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We previously observed a rapid reduction in plasma ceruloplasmin activity in lean Zucker (Fa/Fa) rats fed a marginal copper (Cu)-deficient diet compared to similarly fed obese Zucker (fa/fa) and lean Sprague-Dawley rats. In an effort to understand the mechanisms underlying this response, we utilized the isotope dilution method to investigate the absorption and excretion of Cu in lean Zucker rats fed control and marginal Cu diet. Sprague-Dawley (SD) and homozygous lean Zucker rats were fed either a Cu-adequate (Cont; 7.5 micrograms Cu/g diet) or a low Cu (Low; 1.1 micrograms Cu/g diet) casein-based diet for 23 d. Two weeks following initiation of the dietary treatment, each rat was injected intramuscularly (im) with 11.2 microCi of 67Cu. Urine and feces were collected daily. On the 9th d following isotope injection, rats were killed and tissues collected. Significant dietary effects were observed in the relative absorption and endogenous fecal excretion of 67Cu. The tissue distributions of nonisotopic Cu and 67Cu activity were also different between dietary treatments. Tissues from rats fed the low-Cu diet typically had high concentrations of 67Cu and low concentrations of nonisotopic Cu compared to controls. An increase in relative 67Cu absorption was evident for rats fed the low-Cu diet (57.2 and 39.3%, for SD Low, Zucker Low, respectively, and 17.9, and 28.5% SD Cont and Zucker Cont, respectively). Rats fed the low-Cu diet also had reductions in endogenous fecal excretion of 67Cu compared to their respective controls. Although strain effects were not evident for either percent Cu absorption or endogenous fecal Cu excretion, the relative adaptive changes appeared more marked for the Sprague-Dawley rats compared to the lean Zucker rats.

The United States is experiencing an epidemic of obesity among both adults and children. Approximately 35 percent of women and 31 percent of men age 20 and older are considered obese, as are about one-quarter of children and adolescents. While government health goals for the year 2000 call for no more than 20 percent of adults and 15 percent of adolescents to be obese, the prevalence of this often disabling disease is increasing rather than decreasing. Obesity, of course, is not increasing because people are consciously trying to gain weight. In fact, tens of millions of people in this country are dieting at any one time; they and many others are struggling to manage their weight to improve their appearance, feel better, and be healthier. Many programs and services exist to help individuals achieve weight control. But the limited studies paint a grim picture: those who complete weight-loss programs lose approximately 10 percent of their body weight, only to regain two-thirds of it back within 1 year and almost all of it back within 5 years. These figures point to the fact that obesity is one of the most pervasive public health problems in this country, a complex, multifactorial disease of appetite regulation and energy metabolism involving genetics, physiology, biochemistry, and the neurosciences, as well as environmental, psychosocial, and cultural factors. Unfortunately, the lay public and health-care providers, as well as insurance companies, often view it simply as a problem of willful misconduct--eating too much and exercising too little. Obesity is a remarkable disease in terms of the effort required by an individual for its management and the extent of discrimination its victims suffer. While people often wish to lose weight for the sake of their appearance, public health concerns about obesity relate to this disease's link to numerous chronic diseases that can lead to premature illness and death. The scientific evidence summarized in Chapter 2 suggests strongly that obese individuals who lose even relatively small amounts of weight are likely to decrease their blood pressure (and thereby the risk of hypertension), reduce abnormally high levels of blood glucose (associated with diabetes), bring blood concentrations of cholesterol and triglycerides (associated with cardiovascular disease) down to more desirable levels, reduce sleep apnea, decrease their risk of osteoarthritis of the weight-bearing joints and depression, and increase self-esteem. In many cases, the obese person who loses weight finds that an accompanying comorbidity is improved, its progression is slowed, or the symptoms disappear. Healthy weights are generally associated with a body mass index (BMI; a measure of whether weight is appropriate for height, measured in kg/m2) of 19-25 in those 19-34 years of age and 21-27 in those 35 years of age and older. Beyond these ranges, health risks increase as BMI increases. Health risks also increase with excess abdominal/visceral fat (as estimated by a waist-hip ratio [WHR] > 1.0 for males and > 0.8 for females), high blood pressure (> 140/90), dyslipidemias (total cholesterol and triglyceride concentrations of > 200 and > 225 mg/dl, respectively), non-insulin-dependent diabetes mellitus, and a family history of premature death due to cardiovascular disease (e.g., parent, grandparent, sibling, uncle, or aunt dying before age 50). Weight loss usually improves the management of obesity-related comorbidities or decreases the risks of their development. The high prevalence of obesity in the United States together with its link to numerous chronic diseases leads to the conclusion that this disease is responsible for a substantial proportion of total health-care costs. We estimate that today's health-care costs of obesity exceed $70 billion per year.(ABSTRACT TRUNCATED AT 400 WORDS)

Glucagon response to insulin-induced hypoglycaemia is impared in diabetes, but the mechanism is not established. Pancreatic A cell hyporesponsiveness to adrenergic or cholinergic stimulation could contribute to the impairment. We therefore compared the plasma glucagon responses to intravenous infusion of adrenaline (1200 ng kg(-1) min(-1) for 20 min) or to intravenous injection of the cholinergic agonist carbachol (50 micrograms kg(-1)) in chloral hydrate-anaesthetized rats made diabetic with the use of streptozotocin (80 mg kg(-1) subcutaneously) 6 weeks before and in anaesthetized control rats. Insulin was infused intravenously to reduce plasma glucose levels to below 1.8 mmol L(-1). As expected, the plasma glucagon response was reduced by approximately 45% in streptozotocin-diabetic rats compared with controls (P = 0.045). During adrenaline infusion, plasma glucagon levels increased by 277 +/- 92 pg mL(-1) in controls (P = 0.009) and by 570 +/- 137 pg mL(-1) in the diabetic rats (P = 0.002). Thus, the plasma glucagon response to adrenaline was approximately doubled in the diabetic rats (P = 0.045). Following carbachol injection, plasma glucagon levels were raised by 1211 +/- 208 pg mL(-1) (P < 0.001) in controls but only by 555 +/- 242 pg mL(-1) in the diabetic rats (P = 0.049). Thus, the plasma glucagon response to carbachol was impared by approximately 58% in the diabetic rats (P = 0.028). We conclude that carbachol-stimulated glucagon secretion is impared concomitantly with the impared glucagon response to hypoglycaemia in streptozotocin-diabetic rats, whereas adrenaline-induced glucagon secretion is exaggerated. We suggest that a reduced pancreatic A cell responsiveness to cholinergic stimulation could contribute to the impairment of the glucagon response to insulin-induced hypoglycaemia in diabetes.

