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.     

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.     

Effects of dietary carbohydrate and phenotype on adipose cellularity in female SHR/N-cp rats.

1. Adipose mass and cellularity were studied in congenic female SHR/N-cp rats fed iosenergetic diets containing 54% carbohydrate as sucrose (SU) or cooked cornstarch (CS), 20% protein, 16% mixed dietary fat plus vitamins, minerals, and non-nutritive fiber ad libitum from 5 weeks until 8.5 months of age. Measures of adipocyte lipid content, cell number per depot, and mass of principal white (WAT) and interscapular brown (IBAT) adipoe tissue depots were determined at the end of the study. 2. Final body weights (BW) of corpulent rats were more than twice those for their lean littermates, and were greater when fed the SU than the CS diet in both phenotypes. Phenotype effects (corpulent greater than lean) were present for fat pad weight, adipocyte number, and adipocyte lipid content in the dorsal (DOR) and retroperitoneal (RP) WAT depots. Diet effects were present for depot weight, adipocyte number, and adipocyte lipid content in both WAT depots, and were of qualitatively similar magnitude in both phenotypes. 3. IBAT weights, IBAT:BW ratios, and IBAT cell number of corpulent greater than lean, and were greater than with SU than CS diet in both phenotypes. 4. These results indicate that obesity in the corpulent phenotype of the SHR/N-cp rat occurs as the result of hypertrophy and hyperplasia of white adipose tissue, and that isoenergetic substitution of simple for complex carbohydrate resulted in greater fat accretion in both phenotypes. The greater diet and phenotype-associated adiposity occurred despite greater mass and cellularity of BAT. The results also indicate that sexual dimorphism occurs regarding effects of diet and phenotype on expression of adipose tissue development in this strain.     

Effects of diet and phenotype on adipose cellularity and 5'-deiodinase activity of liver and brown adipose tissue of diabetic SHR/N-cp rats.

1. Groups of lean and obese male SHR/N-cp rats were fed isoenergetic diets containing 54% carbohydrate as cornstarch (CS) or sucrose (SU) plus other nutrients from 5 weeks of age, and measures of adiposity, thyroxine 5' deiodinase (T4-5'DI) activity, and tissue and plasma triiodothyronine (T3) content determined at 9.5 months of age. 2. Body weights (BW) of obese greater than lean, and were greater when fed the SU than CS diet in both phenotypes. Phenotype effects (obese greater than lean) were present for fat pad weights and adipose cellularity in most primary adipose tissue depots, and diet effects (SU greater than CS) were present for epididymal and retroperitoneal depots in both phenotypes. 3. Interscapular brown adipose tissue (IBAT) and IBAT:BW ratios of obese greater than lean, and diet effects (SU greater than CS) were present for lean but not obese rats. Liver T4-5'DI activity and plasma and tissue T3 of lean greater than obese, while IBAT 5'DI activity of obese greater than lean in the CS diet. 4. These results indicate that obesity occurs in the SHR/N-cp rat as the result of hypertrophy and hyperplasia of adipose tissue, and that isoenergetic substitution of simple for complex carbohydrate exaggerates fat accretion in lean but not obese rats. Moreover, the obesity occurs in spite of greater mass, cellularity, and T4-5'DI activity of IBAT, consistent with a thermogenic defect in the obese phenotype of this strain.     

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.     

