Orien L. Tulp

Localization of leptin receptor immunoreactivity in the lean and obese Zucker rat brain

Leptin, a product of the obese (ob) gene, is secreted by adipocytes and appears to act as a hormone to regulate food intake, metabolism and body weight. Subcutaneous administration of leptin causes reductions in food intake and body and fat-depot weights in both lean and genetically obese (ob/ob) mice, and leptin infusion into the lateral cerebral ventricles decreases feeding with short latency, suggesting a central site of action. A gene defect in the Zucker obese rat causes an amino acid substitution in the leptin receptor and reduced leptin binding at the cell surface. An antiserum to a portion of the mouse leptin receptor (AA 877-894) located within the intracellular domain was used to label Zucker lean (Fa/?) and obese (fa/fa) rat brain sections. At optimal dilution (1:8000), only cells in the basal forebrain, preoptic area, hypothalamus and brainstem were moderately or intensely labeled. The most intensely-labeled nuclei, the anterior commissural, magnocellular paraventricular, supraoptic, circularis in the anterior hypothalamus and fornical in the lateral hypothalamus contain large neurons that synthesize and secrete vasopressin or oxytocin and their respective neurophysins. Diminished leptin transport into the central nervous system or defective signal transduction in Zucker obese rats may sufficiently compromise leptin regulation of the HPA axis, NPY-immunoreactive neurons or other hypothalamic elements to cause obesity.

Effects of dietary carbohydrate and phenotype on thyroid hormones and brown adipose tissue locularity in adult LA/N-cp rats

1. Groups of lean and corpulent LA/N-cp rats were fed isoenergetic diets containing, 54% carbohydrate as maize starch (MS) or sucrose (SU), 20% protein, 16% mixed fats, plus other essential nutrients and fiber from 1.5-9 months of age. Final body weights of corpulent rats were 2-3 times those of their lean littermates, and were greater with SU than MS diet in both phenotypes. 2. Interscapular brown adipose tissue (IBAT) mass was greater in corpulent than lean and was greater with SU than MS diet in lean but not corpulent rats. IBAT cell diameters and adipocyte volumes were generally similar in both phenotypes, and were not markedly affected by dietary carbohydrate type. 3. Brown adipocyte locularity profiles were qualitatively similar in both phenotypes, and were morphologically indicative of thermogenic activity in both phenotypes. Locule profiles of corpulent animals contained a greater proportion of thermogenically less active types IV and V brown adipocytes than similarly fed lean animals, however, and locule distribution profiles were not influenced by diet. 4. Serum T3 concentrations were similar in both phenotypes, were greater in SU than MS lean rats and were not influenced by diet in the corpulent phenotype. In contrast, serum thyroxine concentrations and percent thyroxine uptake were not influenced by diet or phenotype. 5. These results are consistent with a partial impairment in BAT-mediated thermogenic activity in the corpulent phenotype and suggest that obesity in this strain may be due to factors other than biochemically defective brown adipose tissue thermogenesis.

Thermogenesis in cafeteria-fed LA/N-cp (corpulent) rats

Abstract The capacity for diet-induced thermogenesis was accessed in groups of 20 week-old lean and corpulent LA/N-cp rats to determine if an impairment in adaptive energy expenditure might be associated with their obese state. Initial body weights of the corpulent rats were twice those of the lean genotype, and the rate of weight gain during cafeteria feeding was four times as rapid as occurred in lean rats. Measurements of resting oxygen consumption were similar in both lean and corpulent rats. Isoproterenol stimulation resulted in a marked increase in oxygen consumption in lean but not in corpulent rats. Acute exposure to a 5°C cold environment resulted in significant decreases in colonic and rectal temperatures in both genotypes but body temperatures recovered more rapidly in lean than in corpulent rats. Cafeteria feeding resulted in an improved cold tolerance only in lean rats. These observations are consistent with an impaired mechanism of diet-induced thermogenesis in the corpulent genotype which may contribute to the development of their obesity.