Attenuated regulatory thermogenesis in genetically obese (fa/fa) Zucker rats involves an impaired capacity to increase sympathetic drive to brown adipose tissue in response to dietary stimuli. Young, growing lean rats fed a low protein diet reduce energetic efficiency to compensate for elevated energy intake; however, it is not known if obese rats adapt similarly to chronic protein restriction by decreasing energetic efficiency and whether this would be accompanied by increased brown adipose tissue thermogenic capacity. Lean (Fa/Fa) and obese Zucker rats were either protein-restricted (protein 8% of total energy) or fed a control diet (21% protein) starting at age 5 wk. At 9 wk, oxygen consumption (VO2) was measured in response to an intubated meal of mixed macronutrient composition. Mass-adjusted food intake (i.e., food intake/body weight 0.67) was greater in protein-restricted than in control lean rats, but not different due to diet in obese rats. Mass-adjusted brown adipose tissue uncoupling protein levels were more than 100% greater in protein-restricted vs. control lean rats, but not different between protein-restricted and control obese rats. The uncoupling protein level was not significantly different in control lean vs. obese rats. Energetic efficiency was 40% lower in protein-restricted vs. control lean, but not different in obese rats; however, the efficiency of protein utilization was significantly greater in obese protein-restricted than in obese control rats. Meal-induced energy expenditure (VO2) did not differ significantly due to diet or genotype. In conclusion, protein restriction led to overfeeding in lean rats which appeared to enhance brown adipose tissue thermogenic capacity and decrease energetic efficiency. Protein efficiency increased to more than two times its original value in obese (fa/fa) rats, but otherwise no metabolic accommodation in the capacity for regulatory thermogenesis was observed in this genotype.

To develop recommendations for the design of special foods for young children, we measured total daily energy consumption from semisolid food mixtures with energy densities of 1.67, 2.93, 4.18, or 6.28 kJ/g (0.4, 0.7, 1.0, or 1.5 kcal/g) and that were fed ad libitum three, four, or five times per day to 18 fully weaned children from 6 to 18 mo of age who were recovering in the hospital from malnutrition. The diets were generally indistinguishable by sensory qualities, and were fed in a randomized sequence. The mean amounts consumed (g.kg body wt-1.d-1) were significantly less with successively greater energy density of the diet (P < 0.001). The total daily consumption was approximately 16% more when the number of meals was increased from three to four per day, with energy density controlled for (P < 0.001), and 7% more when the feeding frequency rose from four to five meals per day (P = 0.005). The total daily energy intakes (kJ.kg body wt-1.d-1) increased significantly with the more concentrated diets (P < 0.001) and varied positively in relation to feeding frequency (P < 0.001). Approximately 15-20 min were required per meal for the children to reach satiety. The total amount of time required to feed the children each day was related to the number of meals served (P < 0.001) and not to energy density. Implications for child feeding are discussed.

The effects of feeding a low protein diet on pancreatic insulin secretion early in life in genetically lean and obese Zucker rats were studied. Four-week-old lean (Fa/Fa) and obese (fa/fa) Zucker rats were fed either a 5% protein or a 20% protein diet for 3 wk. Rats were killed at 7 wk of age. Pancreatic islets were isolated and insulin response of islets was measured in a 60-min static incubation under one of the following conditions: 2.7 mmol/L glucose +/- 10 mmol/L arginine, 8.3 mmol/L glucose +/- 10 mmol/L arginine, and 16.7 mmol/L glucose. Serum insulin was significantly lower (P < or = 0.05) in lean, but not in obese rats fed low protein compared with those fed the normal protein diet. Interestingly, obese rats fed the low protein diet had the highest plasma glucose concentrations (P < or = 0.05) among the four groups. Feeding the low protein diet reduced insulin secretion of islets from lean rats by 70%, and from obese rats by 30 to 50% compared with rats fed the normal protein diet. Insulin content of islets was reduced significantly in lean rats fed the low protein diet (by 70%) and in obese rats (by 50%). A short-term protein deficiency early in life reduced in vitro insulin secretion of islets from both lean and obese rats. However, reductions in insulin content and insulin release from islets resulting from low protein feeding were not sufficient to alter hyperinsulinemia in genetically obese Zucker rats.

A number of investigators have reported on the clinically significant relationship between diabetes mellitus and impaired wound healing. Diabetic patients have an increased frequency of infection, delayed scar formation, and poor bony union. Investigations completed in our laboratory have demonstrated that insulin-like growth factor type 1 (IGF-1), a somatomedin C, has shown promise for accelerating bony repair. The purpose of this study was to examine the effects of recombinant IGF-1 on standardized, critical-size calvarial defects in 25 adult, male streptozocin-induced diabetic rats. From our study, it appears that IGF-1 exerts a potentiating effect on the repair of bony defects in diabetes-induced rats.

This study investigates the relationship between exercise and dietary macronutrient selection. Female Sprague-Dawley rats (5 months old) were placed on a macronutrient self-selection diet for 15 wk. Three food cups, each containing a separate vitamin and mineral supplemented macronutrient, i.e., fat, carbohydrate, or protein, were placed in the cage. Animals were either sedentary (Sed) or treadmill exercised (Ex) at 20 m.min-1, 60 min.d-1, for 6 d.wk-1. Cumulative daily energy and macronutrient intake were determined during this period. Energy intake was not different between Sed and Ex, 211.4 vs 213.5 kjoules.d-1, respectively. However, macronutrient intake differed with less fat eaten for Ex than Sed (81.5 kjoules and 38% for Ex; 114.0 kjoules and 47% for Sed). Carbohydrate and protein intake did not differ significantly between groups. Fifteen weeks of exercise training decreased dietary fat selection, but daily energy intake was not affected.

The Wistar Diabetic Fatty rat (WDF fafa) is a congenic strain of the Wistar Kyoto rat. Studies using blood glucose reveal that only fatty male (not female) WDF rats spontaneously develop hyperglycemia when fed a stock diet. Blood glucose values have not provided consistent results for evaluation of glycemic status in fatty male WDF rats. Zucker fatty (fafa) rats, while sharing the fa gene and the development of hyperinsulinemia and hyperlipemia, do not spontaneously become hyperglycemic. In order to examine strain differences and the effects of age on long-term average glycemic status in WDF and Zucker rats, glycated hemoglobin (GHb) was analyzed. Glycated hemoglobin was measured in male lean and obese WDF and Zucker rats at 2, 3, 6, and 12 months of age. Nonfasted plasma glucose was measured in male lean and obese WDF rats at 2, 3, 6, and 12 months of age and in lean and obese Zucker rats at 3, 6, and 12 months of age. Plasma insulin was measured in lean and obese WDF and Zucker rats at 3, 6, and 12 months of age. Obese WDF rats had significantly elevated GHb compared to lean controls at 3, 6, and 12 months of age. Glycated hemoglobin was substantially above the normal range (3.8-6.5%) at 3 months of age (14.1%). Glycated hemoglobin significantly declined in the obese WDF rats between 6 and 12 months of age. Nonfasted plasma glucose was significantly elevated in the obese WDF rats at 3 months (14.1 +/- 2.1 mM/L) and 6 months of age (16.2 +/- 2.3 mM/L) compared to lean controls. At 12 months of age there was no difference in plasma glucose between obese and lean WDF rats. Obese and lean Zucker rats had similar levels of GHb and plasma glucose at all ages. In conclusion, GHb provides more integrated data for classifying disease status of WDF rats and evaluation of potential long-term complications associated with hyperglycemia.