Plasma lipids and other factors in the LA/N corpulent rat in the presence of chronic exercise and food restriction

The effects of regular exercise and food restriction were studied in the LA/N corpulent rat up to age 9 months. This congenic strain of the Lister and Albany rat is normotensive, corpulent, and hyperlipidemic when homozygous for the corpulent (cp) gene derived from the Koletsky strain. Food restriction of corpulent animals to the intake of matched lean rats caused body weight to be significantly lower, although not as low as that of the lean animals. Plasma total cholesterol in freely eating sedentary corpulent animals was significantly higher (210 mg/100 mL) than in food-restricted rats (165 mg/100 mL), in which plasma cholesterol was considerably elevated compared with lean rats (80 mg/100 mL). Exercise caused a modest but significant increase in both total and high density lipoprotein cholesterol in both corpulent and lean rats. The rise was greater in corpulent rats and, in food-restricted exercising corpulent rats, the cholesterol concentrations were equivalent to those of freely eating corpulent animals. Systolic blood pressure in lean rats fell slowly from 146 mmHg at 8 weeks to 132 mmHg at 36 weeks and was not affected by exercise. Sedentary corpulent rats showed a rapid rise in systolic pressure from 107 mmHg at 7 weeks to 128 mmHg at 11 weeks. This rise was reduced by food restriction and completely prevented by the combination of food restriction and exercise. Thus, in this strain of rats exercise was associated with higher plasma cholesterol concentrations, while food restriction had limited effects.     

Non-shivering thermogenesis and obesity in adult diabetic Wistar fatty rats

1. Characteristics of resting and of norepinephrine (NE)-stimulated thermogenesis, and the glycemic response to NE were determined in adult male Wistar Fatty rats. Rats were maintained on Purina chow No. 5001 until 22 weeks of age, and fed semisynthetic diets containing 54% carbohydrate, 20% protein, 16% mixed fats, plus essential vitamins, minerals, and non-nutritive fiber from 22 until 30 weeks of age. 2. Obese rats were 50% heavier than lean throughout the study. Phenotype effects (obese greater than lean) were present for retroperitoneal (RP) and dorsal (DOR) white fat depot weight, adipocyte number per depot, and adipocyte lipid content. Epididymal mass and cellularity were similar in both phenotypes. 3. Interscapular brown adipose tissue (IBAT) mass, adipocyte size, and adipocyte number were greater in obese than in lean. Resting metabolic rates (RMR) of obese rats were lower than in lean, and increased 79% in lean but only 33% in obese animals following NE (200 micrograms/kg BW, s.c.) stimulation. 4. The glycemic response to NE occurred normally in both phenotypes, and resulted in a 3-fold increment in plasma glucose in lean rats and a 5-6-fold increase in plasma glucose in obese rats. 5. The results of this study are consistent with hyperplasia and hypertrophy of IBAT, RP and DOR depots, and indicate that the capacity for non-shivering thermogenesis is impaired in the obese phenotype of this strain in spite of peripheral sensitivity to NE and greater mass and cellularity of brown adipose tissue.     

The effects of norepinephrine and nutritional status on resting metabolic rates in the LA/N-cp rat

1. The effects of diet and norepinephrine (NE) on resting metabolic rate (RMR) were determined using indirect calorimetry in 6-month-old lean and corpulent LA/N-cp rats. RMRs of lean rats were greater than the corpulent. 2. Ingestion of carbohydrate (CHO) in the unfasted and fasted states increased the RMR of both groups, especially in the lean phenotype when compared to oil. 3. Serum T3 and glucose concentrations were similar in both phenotypes. 4. The effects of NE on RMR were maximal after a 200 micrograms NE/kg body weight injections.     

The effects of the intestinal glucosidase inhibitor acarbose on cholesterogenesis in corpulent rats.

