Mechanisms of impaired growth hormone secretion in genetically obese Zucker rats: roles of growth hormone-releasing factor and somatostatin

GH secretion is markedly blunted in obesity; however, the mechanism(s) mediating this response remains to be elucidated. In the present study we examined the involvement of the two hypothalamic GH-regulatory hormones, GH-releasing factor (GRF) and somatostatin (SRIF), using the genetically obese male Zucker rat. Spontaneous GH, insulin, and glucose secretory profiles obtained from free moving, chronically cannulated rats revealed a marked suppression in amplitude and duration of GH pulses in obese Zucker rats compared to their lean littermates (mean 6-h plasma GH level, 3.9 +/- 0.4 vs. 21.5 +/- 3.8 ng/ml; P less than 0.001). Obese rats also exhibited significant hyperinsulinemia in the presence of normoglycemia. The plasma GH response to an iv bolus of 1 microgram rat GRF-(1-29)NH2, administered during peak and trough periods of the GH rhythm, was significantly attenuated in obese rats at peak (137.4 +/- 26.1 vs. 266.9 +/- 40.7 ng/ml; P less than 0.02), although not at trough, times. Passive immunization of obese rats with a specific antiserum to SRIF failed to restore the amplitude of GH pulses to normal values; the mean 6-h plasma GH level of obese rats given SRIF antiserum was not significantly different from that of obese rats administered normal sheep serum. Both pituitary wet weight and pituitary GH content and concentration were reduced in the obese group. Measurement of hypothalamic GRF immunoreactivity revealed a significant (P less than 0.05) reduction in the mediobasal hypothalamic GRF content in obese rats (503.2 +/- 60.1 pg/fragment) compared to that in lean controls (678.1 +/- 50.2 pg/fragment), although no significant difference was observed in hypothalamic SRIF concentration. Peripheral SRIF immunoreactive levels were significantly (P less than 0.01) elevated in both the pancreas and stomach of obese rats. These results demonstrate that the genetically obese Zucker rat exhibits 1) marked impairment in both spontaneous and GRF-induced GH release, which cannot be reversed by SRIF immunoneutralization, 2) significant reduction in pituitary GH concentration, 3) depressed hypothalamic GRF content, and 4) elevated gastric and pancreatic, but not hypothalamic, SRIF levels. The findings suggest that the defect in pituitary GH secretion observed in the genetically obese Zucker rat is due, at least partially, to insufficient stimulation by hypothalamic GRF, and that SRIF does not play a significant role.     

Changes in hypothalamic expression levels of galanin-like peptide in rat and mouse models support that it is a leptin-target peptide

Galanin-like peptide (GALP) is a novel peptide that has been isolated from the porcine hypothalamus. The expression of GALP mRNA is localized to the hypothalamic arcuate nucleus and is thought to be under the regulation of leptin. First, we confirmed by real-time PCR analysis that sc administration of leptin to Wistar rats under food-deprived conditions resulted in a 1.5-fold increase in hypothalamic GALP mRNA levels. Next, GALP mRNA levels were found to be reduced by 50% in 11-wk-old male Zucker obese rats compared with age-matched Zucker lean rats, whereas neuropeptide Y mRNA levels were increased by 55% and proopiomelanocortin mRNA levels were reduced by 53% in Zucker obese rats. Analysis using a two-site enzyme immunoassay revealed a lower level of hypothalamic GALP immunoreactivity in 11-wk-old Zucker obese rats (5.9 fmol/mg protein) than in age-matched Zucker lean rats (19.6 fmol/mg protein). Immunohistochemical studies demonstrated that Zucker obese rats (11 wk old) had a reduced number of GALP immunoreactivity-positive cells (29.4 cells/3 slices) in the arcuate nucleus compared with age-matched Zucker lean rats (115 cells/3 slices). Furthermore, Zucker obese rats showed increased sensitivity to intracerebroventricularly administered GALP compared with Zucker lean rats, in that a lower dose of GALP increased plasma LH levels in male Zucker obese rats, but not in male Zucker lean rats. In addition, a reduction in the level of hypothalamic GALP mRNA was found in db/db and ob/ob mice. The result supports the hypothesis that the hypothalamic GALP gene expression is controlled by leptin signals and suggests possible involvement of GALP in the reproductive abnormalities of the Zucker obese rat.     