Adipose tissue was obtained from six women undergoing liposuction twice at 6-mo intervals. Samples obtained bilaterally from abdomen, inner thigh, and outer thigh had fatty acids quantified by gas chromatography. There were no important differences between sides or over time. The saturates 14:0, 16:0, 18:0, and 20:0 were higher in abdominal adipose than in outer thigh (P < 0.002 for all); 16:1 and 18:1 omega 9 were lower in abdomen vs outer thigh (P < 0.01), whereas 18:1 omega 7 and 20:1 omega 9 were unchanged. Polyunsaturates 18:2 omega 6, 20:3 omega 6, and 20:4 omega 6 were higher in outer thigh than in abdomen (P < 0.06), and inner thigh values were intermediate. These changes in fatty acid composition resulted in lower mean triglyceride melting points from abdomen to inner thigh to outer thigh, and suggest that temperature may influence the selection process determining the variation in adipose fatty acid composition with anatomical location. Because the site-specific differences included essential fatty acids, selective uptake as well as potential differences in in situ fatty acid modification are indicated.

The purpose of the present investigation was to study the role of two potential contributory factors, hyperphagia and alterations in fuel metabolism, on the development of tissue trace element accumulation in the experimentally induced diabetic rat. The role of increased mineral intake associated with diabetic hyperphagia on tissue trace element accumulation was evaluated by feeding control and diabetic rats high-carbohydrate (HC) diets which varied in Zn, Cu, Mn, and Mg concentrations. Diabetic rats were hyperphagic and had lower plasma Mg, and higher liver Zn, Cu, and Mn concentrations than control rats, regardless of dietary mineral intake. In a second study, diabetic hyperphagia was reduced by feeding control and diabetic rats a HC, high-fat (HF), or high-protein (HP) diet; the effects of altering diabetic metabolism on trace element status was studied. Liver Mn and Zn concentrations of diabetic rats fed the HF diet were lower than diabetic rats fed the HC diet and HP diet, and were similar to control rats. Liver Cu concentrations of diabetic rats fed the HF and HP diets were lower than diabetic rats fed the HC diet and were similar to control rats. While diabetic rats, in general, had higher plasma glucagon concentrations and lower percent body fat than control rats, diabetic rats fed the HF diet had similar plasma glucagon and percent body fat to control rats. These data suggest that tissue-specific biochemical needs, such as the need for metals as cofactors for enzymes, rather than hyperphagia per se, may drive the accumulation of trace elements in the diabetic animal.

The male obese Wistar Diabetic Fatty (WDF) rat is a genetic model of obesity and non-insulin dependent diabetes (NIDDM). The obese Zucker rat shares the same gene for obesity on a different genetic background but is not diabetic. This study evaluated the degree of insulin resistance in both obese strains by examining the binding and post binding effects of muscle insulin receptors in obese rats exhibiting hyperinsulinemia and/or hyperglycemia. Insulin receptor binding and affinity and tyrosine kinase activity were measured in skeletal muscle from male WDF fa/fa (obese) and Fa/? (lean) and Zucker fa/fa (obese) and Fa/Fa (homozygous lean) rats. Rats were fed a high sucrose (68% of total Kcal) or Purina stock diet for 14 weeks. At 27 weeks of age, adipose depots were removed for adipose cellularity analysis and the biceps femoris muscle was removed for measurement of insulin binding and insulin-stimulated receptor kinase activity. Plasma glucose (13.9 vs. 8.4 mM) and insulin levels (14,754 vs. 7440 pmol/L) were significantly higher in WDF obese than in Zucker obese rats. Insulin receptor number and affinity and TK activity were unaffected by diet. Insulin receptor number was significantly reduced in obese WDF rats ( 2.778 +/- 0.617 pmol/mg protein), compared to obese Zucker rats (4.441 +/- 0.913 pmol/mg potein). Both obese strains exhibited down regulation of the insulin receptor compared to their lean controls. Maximal tyrosine kinase (TK) activity was significantly reduced in obese WDF rats (505 +/- 82 fmol/min/mg protein) compared to obese Zucker rats (1907 +/- 610 fmol/min/mg protein). Only obese WDF rats displayed a decrease in TK activity per receptor. These observations establish the obese WDF rat as an excellent model for exploring mechanisms of extreme insulin resistance, particularly post-receptor tyrosine kinase-associated defects, in non-insulin dependent diabetes.

Computerized meal pattern analysis was performed on female Sprague-Dawley rats (n = 10). Rats were housed for 14 days in cages adapted for macronutrient selection. Rats selected their diet from vitamin and mineral supplemented, semipurified sources of carbohydrate, fat and protein, in three individual food cups. For analysis of meal patterns, minimum meal size was > 50 mg, and mean minimum intermeal interval was 7.9 min. Daily energy intake averaged 289.0 kJ, with 75% occurring during the dark cycle. Energy intake was 28% carbohydrate, 50% fat and 22% protein. Of 12.3 daily meals, 56% were from one, 35% from two, and only 9% of the meals were from three food cups. Seventy percent of the time carbohydrate was the first meal of the dark cycle. The average number of meals per day eaten from carbohydrate, fat, and protein were not significantly different (6.9, 6.2 and 5.6, respectively, p > 0.05). Energy intake for a meal was greatest when fat was eaten (18.35 kJ), than when either carbohydrate (8.68 kJ) or protein (8.97 kJ) was eaten. Meal duration was 7.03 min for carbohydrate, 3.75 min for fat, and 7.47 min for protein. These results provide evidence that rats on a macronutrient self-selection diet eat most meals from a single macronutrient source.

Both the parasympathetic and sympathoadrenal inputs to the pancreas can stimulate glucagon release and are activated during hypoglycemia. However, blockade of only one branch of the autonomic nervous system may not reduce hypoglycemia-induced glucagon secretion, because the unblocked neural input is sufficient to mediate the glucagon response, ie, the neural inputs are redundant. Therefore, to determine if parasympathetic and sympathoadrenal activation redundantly mediate increased glucagon secretion during hypoglycemia, insulin was administered to conscious rats pretreated with a muscarinic antagonist (methylatropine, n = 7), combined alpha- and beta-adrenergic receptor blockade (tolazoline + propranolol, n = 5) or adrenergic blockade + methylatropine (n = 7). Insulin administration produced similar hypoglycemia in control and antagonist-treated rats (25 to 32 mg/dL). In control rats (n = 9), plasma immunoreactive glucagon (IRG) increased from a baseline level of 125 +/- 11 to 1,102 +/- 102 pg/mL during hypoglycemia (delta IRG = +977 +/- 98 pg/mL, P < .0005). The plasma IRG response was not significantly altered either by methylatropine (delta IRG = +677 +/- 141 pg/mL) or by adrenergic blockade (delta IRG = +1,374 +/- 314 pg/mL). However, the IRG response to hypoglycemia was reduced to 25% of the control value by the combination of adrenergic blockade + methylatropine (delta IRG = +250 +/- 83 pg/mL, P < .01 v control rats). These results suggest that the plasma glucagon response to hypoglycemia in conscious rats is predominantly the result of autonomic neural activation, and is redundantly mediated by the parasympathetic and sympathoadrenal divisions of the autonomic nervous system.

