be predicted for the change in metabolic mass. In the present study, we examine if this adjustment in metabolic efficiency is affected by the length of time in weight maintenance and if it contributes to the propensity to regain after weight loss. Twenty-four-hour, nonresting, and resting energy expenditure (REE) were obtained by indirect calorimetry and normalized to metabolic mass estimated by dual-energy X-ray absorptiometry. A 10% loss in body weight in weight-reduced rats was accompanied by a 15% suppression in adjusted REE. This enhancement in metabolic efficiency was not altered with either 8 or 16 wk of weight maintenance, but it did resolve when the forced control of intake was removed and the weight was regained. The rate of weight regain increased with the time in weight maintenance and was exceptionally high early during the relapse period. During this high rate of weight gain, the suppression in REE persists while consumption increases to a level that is higher than when they were obese. In summary, an enhanced metabolic efficiency and an elevated appetite both contribute (60% and 40%, respectively) to a large potential energy imbalance that, when the forcible control of energy intake is relieved, becomes actualized and results in an exceptionally high rate of weight regain.     

Pharmacological actions of the peptide hormone amylin in the long-term regulation of food intake, food preference, and body weight

The ability of amylin to reduce acute food intake in rodents is well established. Longer-term administration in rats (up to 24 days) shows a concomitant reduction in body weight, suggesting energy intake plays a significant role in mediating amylin-induced weight loss. The current set of experiments further explores the long-term effects of amylin (4-11 wk) on food preference, energy expenditure, and body weight and composition. Furthermore, we describe the acute effect of amylin on locomotor activity and kaolin consumption to test for possible nonhomeostatic mechanisms that could affect food intake. Four-week subcutaneous amylin infusion of high-fat fed rats (3-300 microg.kg(-1).day(-1)) dose dependently reduced food intake and body weight gain (ED(50) for body weight gain = 16.5 microg.kg(-1).day(-1)). The effect of amylin on body weight gain was durable for up to 11 wks and was associated with a specific loss of fat mass and increased metabolic rate. The body weight of rats withdrawn from amylin (100 microg.kg(-1).day(-1)) after 4 wks of infusion returned to control levels 2 wks after treatment cessation, but did not rebound above control levels. When self-selecting calories from a low- or high-fat diet during 11 wks of infusion, amylin-treated rats (300 microg.kg(-1).day(-1)) consistently chose a larger percentage of calories from the low-fat diet vs. controls. Amylin acutely had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. These results demonstrate pharmacological actions of amylin in long-term body weight regulation in part through appetitive-related mechanisms and possibly via changes in food preference and energy expenditure.     

Roux‐en‐Y Gastric Bypass Enhances Energy Expenditure and Extends Lifespan in Diet‐induced Obese Rats

Gastrointestinal weight‐loss surgery (GIWLS) is currently the most effective treatment for severe obesity, with Roux en‐Y gastric bypass (RYGB) among the best of the available surgical options. Despite its widespread clinical use, the mechanisms by which RYGB induces its profound weight loss remain largely unknown. This procedure effects weight loss by altering the physiology of weight regulation and eating behavior rather than by simple mechanical restriction and/or malabsorption as previously thought. To study how RYGB affects the physiology of energy balance, we developed a rat model of this procedure. In this report, we demonstrate that RYGB in diet‐induced obese (DIO) rats induces a 25% weight loss, prolongs mean survival by 45%, and normalizes glucose homeostasis and lipid metabolism. RYGB induced a 19% increase in total and a 31% increase in resting energy expenditure (REE). These effects, along with a 17% decrease in food intake and a 4% decrease in nutrient absorption account for the normalization of body weight after this procedure. These effects indicate that surgery acts by altering the physiology of weight regulation and help to explain the effectiveness of RYGB in comparison to restrictive dieting and other forms of dietary and pharmacological therapies for obesity. The clinical effectiveness of RYGB and its physiological effects on body weight regulation and energy expenditure (EE) suggest that this operation provides a unique opportunity to explore the mechanisms of energy homeostasis and to identify novel therapies for obesity and related metabolic diseases.     