1. Groups of lean and obese LA/N-cp and obese Type II diabetic SHR/N-cp rats were fed semisynthetic diets with or without the alpha-glucosidase inhibitor acarbose (ACB, 100 mg/kg diet, p.o.) from 8 until 15 weeks of age, and measures of fasting serum total cholesterol (TC), insulin (INS), and hepatic HMG-CoA synthase activity determined at the end of the study. 2. ACB was without marked effect on mean food intake in either strain or either phenotype, and resulted in less weight gain and decreased adipose mass in obese LA/N-cp rats. INS was greater in the obese than the lean phenotype of both strains, and ACB resulted in greater reductions in INS in obese LA/N-cp than in obese LA/N-cp rats. 3. Serum TC concentrations were greater in the obese than in the lean phenotype of both strains, and ACB resulted in decreases in TC in both strains and in lower beta:alpha lipoprotein cholesterol ratios in obese LA/N-cp rats. Liver HMG Co-A synthase activity was greater in lean than obese rats and ACB resulted in normalization of enzyme activity in obese LA/N-cp but not SHR/N-cp rats. 4. These results confirm the hypercholesterolemia which occurs in the obese phenotype of the corpulent rat strains, and indicates that ACB may bring about significant reductions in body weight and fatness, TC, and in improved beta:alpha lipoprotein ratios and HMG-CoA synthase activity in obesity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diazoxide down-regulates leptin and lipid metabolizing enzymes in adipose tissue of Zucker rats.

We have previously reported that attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, increased insulin sensitivity and reduced body weight in obese Zucker rats. These findings prompted us to investigate the effects of DZ on key insulin-sensitive enzymes regulating adipose tissue metabolism, fatty acid synthase (FAS), and lipoprotein lipase (LPL), as well as on circulating levels of leptin. We also determined the direct effects of diazoxide on FAS in 3T3-L1 adipocytes. Seven-week-old female obese and lean Zucker rats were treated with DZ (150 mg/kg/d) or vehicle (C, control) for a period of 6 wk. Changes in plasma parameters by DZ include significant decreases in triglycerides, free fatty acids, glucose, and insulin, consistent with our previous reports. DZ obese rats exhibited lower plasma leptin levels (P<0.03) compared to their C animals. DZ significantly reduced adipose tissue FAS activity in both lean (P<0.0001) and obese (P<0.01) animals. LPL mRNA content was also decreased significantly in DZ-treated obese animals (P<0.009) as compared to their respective controls without a significant effect on lean animals. The possibility that DZ exerted a direct effect on adipocytes was further tested in cultured 3T3-L1 adipocytes. Although diazoxide (5 microM) alone did not change FAS activity in cultured 3T3-L1 adipocytes, it significantly attenuated insulin's effect on FAS activity (P<0.001). We demonstrate that DZ regulates key insulin-sensitive enzymes involved in regulation of adipose tissue metabolism. These findings suggest that modification of insulin-sensitive pathways can be therapeutically beneficial in obesity management.     

Reduction of enhanced mammary carcinogenesis in LA/N-cp (corpulent) rats by energy restriction

Restriction of energy intake significantly reduces mammary tumorigenesis in normal rats exposed to carcinogens. Genetically obese LA/N-cp (corpulent) female rats were given 7,12-dimethylbenz[a]anthracene and fed purified diets ad libitum or restricted to 60% of the ad libitum caloric intake. Phenotypically lean littermates were also fed ad libitum. Obese animals developed large mammary tumors more rapidly than genetically normal rats so that 100% of the animals had tumors in less than 16 weeks. Only 21% of the lean animals developed tumors; the energy restricted obese animals had a tumor incidence of 27%. Although obese rats fed the restricted diet weighed significantly less than those fed ad libitum, percent body fat was not reduced, indicating that lean tissue was affected more. Obese animals were markedly hyperinsulinemic (1003 +/- 193 microunits/ml) and energy restriction reduced this to 328 +/- 41; the lean animals had insulin levels of 12 +/- 2. Tumor-bearing rats had higher insulin levels than rats without tumors. These data suggest that body fatness is not directly associated with risk of carcinogenesis. Lean body mass, adipose tissue mass, and their interaction with insulin in its capacity as a growth factor rather than body fatness per se may be determinants of tumor promotion.     