The existence of a restriction fragment length polymorphism (RFLP) closely linked to the fatty locus between the Zucker (Z) and Brown Norway (BN) rat strains allows evaluation of early effects of the fatty (fa) gene using offspring of back-crosses (N2) between F1 females and Zucker obese males. We examined several metabolic characteristics of N2 animals to determine if these hybrid animals exhibited similar characteristics of the obese syndrome to those of Zucker rats. Females from crosses of obese male Zucker (fa/fa) and lean female BN (+/+) rats were back-crossed to their sires, resulting in twelve N2 litters. At 9 weeks of age, liver, spleen, interscapular brown fat (IBAT), and gonadal, retroperitoneal (RP), and inguinal fat depots were removed and weighed. Samples of the RP depot were analyzed for cell size and number. Obese N2 rats were hyperphagic, with body weights in the range of those of obese Zucker rats. Obese N2 rats were also hyperinsulinemic [mean +/- SEM, microU/ml: females, 7.9 +/- 0.6 vs. 82.1 +/- 8.4 (lean vs. obese); males, 10.5 +/- 1.6 vs. 128.5 +/- 13.4 (lean vs. obese)] and mildly hyperglycemic [mean +/- SEM, mg/dl: females, 104.1 +/- 2.0 vs. 139.0 +/- 14.7 (lean vs. obese); males, 100.9 +/- 2.6 vs. 132.0 +/- 2.8 (lean vs. obese) p < or = 0.05]. White fat depots in obese rats were 3 to 7 times heavier than those in lean rats; adipocyte numbers in RP depots were 50% greater in obese than in lean rats; and cell size was more than 3 times larger. IBAT, liver, and spleen were also heavier in obese vs. lean rats, while tail lengths were shorter. Percent lean carcass mass and % carcass protein were about 30% greater in lean vs. obese rats, while % carcass fat in obese rats was 5 times greater than that of lean rats. Thus, phenotypic expression of the fa gene in ZBN hybrid animals, with approximately 25% of their genetic background coming from the BN strain, appears to be similar to that in Zucker rats. Given the similarity of phenotypic expression of the fa gene between the Zucker strain and ZBN hybrids, it is plausible to consider using ZBN hybrids for studies of early manifestations of fa gene action prior to onset of detectable obesity.

We previously reported that serotonergic activity was reduced in the ventromedial hypothalamic nucleus (VMN) of obese vs. lean male Zucker rats. To verify that this reduction was associated with genotype rather than gender, we measured monoamines and their major metabolites in hypothalamic nuclei of 11-week-old female lean (Fa/Fa) and obese (fa/fa) Zucker rats. In addition, since the thermic response to cold is reported to differ between lean and obese rats, some rats were also exposed to 9 degrees or 22 degrees C for 2h to determine if cold exposure altered hypothalamic monoaminergic activity. As in males, levels of 5-hydroxyindoleacetic acid [5-HIAA; major metabolite of serotonin (5-HT)] and the ratio of 5-HIAA/5-HT were lower in the VMN of obese vs. lean females (P = 0.008, 0.001, respectively). 5-HIAA/5-HT was also reduced in the paraventricular (PVN) and suprachiasmatic nuclei (SCN) of the obese compared to the lean females. Cold exposure significantly stimulated brown fat mitochondrial GDP binding in lean but not obese rats. Similarly, levels of norepinephrine, dopamine (DA), 5-HIAA, and 5-HT in the PVN, and 5-HIAA in the SCN increased in cold-exposed lean but not obese rats. In contrast, VMN and preoptic 3,4-dihydroxyphenylacetic acid (DOPAC; major metabolite of DA) increased in the cold-exposed obese but not lean animals. We conclude that: (1) the blunted peripheral response to cold in obese vs. lean Zucker rats is accompanied by altered hypothalamic monoaminergic activity, the physiological role of which needs further evaluation; and 2) depressed VMN serotonergic activity is associated with the obese genotype (fa/fa) rather than gender and as such may contribute to the reduced sympathetic and enhanced parasympathetic outflow from the VMN.

Insulin secretion was evaluated in response to the muscarinic agonist, bethanechol, and to the antagonist, atropine, in three-month-old female homozygous lean (Fa/Fa) and obese (fa/fa) Zucker rats, using an in vitro pancreas perfusion. Three doses of bethanechol were used (0.5, 5 or 50 microM). Bethanechol at 50 microM concentration had a significant potentiating effect on glucose-induced insulin secretion in pancreata from both lean and obese rats. There was no effect of atropine (25 microM) on insulin secretion in pancreata from either lean or obese rats. In another study, the perfusate used contained glucose at 75, 125 or 200 mg/dl for the entire 60 min period. Perfusate, with or without bethanechol (50 microM), was infused from 21-40 min, using a side-arm syringe. In general, bethanechol significantly increased insulin secretory rates in both lean and obese rats. Since the pancreas of obese rats secretes more insulin to the same glucose concentration than the pancreas of lean rats, we compared changes in insulin release due to bethanechol in obese and lean rats having comparable basal insulin secretory rates during the 11-20 min period. To produce comparable insulin secretion, glucose levels in the perfusate were kept lower in the obese group (75 mg/dl). In the comparably secreting lean group, a glucose level of 200 mg/dl was required. We also compared changes in insulin secretory rate due to bethanechol stimulation between groups with comparable insulin secretory rates during the 21-40 min period in the control groups, i.e. 75 mg/dl glucose in the obese group vs. 125 mg/dl glucose in the lean group.(ABSTRACT TRUNCATED AT 250 WORDS)

It has long been known that the central nervous system (CNS) directly affects pancreatic insulin release. This study was undertaken to determine the effect of the CNS on pancreatic insulin release in three-month-old female lean (Fa/Fa) and hyperinsulinemic obese (fa/fa) Zucker rats. Chloral hydrate (400 mg/kg) was used as the anesthetic agent. The in situ brain-pancreas perfusion model with intact pancreatic innervation was used in this investigation. The study measured insulin secretion in response to a 60-minute glucose stimulus (200 mg/dl). CNS-intact and CNS-functionally ablated obese and lean rats were used. During the 60-minute perfusion period significantly more insulin was released by pancreata from obese rats compared to those from lean rats. In lean rats, about twice as much insulin was released by pancreata from CNS-ablated rats than from CNS-intact rats (P < 0.05), demonstrating a CNS tonic inhibition of insulin secretion. In obese rats, there was no significant difference in insulin released by the pancreata of the CNS-intact and CNS-ablated rats. To determine if there was a masking effect of predominant PNS activity over the SNS in the CNS-intact obese rats, bilateral vagotomy was performed in a group of otherwise CNS-intact obese rats prior to the onset of perfusion. Tonic inhibition was still not observed in the CNS-vagotomized obese rats. In conclusion, hypersecretion of insulin in obese rats is partially due to diminished tonic sympathetic nervous system inhibition of insulin release. These results provide additional evidence regarding abnormal CNS control of insulin secretion in obese Zucker rats.