In vitro and in vivo growth hormone responsiveness to growth hormone-releasing factor in male and female Zucker rats

In order to determine whether there is an anomaly in the pituitary responsiveness to growth hormone (GH)-releasing factor in the genetically obese rat, we examined the in vitro and in vivo effects of rGRF(1-29)NH2 (GRF) on GH release in male and female Zucker rats. The effect of increasing GRF concentrations (1.56, 6.25, 12.5 25 and 50 pM) was first tested on GH release from freshly perifused anterior pituitary cells. In both sexes, the GH response per one pituitary equivalent to each GRF concentration tested was reduced in the obese group. However, when GH release was expressed as a percent of initial cell GH content, there was no difference between the lean and the obese groups. Furthermore, under pentobarbital anesthesia, GRF was injected intravenously at two consecutive doses of 0.8 and 4.0 microgram/kg body weight in obese and lean animals. In both sexes, the GH response to each dose of GRF tested was decreased in the obese group. Basal serum GH concentrations were similar in male and female obese rats compared to their respective lean siblings. In conclusion, this study demonstrates a decrease of the in vitro and in vivo pituitary response to GRF in the obese Zucker rat, suggesting a possible secondary defect at the pituitary level.     

Testosterone supplementation in male obese Zucker rats reduces body weight and improves insulin sensitivity but increases blood pressure

Androgen levels are lower in obese men as compared with normal weight individuals. However, there are no safety data regarding the chronic use of androgen supplements in middle-aged men. The present study was undertaken to determine the cardiovascular and metabolic effects of chronic (10 weeks) testosterone treatment in male obese Zucker rats, starting at 22 weeks of age, when testosterone levels were significantly decreased. Testosterone supplements increased plasma levels, 10-fold in both obese Zucker rats and lean Zucker rats. In obese Zucker rats, testosterone supplements reduced body weight, plasma insulin, and cholesterol levels and improved the oral glucose tolerance test. None of these parameters were affected in lean Zucker rats. Mean arterial pressure was significantly increased in obese Zucker rats but not lean Zucker rats. Testosterone supplements increased proteinuria and accelerated renal injury in lean Zucker rats only. Thus, treatment of obese men with chronic testosterone supplements should be done with careful monitoring of blood pressure.     

Physiological difference between obese (fa/fa) Zucker rats and lean Zucker rats concerning adiponectin

Obese (fa/fa) Zucker rat is a spontaneous genetic obesity model and, by comparison with lean Zucker rat, exhibits hyperphagia, hyperinsulinemia, and hyperlipidemia. The aim of this study was to examine the physiological difference concerning adiponectin between obese (fa/fa) Zucker rats and control lean Zucker rats. We therefore measured plasma adiponectin level and analyzed adiponectin and adiponectin receptor 1 mRNA expression in retroperitoneal white adipose tissue (RT WAT), brown adipose tissue (BAT), liver, and soleus muscle. We also examined the tissue mRNA expression of peroxisome proliferator-activated receptor alpha (PPAR alpha), PPAR delta, and PPAR gamma, which regulate adiponectin expression sensitivity to a PPAR gamma agonist shown by brown adipocytes from obese (fa/fa) Zucker rats and lean Zucker rats, by measuring adiponectin release from these cells. Plasma adiponectin levels of obese (fa/fa) Zucker rats were significantly higher than those of lean Zucker rats. Adiponectin mRNA expression levels in RT WAT were lower in obese (fa/fa) Zucker rats than in lean Zucker rats, but those in BAT were higher. Adiponectin receptor 1 expression levels in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats were lower than in lean Zucker rats. The expression level of PPAR alpha, PPAR delta, and PPAR gamma in BAT was lower in obese (fa/fa) Zucker rats than in lean Zucker rats. Moreover, the PPAR gamma agonist increased adiponectin release only from the brown adipocytes isolated from lean Zucker rats. It is the conclusive difference between obese (fa/fa) Zucker rats and lean Zucker rats that plasma adiponectin levels of obese (fa/fa) Zucker rats are significantly higher than those of lean Zucker rats. Moreover, we clarified that mRNA expression level of adiponectin receptor 1 in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats is low despite high plasma adiponectin level, and low expression of PPARs in BAT leads to less sensibility of adiponectin release from brown adipocytes to a PPAR gamma agonist in obese (fa/fa) Zucker rats.     

Effects of coadministered growth hormone (GH)-releasing hormone and GH-releasing hexapeptide on maladaptive aspects of obesity in Zucker rats.