Effect of dietary carbohydrates on insulin and glucagon receptors in a new model of noninsulin-dependent diabetes-SHR/N-corpulent rat

A new congenic strain of rat, the SHR/N-corpulent, provides a good model for noninsulin-dependent diabetes and was used in the present study. Corpulent rats as compared to their lean littermates are obese, hyperlipidemic, and severely hyperinsulinemic, and show an age-dependent loss of glucose tolerance. Mild fasting hyperglycemia is seen only in corpulent rats fed sucrose. Since dietary sucrose is more lipogenic than starch and since insulin and glucagon are involved in lipid and carbohydrate metabolism, we studied the effect of the type of dietary carbohydrate on insulin and glucagon levels and their receptors in lean and corpulent SHR/N rats. A significant phenotypic effect was observed (corpulent greater than lean) on plasma levels of triglyceride, cholesterol, and insulin. Dietary sucrose increased these parameters in corpulent rats but not in lean rats. Insulin and glucagon binding to liver plasma membranes was lower in corpulent rats than in lean; decreases were due to fewer receptors without a significant change in affinity. Thus, in corpulent rats, in addition to hyperinsulinemia, fewer glucagon receptors and their failure to be regulated by plasma glucagon levels appear to contribute to the hyperlipidemia. Furthermore, the hyperglycemia observed in sucrose-fed corpulent rats may be due to extreme resistance to insulin despite lower plasma glucagon and fewer glucagon receptors.     

Effect of age on serum lipids and lipoproteins of male and female JCR:LA-corpulent rats

The JCR:LA-cp rat is a strain incorporating the corpulent (cp) gene. When homozygous for the cp gene, the rats are hyperphagous, hyperinsulinemic, hyperlipidemic and obese. The corpulent male rats develop atherosclerotic and myocardial lesions from an early age, while corpulent female and lean rats do not develop lesions. The hyperlipidemia is due to elevated levels of VLDL resulting in moderately raised cholesterol levels and markedly elevated triacylglycerol levels. The VLDL concentrations are similar in corpulent male and female rats at an early age with both having much higher levels than lean rats. As the animals age, the VLDL hyperlipidemia in the corpulent male increases at 3 months and then decreases slowly and rises again at 12 months of age. The corpulent female rats show higher triacylglycerol and phospholipid concentrations than the males at 3 months age and reach values over 1000 mg/100 ml by 9 months of age, then decrease at 12 months of age. The cholesterol concentrations of the corpulent females are greater than those of the males from 9 months of age. Thus, in the period of life up to middle age, the cardiovascular disease incidence does not correlate with the degree of hyperlipidemia. The disease progression does correlate with the severity of insulin resistance and glucose intolerance, which is more severe in the corpulent male than female rats. The results suggest that the hyperlipidemia must be a necessary condition for development of atherosclerotic disease in this strain of rats, but it is not a sufficient condition.     

Nonreceptor-mediated responses of adenylate cyclase in membranes from liver, muscle, and white and brown adipose tissue of obese (fa/fa) and lean (Fa/) Zucker rats

Adenylate cyclase activity was determined in membranes of liver, muscle, white adipose tissue, and brown adipose tissue (BAT) of lean (Fa/) and obese (fa/fa) Zucker rats. Responses were monitored following beta-adrenergic receptor stimulation and addition of GTP, GTP gamma S, or forskolin. beta-Adrenergic responses in liver, white adipose tissue, and BAT were lower in obese than in lean animals. No such difference was observed in muscle membranes. Production of cAMP after addition of guanine nucleotides was lower in liver and white adipose tissue membranes from obese rats compared with their lean littermates. Synthesis of cAMP in muscle membranes of obese animals after addition of GTP was either not different, or slightly higher, than that observed in muscle membranes from lean animals. Furthermore, production of cAMP after forskolin addition to muscle membranes of obese rats was significantly higher than that observed from lean rats under the same conditions. Interestingly, BAT membranes of obese rats were significantly more sensitive to guanine nucleotide activation than those of lean animals. The results confirm recent findings indicating inferior function of G proteins in liver plasma membranes of obese Zucker rats, and extend this observation to adipose tissue. The present results further suggest that the "nonreceptor" components (e.g., G proteins) responsible for the activation of adenylate cyclase in BAT membranes of obese rats are more responsive to stimulation than those of lean animals. Such sensitivity may be related to and perhaps compensate for the reduced thermogenic activity in the obese Zucker rat during the development of obesity.     