Below-normal proportions of phospholipid (PL) arachidonic acid (20:4 omega 6) have been reported in serum from obese humans and in liver from obese Zucker rats. This implies an abnormality of 20:4 omega 6 formation from linoleic acid (18:2 omega 6), possibly in the delta 6 desaturase step, or alternatively an abnormality in the catabolism or distribution of arachidonate. We previously speculated that a reduced proportion of 20:4 omega 6 in hepatic PL could contribute to the etiology of genetic obesity. Providing 18:3 omega 6 would bypass delta 6 desaturase and possibly normalize hepatic PL 20:4 omega 6. Therefore weanling Zucker rats were given free access to a defined diet (11% of energy as soy oil) and gavaged daily with 100 microL of either black currant oil concentrate ([BCO] 8% 18:2 omega 6 and 70% 18:3 omega 6) or soy oil ([Soy] 55% 18:2 omega 6 and < 0.1% 18:3 omega 6). Groups of eight lean and eight obese animals were randomized to receive Soy or BCO in a 2 x 2 design; 10 obese and 10 lean rats were fed a stock diet (nongavaged reference). All groups of lean rats had identical weight gain; food intake for Soy lean and BCO lean did not differ. The obese reference animals and Soy obese animals did not differ in weight gain. However, BCO obese animals ate less food (P < .06), gained less weight (P < .0001), and had lower percent body fat (P < .05) compared with the Soy obese animals. The fatty acid constituents from serum, liver, and adipose tissue showed marked differences between lean and obese animals. Hepatic PL 20:4 omega 6 was lower in Soy obese than in lean (P < .002), but was normalized by BCO gavage (diet effect, P < .007). The paucity of hepatic PL 20:4 omega 6 was not due to reduced desaturase activity, as the proportions of other desaturase products (20:3 omega 6, 20:3 omega 9, 20:5 omega 3) were significantly elevated in Soy obese rat liver and serum. Serum and hepatic cholesteryl ester 20:4 omega 6 levels were elevated in obese versus lean rats (P < .02 and P < .0001), indicating abnormal arachidonate distribution in the obese Zucker rat. Because BCO selectively reduced weight gain and percent body fat in obese Zucker rats, our results imply a role for abnormal omega 6 fatty acid metabolism in the etiology of Zucker obesity.(ABSTRACT TRUNCATED AT 400 WORDS)

While many autonomic and metabolic defects associated with genetic obesity in the Zucker rat are corrected by adrenalectomy (Adx), brain adrenoceptor function has not been examined in this context. Here, 3 weeks after Adx or sham surgery, brains of 11 weeks old lean (Fa/Fa) and obese (fa/fa) male Zucker rats were assayed for alpha 1-([3H]prazosin; [3H]PRZ) and alpha 2-adrenoceptor ([3H]paraminoclonidine; [3H]PAC) binding by autoradiography. By genotype, obese rats had 19-256% higher [3H]PRZ binding than lean rats in the amygdala (central [ACN], basolateral [ABL], basomedial [ABM] and medial [MAN] nuclei [n.]), hypothalamus (dorsomedial n. [DMN] and lateral [LH]) and somatosensory cortex. In the ABL and ACN, increased maximal binding (Bmax) in obese rats was associated with decreased affinity (increased Kd). Three weeks after surgery, sham-operated obese rats gained 27% more weight than lean rats but lean and obese Adx rats gained the same amount of weight. Adx reduced [3H]PRZ binding in both lean and obese rats by 37-70% in the amygdala (ABM, ACN, MAN) compared to sham-operated rats. But, Adx selectively reduced [3H]PRZ binding only in lean rats in the ABL, DMN, ventromedial hypothalamic n. (VMN) and ventroposteromedial thalamic n. In most areas, decreases in maximal binding (Bmax) associated with Adx were accompanied by decreases in Kd. Unlike [3H]PRZ binding, there was no consistent genotype difference in [3H]PAC binding although Adx was followed by increased binding in obese and decreased binding in lean rats in the ABL. In only the VMN, obese rats had a 21% higher alpha 2- to alpha 1-adrenoceptor ratio than lean rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Obese Zucker rats (fa/fa) have low levels of arachidonic acid (AA) in liver phospholipids (PL). We have previously shown that a 70% gamma-linolenate concentrate (GLA; an AA intermediate) fed at a fixed dose (0.07 g/day) normalized hepatic PL AA and reduced weight gain selectively in the obese animals. In a follow-up study, 16 obese (fa/fa) and 16 lean (Fa/Fa) 4-week-old male rats were randomized into 4 groups of 8 each and gavaged daily with soybean oil (SOY) containing 55% 18:2omega6 (an AA precursor) or GLA, using a progressive dose (< or = 5% of total calories) based on body weight. A defined diet with 11% of energy as SOY was fed ad libitum for 60 days. GLA obese had lower body weight (p<0.0001) and 60-day cumulative food intake (p<0.05) compared to SOY obese, but neither parameter differed between the lean groups. For the last twenty days cumulative food intake was identical for GLA obese and SOY lean, whereas SOY obese consumed 18% more (p<0.05). Thus the progressive dose of GLA selectively suppressed hyperphagia in obese Zucker rats. Erythrocytes collected at 15-day intervals showed parallel increases in AA in both genotypes over time, suggesting normal AA availability during rapid growth. Thus, the reduced PL AA in the livers from the obese rats probably reflects impaired distribution in selected tissues rather than reduced hepatic production. Due to the potential health risks of enriching tissue lipids with AA, great caution is advised in considering GLA as therapy for human obesity.

To determine if diet-induced obesity is associated with depressed serotonergic activity (as is genetic obesity), we examined hypothalamic biogenic amines in 11-wk-old genetically lean (Fa/Fa) male Zucker rats raised in small (3 pups/dam) or control (8-9 pups/dam) litters. Five-week-old rats were adrenalectomized or sham-operated and, 1 wk later, fed either 11% of energy as fat (low fat) or 68% of energy as fat (high fat) diets for 5 wk. Tissue punches from the ventromedial nucleus (VMN), the paraventricular nucleus and the preoptic area were assayed via HPLC. Rats fed high vs. low fat had a greater percentage of body fat and brown fat mitochondrial GDP binding, whereas serotonergic turnover was lower. Small litter vs. control litter animals had lower VMN and preoptic concentrations of 3,4-dihydroxyphenylacetic acid, a major metabolite of dopamine. Although adrenalectomy resulted in smaller, leaner rats, it did not differentially affect the rats that became fatter. Because VMN and preoptic dopaminergic activities were depressed in small litter vs. control litter rats but the percentage of body fat was unchanged, this decreased dopamine metabolism is probably not causal to the obesity development. However, the same cannot be said for the attenuated serotonergic activity, although such activity may not be directly related to the degree of obesity.