The effect of acarbose on the food intake, weight gain, and adiposity of LA/N-cp rats

1. Groups of lean and obese LA/N-cp rats were administered the intestinal glucosidase inhibitor acarbose at 150 or 300 mg/kg diet from 7 until 17 weeks of age and the effects of the drug on food intake patterns and adiposity determined. 2. Dose related effects on body weights, adiposity and feed efficiency ratio were observed (control greater than 150 mg greater than 300 mg drug/kg diet) following treatment in both phenotypes, with the greatest differences observed in the obese phenotype. 3. Acarbose at both dosages was associated with phenotype-specific alterations in food intake amount and feeding pattern, resulting in an attenuation of age-associated increases in food intake. The feed efficiency ratio decreased in both phenotypes, and approached normally fed lean controls in obese rats administered the greater dosage. 4. These results indicate that patterns of food intake and weight gain differ markedly between lean and obese rats of this strain, and acarbose brings about a dose-related attenuation of developing food intake patterns in both phenotypes and which are associated with decreases in weight gain and adiposity. Thus, this drug may have therapeutic potential as an adjunct agent in the treatment of obesity and/or other disorders of carbohydrate intolerance.

Caffeine and ephedrine stimulated thermogenesis in la-corpulent rats☆

Resting metabolic rate (RMR), as well as caffeine (CAF) and ephedrine (EPH) stimulated thermogenesis (VO2) were measured in young adult corpulent (corp) LA/N-cp (LA-corpulent) rats. RMR of lean was greater than corp. Administration of EPH, CAF and EPH + CAF resulted in 32, 48 and 50% increases in VO2, respectively, in both lean and corp rats. The time to attain maximal VO2 was similar for both drugs in both phenotypes, but the duration of maximal VO2 averaged 50, 26 and 42% longer in corp than lean for EPH, CAF and EPH + CAF, respectively. Acute weight loss following these treatments was greater for corp than lean, and corresponded with the duration of elevated VO2. These results are consistent with a normally functioning end-organ sympathomimetic receptor system in the corp phenotype of the LA/N-cp rat, and suggest that obesity in this model may be caused by factors other than defective brown fat thermogenesis at the end organ level.

Effects of increased energy expenditure on weight gain and adiposity in the LA-corpulent rat

Groups of lean or pre-obese LA/N-cp rats were subjected to a program of vigorous exercise (less than 4 hr/day) or remained sedentary from 6 weeks until 12 weeks of age. Sedentary pre-obese rats gained weight twice as rapidly as sedentary lean rats. Exercise treatment resulted in greater decrements in body wt in obese than in lean rats, but did not result in absolute weight loss in either group. At 12 weeks of age, fat pad weights in principle depots were 10-15 times greater in corpulent than in lean rats and were significantly smaller in the exercised groups of both phenotypes, and corresponded with lower relative adiposity compared to corresponding sedentary groups. Heart weights were greater in corpulent than lean, while gastrocnemius muscle weights were similar in both phenotypes. Exercise was without effect on the weight of either muscle tissue in either phenotype. Interscapular brown adipose tissue weights and the IBAT:BW ratio were greater in obese than in lean rats. IBAT weights were lower in exercised than sedentary rats of either phenotype, but the IBAT:BW ratio was lower only in the obese exercised rats. In sedentary rats, L-alpha-glycerophosphate dehydrogenase and malic enzyme activity were greater in obese than lean, and exercise treatment resulted in increased L-alpha-glycerophosphate dehydrogenase and malic enzyme only in lean rats. These results are consistent with a redistribution of energy expenditure from energy storing to energy dissipating pathways following vigorous exercise, resulting in slowed rates of weight gain and body fat accretion in both lean and obese animals, with the most significant decrements among pre-obese rats.

Impaired activation of thermogenesis in the corpulent rat

The capacity for non-shivering thermogenesis was measured in groups of 12 week-old congenic lean and corpulent LA/N-cp rats of both sexes to determine if their obese state might be associated with an impairment in energy expenditure via non-shivering thermogenesis. Body weights of the corpulent phenotypes were 1.6 to 1.8 times greater than those of the lean phenotype. Measurements of resting oxygen consumption were similar in lean and in corpulent rats, and were greater in female than in male rats. Isoproterenol stimulation resulted in a significant increase in oxygen consumption in lean rats, while the rates of oxygen consumption of isoproterenol-stimulated corpulent rats were unchanged. Acute exposure of male rats to a 5 degrees C cold environment resulted in significant decreases in colonic and in rectal temperature in both phenotypes, but body temperatures recovered more rapidly in lean than in corpulent rats. Urinary VMA excretion was greater in lean than in corpulent rats and increased following cafeteria-feeding in lean but not in corpulent rats. These observations are consistent with an impaired mechanism of sympathetically-mediated thermogenesis in the corpulent phenotype of the LA/N-cp rat, and which may be a contributing factor in the development of their obese state via a decreased capacity for energy expenditure.