Evidence for a high fatty acid synthesis activity in interscapular brown adipose tissue of genetically obese Zucker rats.

Obese (fa/fa) rats (30 days old) exhibited a 50% increase in the weight of interscapular brown adipose tissue compared with their lean (Fa/fa) littermates. The tissue weight increase was accounted for by an increased fat content. Lipogenesis in vivo, as assessed by the incorporation of 3H from 3H2O into lipid, was increased 5-fold in brown adipose tissue of obese as compared with lean rats. Accordingly, acetyl-CoA carboxylase, fatty acid synthetase, citrate-cleavage enzyme and malic enzyme in this tissue were 4-8 times more active in obese than in lean rats.     

Radioglucose metabolism by richardson's ground squirrels in the weight-gain and weight-loss phases of the circannual cycle

Summary Captive fed, starved, and refed Richardson's ground squirrels in the weight-gain and weight-loss phases of the circannual cycle were injected with radioglucose and the activity of the label in skeletal muscle proteins and white adipose tissue lipids four hours after injection was used to determine if lean body mass and white adipose tissue would be rapidly restored when starved animals were refed. Starvation for six days reduced carcass mass 27–31% and white adipose tissue mass 23–24% (Table 1). Activity of the label in both tissues of weight-gain and weight-loss animals was reduced by starvation. After four days of refeeding activities retured to levels similar to those in fed animals, with the exception of lower activity in skeletal muscle proteins of weight-gain animals. Furthermore, activity in each tissue fraction of starved and refed weight-gain animals was similar to that in weight-loss animals when expressed as per cent of activity in the respective fed state (Table 2). Radioglucose incorporation indicated that when skeletal muscle and adipose tissue are depleted by starvation, distribution of the label upon refeeding is similar to that in the fed state. Four days after refeeding weight-gain phase ground squirrels had restored 5.5 g of lean body mass and 7.5 g of adipose tissue, including 1.4 g (6 kcal) of protein and 7.0 g (66 kcal) of lipid, respectively. These results are also consistent with the fed state, in which weight-gain animals were depositing more lipid than lean body mass.     

Hepatic and adipose tissue lipogenesis as related to age and thyroid status in the rat

We have previously reported that, in the rat, chronic thyroxine (T4) treatment induced a transient adipose tissue hyperplasia and that, in preadipocytes cultures, lipogenesis as well as adipose conversion were enhanced by triiodothyronine. Therefore we looked for the possibility of a relationship between in vivo stimulation of adipose tissue lipogenesis and the stimulation of fat cell recruitment by thyroid hormones. Hepatic and adipose tissue de novo lipogenesis were estimated by the incorporation of 3H2O into lipids in rats of various ages made slightly hyperthyroid by daily injections of T4 (0.2 microgram/g/day) from birth. Hepatic and adipose tissue lipogenesis were increased at 3 and 6 weeks of age, no stimulation being observed when animals get older. 21 week-old animals were therefore acutely treated with 0.2 or 2 micrograms T4/g/day. In this case, only the high T4 dose was able to induce a consistent lipogenesis stimulation in liver and in retroperitoneal adipose tissue and failed to induce it in epididymal adipose tissue. These results pointed out that thyroid hormones can stimulate lipogenesis both in liver and adipose tissue. However, there is an age related fall in the sensitivity to thyroid hormones for lipogenesis stimulation, not only in the liver, but also and more pronounced in adipose tissue, in parallel to that observed in vivo for adipose differentiation; moreover, this decreased sensitivity seems to be accelerated by a long lasting hyperthyroidal state.     