To explore recent suggestions that genetically obese Zucker rats show less anorexia when brain gamma-aminobutyric acid (GABA) is elevated, obese vs. lean littermates received 100, 50 and 0 micrograms of the GABA-transaminase inhibitor, ethanolamine-O-sulfate (EOS), intra-cisternally in a longitudinal design where their feeding patterns were monitored 24 h daily. Obese rats were refractory to EOS-induced anorexia as evidenced by less suppression of daily food intake and fewer alterations to both meal size and meal frequency, particularly in the night. This effect was not due to an inability of EOS to increase brain GABA since equivalent, specific dose-dependent increments were seen in the brains of separate obese vs. lean rats after analysis of endogenous GABA and seven other amino acids. An unexpected finding was elevated levels of brain taurine for obese rats regardless of EOS dosage, implying a hitherto unknown neurochemical trait whose potential significance is unclear. The primary data obtained provide further support for recent hypotheses that obese Zucker rats possess altered brain GABAergic mechanisms that may serve as one contributor to their over-eating.

RNA blot analysis of rat liver and adipose tissues detected two glycogen phosphorylase (GP)-encoding transcripts. The polymerase chain reaction was used to characterize the 3'-noncoding region of the gene (L-GP) encoding liver-GP (L-GP) from the lean Zucker rat (Fa/Fa). Three distinct classes of colinear cDNA clones were identified by nucleotide (nt) sequence analysis, demonstrating that the L-GP gene contains at least three functional polyadenylation sites. The predominant L-GP transcript was generated by polyadenylation 130 nt 3' from the end of the coding region. A previously uncharacterized L-GP transcript is generated by polyadenylation at 346 nt 3' of the first polyadenylation site. Polyadenylation site selection does not appear to be regulated in a tissue-specific fashion. The relative steady-state L-GP mRNA levels in the different types of adipose tissues were comparable to, or exceeded transcript levels in liver.

Insulin was chronically administered to rats to determine its effect on the daily changes in food intake and body weight. Animals received regular insulin via 14-day osmotic minipumps in doses of 0.0, 0.5, 1.0, 3.0, and 5.0 IU/day treated either with (+GLU) or without glutamic acid (-GLU). Previous studies have shown that glutamic acid prevents insulin aggregation in the minipumps to provide a more stable flow rate. Food intake and body weights were measured each day of treatment. Chronic insulin treatment was ineffective in promoting changes in animals receiving any dose of insulin except the highest dose. Animals receiving 5.0 IU/day insulin + GLU experienced a transient hyperphagia and weight gain followed by a suppression in food intake and body weight by Day 4 of treatment. Effects were attenuated in animals receiving insulin -GLU. Plasma insulin concentrations on Day 14 were similar for all doses, suggesting a compensation took place either in insulin degradation or endogenous insulin production. Results indicate that glutamic acid treatment enhances the effects of chronic insulin administration via osmotic minipumps.

The purpose of this study was to evaluate the effect of aging (12 vs. 24 mo) on skeletal muscle insulin receptor function of male Sprague-Dawley rats fed either a 33% sucrose (wt/wt) or sucrose-free diet. The effect of exercise in combination with the sucrose diet was also evaluated by exercising half of the sucrose-fed group on a motorized treadmill. Insulin-receptor function was assessed in vitro by measuring the binding capacity of [125I]-insulin to partially purified receptors of the biceps femoris and vastus lateralis. Tyrosine kinase activity was measured as an index of postreceptor function. Insulin-receptor number was significantly decreased in 24-mo-old sucrose-fed rats compared to 12-mo-old rats fed the sucrose or sucrose-free diets. The affinity of insulin for the receptor did not significantly differ among groups. Maximal tyrosine kinase activity in vastus lateralis was significantly decreased in 12-mo-old sucrose-fed rats compared with sedentary 24-mo-old rats fed the sucrose-free diet or 24-mo-old rats fed the sucrose diet in combination with exercise. Exercise prevented the decrease in receptor function in both 12- and 24-mo-old sucrose-fed rats as measured by insulin binding and tyrosine kinase activity. These data suggest that diet and/or exercise rather than aging per se has a greater influence on insulin-receptor function.

1. Measurements have been made of the inhibition by mono- and divalent cations of the binding of [3H]-(+)-N-methyl-4-methyldiphenhydramine ([3H]-QMDP) to histamine H1-receptors in homogenates of guinea-pig cerebellum. 2. The binding of [3H]-QMDP was inhibited by monovalent cations with an order of potency Li+ = Na+ greater than K+ greater than Cs+ = Rb+. The IC50 for Li+ was 39 mM, but that for K+ was 132 mM. Hill coefficients for inhibition curves for Li+ and Na+ were less than 1. 3. Divalent cations also inhibited the binding of [3H]-QMDP. The most potent cations examined were Hg2+, Cd2+ and Zn2+, with IC50 values of 5, 17 and 41 microM, respectively. Ca2+ and Mg2+ were relatively weak inhibitors (IC50 12 and 34 mM, respectively). The potency of Ni2+, Co2+ and Mn2+ was intermediate between these groups. Hill coefficients for inhibition curves for Hg2+, Cd2+ and Zn2+ were greater than 1, but Hill coefficients for the other cations were less than 1. 4. Both mono- and divalent cations also inhibited the binding of [3H]-mepyramine. The divalent cations were approximately equipotent in inhibiting the binding of [3H]-QMDP and [3H]-mepyramine. The same was true for Li+. However, Na+ was markedly more effective against [3H]-QMDP binding than against the binding of [3H]-mepyramine. 5. The effect of 40 mM Li+ on the parameters of binding of [3H]-mepyramine was to increase the best-fit value of the concentration giving half-maximal binding EC50, by approximately 2 fold without having any significant effect on the maximum amount of binding. Cd2+ (15 microM) caused both an increase in EC 0 and a decrease in Bmax (32 +/- 4% inhibition). Na+, 100 mm, had no significant effect on either EC50 or Bmax for [3H]-mepyramine binding.

The binding of the quaternary radioligand [3H] QMDP to the histamine H1-receptor was inhibited by a series of mono- and di-valent cations. The order of potency was Hg2+ greater than Cd2+ greater than Zn2+ greater than Ni2+ greater than Co2+ greater than Mn2+ greater than Ca2+ greater than Mg2+ greater than Li+ = Na+ greater than K+ greater than Cs+. The binding of [3H] mepyramine, a tertiary amine, was inhibited by the divalent cations to a similar extent as the binding of [3H] QMDP. Li+ also had a similar potency against the two ligands, but Na+ was a much more potent inhibitor of the binding of [3H] QMDP than that of [3H] mepyramine.