Liraglutide, a once-daily human glucagon-like peptide-1 analog, minimizes food intake in severely obese minipigs

Objectives: To evaluate the efficacy of liraglutide, a new, stable, once‐daily human analog of glucagon‐like peptide‐1, in a new animal model of obesity. Research Methods and Procedures: Liraglutide was administered subcutaneously once daily (7 μg/kg for 7 weeks) to six female obese Göttingen minipigs. Food intake and feeding patterns were monitored using a novel automated feeding system that allowed continuous recording of food intake. Results: Food intake was strongly suppressed. A steady‐state level of reduced food intake was achieved within 3 weeks and was maintained for the remaining 4 weeks of the treatment period. During the 4‐week steady‐state period with liraglutide treatment, daily food intake was 7.3 ± 0.3 megajoule (MJ) compared with 18.4 ± 0.6 MJ in the pre‐treatment period and 19.2 ± 0.5 MJ in the post‐treatment period (p < 0.001). The food intake in the treatment period was equivalent to the amount of food that would have been offered to normal‐weight pigs for maintenance. Body weight decreased 4.3 ± 1.2 kg (4% to 5%) during the 7 weeks of treatment and increased 7.0 ± 1.0 kg during the 7 weeks of post‐treatment (p < 0.01). Appetite suppression was quickly reversed within 4 days after termination of liraglutide administration. Discussion: Overall, liraglutide was well tolerated and had a profound and persistent anorectic effect that resulted in weight loss. These results, in conjunction with the previously established glucose‐lowering efficacy of liraglutide, suggest that the anorectic actions of liraglutide will be very important in clinical trials of both obese patients with type 2 diabetes and obese non‐diabetic patients.     

Comparative effects of the long-acting GLP-1 receptor ligands, liraglutide and exendin-4, on food intake and body weight suppression in rats

The glucagon-like-peptide-1 receptor (GLP-1R) agonists, liraglutide (Victoza) and the synthetic product of exendin-4 (Byetta), are approved for type II diabetes mellitus (T2DM) treatment and may be efficacious in obesity treatment as well, in part, due to the drugs' resistance to enzymatic degradation and prolonged half-life relative to endogenous GLP-1. To address the need to directly compare the food intake- and body weight-suppressive effects of these two GLP-1R ligands, acute and chronic dosing experiments were performed. Once-daily (q.d.) exendin-4 (0, 0.33, 1.5, and 3.0 μg/kg) and liraglutide (0, 50, 100, and 300 μg/kg, q.d.) both reduced the chow intake in nonobese rats in a dose-dependent fashion following either intraperitoneal (IP) or subcutaneous (SC) administration, whereas only liraglutide reduced 24 and 48 h body weight in nonobese, chow-maintained rats. Chow intake and body weight suppression by liraglutide were of greater magnitude and shorter latency following IP compared to SC delivery, whereas for exendin-4, the magnitude of intake-suppression was similar for IP and SC administration. The effects of chronic delivery (7 consecutive days; IP) of liraglutide (25 and 50 μg/kg; q.d.) and exendin-4 (3 μg/kg; q.d. and twice-daily (b.i.d.)) on food intake and body weight were also examined in diet-induced obese (DIO) rats. Liraglutide (50 μg/kg q.d.) and exendin-4 (3 μg/kg b.i.d.) were comparable in suppressing overall high fat/sucrose diet (HFS; 60% kcal from fat) intake. Both drugs regimens yielded marked weight loss over the 7-day period. The weight loss effect of liraglutide was achieved in the first 2 days and remained stable for the duration of the experiment; weight loss with exendin-4 appeared more linear over the 7-day period. In conclusion, administration of the GLP-1R ligands, exendin-4 (b.i.d.) and liraglutide (q.d.), lead to comparable and pronounced suppression of food intake and body weight in DIO rats, suggesting a potential role for these drugs as a clinical tool for obesity treatment.     

Feeding and temperature responses to intravenous leptin infusion are differential predictors of obesity in rats

Obesity is frequently associated with leptin resistance. The present study investigated whether leptin resistance in rats is present before obesity develops, and thus could underlie obesity induced by 16 wk exposure to a liquid, palatable, high-energy diet (HED). Before HED exposure, male Wistar rats (weighing between 330 and 360 g) received intravenous infusions of 20 microg leptin 2 h before dark (approximately 57 microg/kg rat). Relative to saline infusion, this caused a highly variable effect on food intake (ranging between -94 and +129%), with food intake suppression that appeared negatively correlated with HED-induced increases in body weight gain, caloric intake, adiposity, and plasma leptin levels. In contrast, leptin's thermogenic response was positively correlated to body weight gain linked to weights of viscera, but not to adiposity. Before HED exposure, leptin unexpectedly increased food intake in some rats (fi+, n = 8), whereas others displayed the normal reduction in food intake (fi-, n = 7). HED-exposed fi+ rats had higher plasma leptin levels, retroperitoneal fat pad weight, HED intake, and body weight gain than fi- and chow-fed rats. These parameters were also higher in HED-exposed fi-rats relative to chow rats, except for plasma leptin concentrations. It is concluded that leptin's reduced efficacy to suppress food intake could predict obesity on an HED. An unexpected orexigenic effect of leptin might potentially contribute to this as well.