The purpose of this study was to determine the effect of chronic pharmacological stimulation of the pituitary gland on GH hyposecretion and other maladaptive aspects of obesity. Obese Zucker rats were coadministered GH-releasing hormone (GHRH; 3 micrograms/kg) and GH-releasing hexapeptide (GHRP-6; 300 micrograms/kg), a potent combination of synergistic GH secretagogues, once daily for 60 consecutive days. Although pituitary weights and GH concentrations were higher in obese rats administered the peptides than in obese rats administered saline, stimulated GH secretion was lower in obese rats than in lean rats. However, compared to those in lean rats, plasma insulin-like growth factor-I and insulin concentrations were higher in the obese rats regardless of treatment. The GH secretagogues did not alter food intake or body weight gain in sexually mature obese rats, whereas body weight gain was significantly increased when they were administered to prepubertal obese rats. Although glucose tolerance was impaired in both groups of obese rats, it improved in obese rats administered GHRH and GHRP-6 compared to that in obese rats administered saline. On the other hand, plasma cholesterol concentrations were elevated in obese rats administered the GH secretagogues but not saline. In conclusion, the results of this study suggest that hyposensitivity to GHRH and GHRP-6 in obese Zucker rats results from high concentrations of plasma insulin-like growth factor-I that negatively feedback on stimulated GH secretion. Nonetheless, daily episodes of endogenous GH secretion resulting from chronic coadministration of GH secretagogues significantly influenced the pituitary gland as well as lipid and carbohydrate metabolism.     

The metabolic clearance rate of corticosterone in lean and obese male Zucker rats

The obese Zucker rat is an animal model of human juvenile-onset obesity. These rats exhibit numerous endocrine and metabolic abnormalities. Adrenalectomy of obese rats has been shown to reduce or reverse several of these abnormalities, thereby implying that corticosterone may contribute to the expression of obesity in this animal. Furthermore, it has been shown that the circadian rhythm of plasma corticosterone is disturbed in obese Zucker rats resulting in elevated morning plasma corticosterone concentrations in obese rats as compared to lean rats. In a effort to better elucidate the mechanism of the elevated morning levels of plasma corticosterone, the metabolic clearance rate of corticosterone was determined in the morning for lean and obese male Zucker rats (12 to 20 weeks). Additionally, the biliary and urinary excretion of labeled corticosterone and/or its metabolites were determined. The metabolic clearance rate of corticosterone was significantly greater in obese rats than in their lean counterparts. Both the metabolic clearance rate and the volume of compartments significantly correlated with body weight. No correlation was found between body weight and the elimination rate constant. The increased metabolic clearance rate of obese rats appeared to be due to an increase in the physiologic distribution of corticosterone and not to an alteration in the enzymes responsible for corticosterone metabolism. It appears that the metabolic clearance rate of corticosterone in obese Zucker rats does not contribute to elevated morning concentrations of plasma corticosterone previously observed in these animals. It suggests that the adrenal corticosterone secretion rate must actually be greater than one would expect from the plasma corticosterone concentrations alone.     

Different responsiveness in body weight and hepatic 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 mrna to 11beta-HSD inhibition by glycyrrhetinic acid treatment in obese and lean zucker rats

Tissue-specific dysregulation of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity in obese humans and animals may be associated with obesity and the metabolic syndrome. We investigated the effect of inhibition of 11beta-HSD with glycyrrhetinic acid (GE), an effective 11beta-HSD inhibitor, on body weight regulation in obese Zucker rats, which have a defect in the leptin receptor gene. GE (280 mg/kg/d) was administered in drinking water to 8-week-old male Zucker rats for 14 weeks. GE had no effect on food intake or weight gain, and did not affect hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels in obese rats. In contrast, average daily food intake and body weight on week 14 were significantly reduced by GE in lean rats (both P <.0001). Hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels were also significantly decreased by GE in lean rats (both P <.05). GE had no significant effect on plasma corticosterone levels in obese rats but lowered them in lean rats (P <.05). Plasma leptin levels declined in both GE-treated obese and lean rats (both P <.01). In conclusion, long-term GE treatment decreased weight gain in lean Zucker rats but not in obese Zucker rats. These findings suggest that the differing responses of 11beta-HSD1 to GE in obese and lean Zucker rats are closely associated with the different weight-gain responses. Furthermore, the weight-lowering effect of GE may require intact leptin receptors.     

The effect of vigorous treadmill exercise on plasma lipoproteins and hepatic lipoprotein production in Zucker rats

Chronic exercise has been shown to alter plasma lipids in man and animals, but the mechanism(s) responsible for this phenomenon have not been clarified. In the present study we have examined the role of the liver in the production of lipoproteins following an intensive exercise regimen in lean and obese Zucker rats. Four-week-old lean and obese male Zucker rats were subjected to a vigorous exercise regimen of running on a motor-driven treadmill for 10 weeks. Hepatic lipoprotein cholesterol production was then assessed using liver perfusion techniques. Plasma cholesterol concentration was significantly lower in both lean and obese runners versus appropriate non-exercised controls. This decrease was due to a decline in both chylomicron and HDL cholesterol. Exercise had no affect on plasma VLDL and LDL cholesterol concentrations. Hepatic VLDL cholesterol production was elevated in obese rats versus lean rats and was not affected by exercise in runners of either phenotype. Hepatic HDL cholesterol production was higher in lean runners but was unchanged in obese runners. Plasma triglyceride was reduced by 50% in exercised obese rats. In summary, intense exercise decreased plasma triglyceride, cholesterol, and HDL cholesterol concentrations in lean and obese Zucker rats. Since hepatic HDL cholesterol production was increased and hepatic VLDL cholesterol production was unaffected by exercise, the changes in plasma lipid levels observed following exercise appear to be mediated by extrahepatic mechanisms.     