Although the rat is usually not considered to be sensitive to photoperiod, under some experimental conditions photoperiod responses are unmasked. In addition, we have observed photoperiod-induced changes in body weight gain in lean and obese Zucker rats. In this experiment, body mass, food intake, body composition, brown adipose tissue (BAT) thermogenic state, and blood concentrations of corticosterone, insulin, and glucose were evaluated under one of two lighting conditions: a short (10 h light: 14 h dark) or a long (14 h light: 10 h dark) photoperiod. Plasma corticosterone and glucose concentrations measured under fasting conditions were unaffected by photoperiod in either genotype. The amount of BAT mitochondrial protein isolated was less in long photoperiod rats. BAT mitochondrial GDP binding was unaffected by photoperiod in the lean rats, but tended to be lower in long photoperiod obese rats than in short photoperiod obese rats. Although, photoperiod had no effect on daily food intake of rats exposed to the short versus long photoperiod, body mass was heaviest in obese rats raised in long photoperiod. Plasma insulin was increased in both lean and obese rats in long photoperiod. In addition, fat storage appeared to shift to internal depots in the lean rats exposed to long photoperiod. Our data demonstrate that photoperiod does have an effect on male Zucker rats with respect to body weight and fat distribution, with the obese rats being more sensitive to changes in photoperiod than the lean rats.

Central neural activity was assessed by measuring relative cytochrome oxidase (CO) activity in the ventromedial nucleus (VMN; thermogenesis regulation), the parvocellular paraventricular nucleus (PVN; feeding regulation), and the magnocellular PVN (secretion of vasopressin and oxytocin) in 10 age-matched pairs of 39- to 42-day-old Zucker rats. When obese (fa/fa) were compared to lean (Fa/Fa) rats, relative CO activity was significantly lower (approximately 10 percent) in the VMN and parvocellular PVN, but not in the magnocellular PVN. Cell diameters did not differ. To determine if there were corresponding differences in levels or release of hypothalamic monoamines, we compared 7 pairs of 90- to 94-day-old lean (Fa/?) and obese (fa/fa) rats at rest and after 2 h of 9 degrees C. Tissue punches from frozen PVN, VMN, and preoptic area (the latter being a site of thermosensitive units modulating VMN output) were assayed. In obese vs. lean noncold-exposed rats, we observed lower concentrations of: 5-hydroxyindoleacetic acid (5HIAA; metabolite of serotonin, 5HT) in the VMN; 3-methoxy-4-hydroxyphenylglycol (MHPG; metabolite of norepinephrine, NE) and NE + MHPG (index of total NE) in the preoptic area; and 3,4-dihydroxyphenylacetic acid (DOPAC; metabolite of dopamine, DA) in the PVN. Additionally, in the VMN, cold exposure resulted in: elevated concentrations of MHPG and MHPG + NE in both lean and obese rats; elevated concentrations of 5HT, 5HIAA, and 5HT + 5HIAA in obese rats, with no significant changes in these variables in lean animals; decreased ratio of 5HIAA/5HT in obese rats and increased ratio in leans. In the preoptic region, cold exposure led to increased concentrations of MHPG, NE + MHPG, 5HT, and 5HT + 5HIAA in obese but not lean rats. In the PVN, 5HT concentrations were increased in cold-exposed obese but not lean rats. Our data support the hypothesis that neuronal activity in obese rats differs from that of lean rats at rest and during cold exposure and suggest that several monoamine systems play a role in such differences.

Magnesium deficiency lowers endurance capacity of untrained rats by an as yet unknown mechanism. We tested the hypothesis that low plasma and blood Mg concentrations would reduce blood 2,3-diphosphoglycerate (2,3-DPG) concentrations, thus diminishing the oxygen delivery system of the Mg-deficient rat. Untrained male Osborne-Mendel rats (95 g) were studied at rest or following exhaustive exercise after three weeks of dietary treatment (400 or 100 micrograms Mg/g diet; deionized or high Mg water [greater than 85 micrograms Mg/ml]). Magnesium deficiency resulted in lowered plasma and red blood cell (RBC) Mg concentrations and reduced endurance capacity compared with controls. Magnesium supplementation normalized these parameters. 2,3-DPG was elevated by 10% in rats acutely exercised compared with sedentary rats; however, 2,3-DPG levels were not affected by dietary Mg intake. Acute exercise tended to increase erythrocyte Mg concentrations in control rats and lower erythrocyte Mg levels in deficient rats. In conclusion, the reduced endurance capacity of Mg-deficient rats is not due to impaired 2,3-DPG production.

The effects of high fat feeding on brown fat thermogenesis in rodents are controversial. In this study, we examined the effects of 8 d of high fat feeding on brown fat mitochondrial GDP binding (an in vitro index of thermogenic activity) in lean (Fa/?) and obese (fa/fa) Zucker rats. Six-week-old female rats were fed a defined low fat control diet (9.5% of energy from fat) only during the dark cycle (1200-2400 h), and food intake was measured daily at 1200, 1600, 2300, and 2400 h for 7 d (the control period). For the next 8 d, half of the lean and obese rats were fed a high fat diet (65% of energy from fat), and the others remained on the low fat control diet. Each rat was fed the amount of energy equivalent to its average energy intake during the 7-d control period. Rats were killed at 0800-1000 h. In the lean rats, high fat feeding increased GDP binding. This increased binding in the lean rats appeared to reflect levels of dietary fat and carbohydrate and was independent of caloric intake. The blunted GDP binding of the obese rats failed to respond to dietary changes.

Central administration of 2-deoxy-D-glucose (2-DG) decreases brown fat thermogenesis. This effect is suggested to be mediated via a central control mechanism. Our study was designed to determine the importance of the sympathetic nervous system in the response of brown fat to intraperitoneal (i.p.) injection of 2-DG. Unilateral denervation of interscapular brown adipose tissue (IBAT) was performed on male Sprague-Dawley rats (300 g body weight). Nine days after surgery, rats were injected i.p. with either saline vehicle (0.9% sodium chloride) or 2-DG (360 mg/kg wt) and then killed one hour later. Sympathetic denervation resulted in 50% decreases in total IBAT protein and in mitochondrial protein recovered. In the denervated lobes, mitochondrial GDP binding (expressed as nmol/mg mitochondrial protein and as total activity recovered) was decreased to 36% and 18%, respectively. Injection of 2-DG did not change mitochondrial protein content in either the innervated or denervated IBAT. In the innervated lobes, 2-DG significantly lowered GDP binding to 55% of that in saline-treated animals, whether expressed per mg mitochondrial protein or as total recovered activity. In contrast, 2-DG did not further decrease GDP binding in the denervated lobes. In conclusion, the effects of i.p. injection of 2-DG on brown fat thermogenesis (as evidenced by GDP binding) appear to be primarily mediated via the sympathetic nervous system.