The effects of the intestinal glucosidase inhibitor BAY M 1099 (miglitol) on glycemic status of obese-diabetic rats

1. Groups of lean and obese-diabetic (NIDDM) congenic male SHR/Nutl parallel-cp rats were fed a nutritionally adequate, high carbohydrate diet ad libitum with or without the alpha-glucosidase inhibitor miglitol (150 mg/kg diet) from 8 until 15 weeks of age, and key glycemic parameters were monitored throughout the study. 2. Miglitol treatment resulted in clinical improvement toward normal in percent glycosylated hemoglobin, glycemic and insulinogenic responses to an oral glucose tolerance, and in liver glucokinase activity, in concert with modest decreases in weight gain in obese rats. 3. These observations are consistent with improved insulin sensitivity in peripheral tissues following miglitol treatment, and indicate that this drug may be a useful adjunct to diet in the treatment of obesity, NIDDM, and possibly other disorders of carbohydrate metabolism.

The effects of the intestinal glucosidase inhibitor bay m 1099 (Miglitol) on glycemic status of obese rats

Abstract An experimental pharmacological intestinal glucosidase inhibitor, Bay m 1099 (Miglitol), was used to investigate the effects of delayed carbohydrate absorption on parameters of glycemic status in a congenic rat strain that exhibits characteristics of early onset obesity and impaired glucose tolerance (IGT), LA/N-cp (LA-corpulent). Male, lean and obese 8 week old rats were fed diets ad libitum containing 54% sucrose, 20% protein, 16% fat plus other essential nutients with and without Bay m 1099 (15 mg/100g diet) for 7 weeks. Periodic measures of body weight, food intake, glycemic status including daily postprandial glycosuria, and oral glucose tolerance testing (OGTT), and glycosylated hemoglobin content were performed. Drug treatment was without effect on food intake or body weight, but resulted in improvement in several insulin-dependent metabolic parameters indicative of glycemic status including prominent reduction of glycosuria, gradual improvement in fasting insulin levels with partial normalization of OGTT in obese animals, and in lowered % glycosylated hemoglobin content in animals of both phenotypes. These results are consistent with improved insulin sensitivity and post-prandial glycemia following drug treatment, and suggest that Bay m 1099 may be a useful dietary adjunct in the treatment of obesity, type IV hyperlipoproteinemia, and other disorders associated with the insulin resistant state.

Effect of high protein-cafeteria feeding on serum cholesterol and atherogenesis in the corpulent rat

Abstract The effect of experimental overnutrition via high-protein cafeteria feeding on atherogenesis and adiposity were determined in groups of congenic adult lean and corpulent LA/N-cp (corpulent) rats derived from the Koletsky strain, and fed Purina Laboratory Chow or a high-protein cafeteria diet consisting of the Purina Chow plus cooked eggs and red meat for 8 weeks. High protein cafeteria feeding resulted in more marked increases in body weight and adiposity in corpulent than in lean rats. Oral glucose tolerance was similarly impaired in corpulent rats before and after cafeteria feeding. Serum cholesterol concentrations were greater in corpulent than in lean rats initially, and increased 2-fold following the cafeteria feeding. In contrast, HDL cholesterol increased proportionately to the total cholesterol concentrations in cafeteria fed lean but not corpulent rats, resulting in highly significant increases in the VLDL+LDL: HDL and Total: HDL cholesterol ratios in the cafeteria-fed corpulent group. These results indicate that the corpulent phenotype of the LA/N-cp rat strain may be predisposed to atherogenesis in association with an exaggeration of their obesity when fed atherogenic high-animal-protein cafeteria diets for a prolonged period of time.