Expression of CA III in rodent models of obesity

To achieve a better understanding of the biochemical basis of obesity, we have undertaken comparative analyses of adipose tissue of lean and obese mice. By two-dimensional gel analysis, carbonic anhydrase-III (CA III) has been identified as a major constituent of murine adipose tissue. Quantitative comparisons of CA III protein and mRNA levels indicate that this enzyme is expressed at lower levels in adipose tissue from animals that were either genetically obese or had experimentally induced obesity compared to levels in the corresponding lean controls. This decrease in CA III expression was unique to adipose tissue, since other CA III-containing organs and tissues did not show a change when lean and obese animals were compared. Additionally, levels of CA III in adipose tissue from obese animals responded to acute changes in energy balance of the animal. These results are discussed in light of possible metabolic roles for CA III.     

Adrenalectomy increases norepinephrine turnover in brown adipose tissue of obese (ob/ob) mice

The hyperphagia and rapid body weight gain normally observed in young obese (ob/ob) mice were abolished by removal of their adrenal glands, whereas food intake and weight gain of lean mice were not significantly affected by adrenalectomy. Adrenalectomy lowered body energy density (kcal/g carcass) in obese mice more than could be attributed to reduced food intake per se, suggesting that their energy expenditure was also increased. In control obese mice, low stimulation of brown adipose tissue by the sympathetic nervous system, as indicated by the low fractional rates of norepinephrine (NE) turnover in their brown adipose tissue may have contributed to the reduced energy expenditure in these animals. Adrenalectomy increased the rates of NE turnover in brown adipose tissue of obese mice to rates nearly equal to those observed in lean mice without affecting NE turnover in this tissue of lean mice. Likewise, removal of the adrenals normalized the low rates of NE turnover in hearts of obese mice without affecting lean mice. Rates of NE turnover in two other organs, white adipose tissue and pancreas, of control and adrenalectomized obese mice were similar to rates observed in lean counterparts. The adrenal may thus contribute to both the hyperphagia and the low energy expenditure by brown adipose tissue that together cause gross obesity in ob/ob mice.     

Genetic obesity and dietary sucrose decrease hepatic glucagon and insulin receptors in LA/N-corpulent rats

A catabolic and hypolipemic effect of glucagon has been described in normal animals. We therefore studied the role of glucagon in genetically obese, hyperlipemic rats. Twelve genetically obese hyperlipemic LA/N-cp/cp (corpulent) rats and 12 lean littermates were fed either 54% starch or 54% sucrose for 12 weeks. Plasma glucagon and insulin levels and glucagon and insulin binding to liver membranes were measured. Comparing all corpulent and lean animals regardless of diet, a significant (P less than 0.0001) phenotypical effect (cp/cp greater than lean) was observed in plasma insulin levels (464 +/- 54 vs 70.3 +/- 7.6 muu/ml, mean +/- SEM). Insulin binding (2.68 vs 16.1%/50 micrograms protein) and glucagon binding (25.6 vs 47.3%/50 micrograms protein) were both significantly lower (P less than 0.0001) in corpulent rats as compared to their lean littermates. Sucrose feeding had marginal effect on plasma insulin or insulin binding. It, however, decreased glucagon binding in corpulent rats but not in their controls. A significant negative correlation was observed between plasma insulin and insulin binding, while a positive correlation was seen for plasma glucagon and glucagon binding. A significant negative correlation was observed between plasma glucagon and lipogenic enzymes (glucose-6-phosphate dehydrogenase and malic enzyme) in liver and between glucagon binding and these enzymes. We propose that in these genetically obese rats, in addition to hyperinsulinemia, impaired glucagon activity as manifested by decreased glucagon binding to target cells may be an important contributor to the hyperlipemia and obesity. A further decrease in glucagon binding in rats fed sucrose indicates that sucrose, per se, may be an additional contributory factor.