The effect of a high fat diet in stimulating adipocyte proliferation, as measured by the incorporation of [3H]-thymidine into fat cell DNA, was studied in 22-month-old female Sprague-Dawley rats. Rats were fed a low fat (n = 10) or a high fat diet (n = 9) for a total of six days. On days 4 and 5 of dietary manipulation, rats were injected with 80 microCi/100 g body weight of [3H]-thymidine. Rats were continued on their respective diets for one more day, starved for 72 h and then refed a stock diet for three weeks in order to increase turnover of stroma cells, thus diluting the specific activity of stromal DNA with minimal effect on specific activity of fat cell DNA. The diet groups did not differ significantly with respect to body masses, food intake, parametrial (PARA) and retroperitoneal (RP) depot masses, cell number or cell size. The specific activity of DNA in both PARA and RP depots was greater in the adipocyte than in the stromavascular fraction. Specific activity of fat cells was significantly greater from rats fed the high fat than the low fat diet in both PARA and RP depots. Radioautography of adipose tissue confirmed that there was a greater percentage of adipocyte nuclei labeled in the rats fed the high fat diet. Also, there were few labeled nuclei found in stroma cells. In conclusion, older female rats increased adipocyte proliferation when fed a high fat diet.

The effect of exercise on in vivo insulin sensitivity was examined in lean and obese Zucker rats. Rats (6 to 7 weeks of age) were swum two hours per day or kept sedentary for 8 weeks. Exercise decreased body weight gain as well as percent of fat in both genotypes. Sedentary obese rats had 62% higher gastrocnemius citrate synthase activity per gram of muscle than did lean rats. Exercise increased activity of this oxidative enzyme similarly in both genotypes. Compared to lean rats, obese rats had higher plasma-insulin levels and were less sensitive to insulin during an insulin tolerance test. Although training had no effect on plasma-insulin levels, exercise trained obese rats showed a greater drop in plasma glucose relative to sedentary controls following intravenous injection of three concentrations of insulin. It was concluded that moderate exercise training improved the insulin sensitivity of the obese Zucker rat.

Lean (Fa/?) and obese (fa/fa) Zucker rats were adrenalectomized (ADX) in order to assess the contribution of adrenal hormones to insulin resistance of the obese Zucker rat. Glucose utilization was measured using an insulin suppression test. Sham-operated obese rats gained almost twice as much weight as sham-operated lean littermates. However, body weight gain of ADX animals was comparable in both genotypes. It was significantly less than that of the respective sham-operated controls. Body weight differences can be accounted for almost entirely by a marked loss of adipose tissue. Although insulin resistance may be attributable to obesity in part, steroid hormones are thought to be directly antagonistic to insulin for glucose metabolism. Adrenalectomy resulted in a decrease in serum glucose concentrations for both lean and obese Zucker rats compared with their respective sham-operated groups. Serum insulin concentration of lean ADX rats was 23% of sham-operated controls; in obese ADX rats, it was 9% of controls. Elevated levels of steady state serum glucose (SSSG) levels in sham-operated obese rats demonstrate a marked resistance to insulin induced glucose uptake compared with sham-operated lean animals. Adrenalectomy caused a marked improvement in insulin sensitivity of obese rats. The hyperglycemic SSSG levels of the obese rats were reduced 2.5 times by ADX. These results indicate that insulin resistance of Zucker obese rats can be ameliorated by ADX, suggesting adrenal hormones contribute to insulin resistance in these animals.

Adrenalectomized rats were given access to corticosterone-supplemented (20 micrograms/ml) and -unsupplemented saline (0.9% NaCl) in two separate bottles and preferences were measured for each. Half of the rats received corticosterone in maple-flavored saline (MAPLE group), while the other half received corticosterone in anise-flavored saline (ANISE group). Each rat also received unsupplemented saline in the alternate flavor. After an initial preference test, preferences were measured again following a period of forced choice (where rats were given the supplemented saline only) and again following a period of deprivation (where rats were given the unsupplemented saline only). All three independent variables (flavor, forced-choice and deprivation) played roles in determining self-administration of corticosterone. Results from the initial preference test demonstrated that both groups preferred the maple-flavored saline whether it contained corticosterone or not. However, consumption of corticosterone-supplemented saline regardless of flavor increased following both forced-choice and deprivation suggesting that the adrenalectomized rats were controlling their corticosterone levels. Strong negative correlations were found between intake of corticosterone-supplemented saline and body weight suggesting that the adrenalectomized rat may be controlling corticosterone levels based on some correlate of body weight.

The results of percutaneous endoscopic gastrostomies in 100 patients in a community hospital were compared with those of surgically placed gastrostomies in 50 patients. The morbidity rate for the percutaneous endoscopic gastrostomy group was 4%, compared with 30% for the patients with surgically placed gastrostomies. The procedure-related mortality for percutaneous endoscopic gastrostomy was 1%, compared with 16% for surgically placed gastrostomies. Patients admitted to the hospital for percutaneous endoscopic gastrostomy stayed an average of 4 days compared with 10 days for the surgical patients; 14 patients had the percutaneous endoscopic gastrostomy performed as an outpatient procedure. There were no complications in this group, suggesting that percutaneous endoscopic gastrostomy can be safely performed as an outpatient. In this community hospital, percutaneous endoscopic gastrostomy was both substantially safer and far less expensive than surgically placed gastrostomy.

1. The dynamics of insulin and glucagon secretion by the isolated perfused cat pancreas was studied in response to glucose and amino acid stimuli. 2. Insulin secretion is biphasic in response to either glucose or amino acid stimuli. 3. Glucose caused a much more pronounced first phase release than did a complete amino acid mixture; whereas glucose and the amino acid mixture stimulated late second phase insulin secretion equipotently. 4. The same amino acid mixture produced a biphasic secretion of glucagon characterized by a rapid and transient spike-release which was followed by a substantial, relatively steady-state, second secretory phase. 5. Various combinations of glucose and amino acids resulted in insulin secretion which suggests a simple additive stimuli phenomenon; whereas no such additive effect was observed with respect to amino acid stimulation of glucagon secretion. 6. Instead, various of the amino acids appear to stimulate maximal glucagon secretion independently. 7. Glucose failed to cause a suppression of amino acid induced glucagon release. 8. The quantitative aspects of this study suggest that the cat pancreas is very responsive to amino acid modulation of hormone release, a fact which may well reflect the high amino acid content of the cat's diet.

Dietary fat intake, with special emphasis on dairy products, was estimated from questionnaires for 42 underweight, 80 normal weight, and 64 overweight adult women. Frequency of consumption of fresh and processed meats, frozen dairy desserts, pastries, and snacks such as potato chips was greater for the overweight than for the underweight subjects. However, preferences between verbally-described high- and low-fat versions of 14 food pairs did not differ by body size. Overweight subjects reported that they consumed more non-fat milk and less whole milk than did the other groups. Discrimination, perceived intensity, paired preference, and hedonic rating of fat in milk and in chocolate milk did not differ significantly according to body size, fat intake, or type of milk consumed. Ad libitum mixing of non-fat milk and "half and half" (12% fat) to individual levels of liking also showed no significant variation with body size. However, subjects with higher dietary fat intakes mixed to higher fat-preference levels in milk than did the low- and medium-fat intake subjects. Those reporting consumption of regular milk (3.5% fat) mixed to higher fat levels than did those who consumed low-fat (2% fat) or non-fat milk. The ad libitum procedure gave better reproducibility and appeared to be a more realistic measure of liking than the hedonic rating or paired-preference tests.