Carbohydrate metabolism in lean and obese Zucker rats

Carbohydrate metabolism was evaluated in lean and obese Zucker rats. Plasma glucose concentration, renal and hepatic gluconeogenesis, and hepatic glycogen content and rates of synthesis were investigated in 2-mo and 8-mo-old animals. Mild hyperglycemia was observed in obese Zucker rats compared to lean rats and was more pronounced in males than in females. Rates of glucose disappearance were normal in both female and male rats, although there was a trend toward decreased clearance in the male. Total organ hepatic and kidney PEPCK activity and kidney glucose production were elevated in obese compared to lean rats. Total organ hepatic glycogen levels and rates of glycogen synthesis were increased significantly in obese compared to lean, the increase being greater in males than females. The mild hyperglycemia present in obese Zucker rats is not associated with delayed disappearance of intravenously administered glucose, but may be due to the increased production of glucose by whole kidney and liver.     

Atherogenesis in two strains of obese rats. The fatty Zucker and LA/N-corpulent

Two strains of obese rats, the fatty Zucker and the LA/N-corpulent have been compared at 6 months age for the presence of vascular and myocardial disease. Both strains, when obese, exhibit a VLDL hyperlipidemia with elevated triglycerides and moderate elevations of plasma cholesterol concentrations compared to the lean rats of the same strain. The hyperlipidemia is more modest in the fatty Zucker than the corpulent LA/N, and the serum lipid concentrations of the lean Zucker are lower than those of the lean LA/N. Apolipoprotein concentrations were similar and elevated in the two obese genotypes compared to the lean genotypes which were also similar to each other. Male and female obese animals of both strains exhibited hyperinsulinemia under fasting conditions and after oral glucose, with obese male LA/N rats exhibiting the most severe hyperinsulinemia. Glucose tolerance was impaired in obese LA/N animals but was normal in lean rats of both strains and fatty Zucker rats of both sexes. The glucose intolerance observed in obese LA/N animals was more severe in the male than in the female rats. Unlike the corpulent rat, which develops atherosclerotic lesions, the fatty Zucker shows no evidence of advanced vascular lesions on scanning electron microscopy. The fatty Zucker also does not develop the myocardial lesions that are frequent in the male corpulent LA/N rat. It is suggested that the initiation of the atherogenic process is dependent upon elevated insulin levels or transient hyperglycemia. Development of the advanced lesions appears to require the presence of hyperlipidemia.     

The effects of gonadectomy on glucose tolerance of genetically obese (fa/fa) rats: influence of sex and genetic background.

In both humans and rodents the occurrence and severity of obesity-associated non-insulin dependent diabetes mellitus (NIDDM) may be influenced by both gonadal hormones and genetic background. Early gonadectomy (at 3-5 days of age) of female and male Wistar diabetic fatty (WDF) rats and of male Zucker rats allowed us to examine these effects in genetically obese rats carrying the fatty (fa) gene. Impairment of glucose tolerance and insulin sensitivity by obesity, and amelioration or exacerbation (in the case of female rats) of this impairment by gonadectomy were assessed by intragastric glucose tolerance tests when the rats reached adulthood. Both glucose tolerance and insulin sensitivity were significantly deranged in obese WDF rats of both sexes and in obese male Zucker rats compared to lean controls of the same sex and strain. Obese male WDF rats were less glucose tolerant and insulin sensitive than were obese male Zucker rats. Glucose intolerance was not ameliorated by castration in lean or obese male WDF or Zucker rats. Insulin sensitivity was significantly improved by castration in obese male rats of both strains, as fasting plasma insulin levels and total areas under the insulin curves were significantly reduced compared to obese sham-operated controls. This effect was greater in the Zucker than in the WDF male rats. Castration significantly decreased the insulin response areas in obese male Zucker rats, but did not alter those of the obese male WDF rats. Ovariectomy did not alter glucose homeostasis of obese female WDF rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cholesterol homeostasis in lean and obese male Zucker rats

Studies were performed in male Zucker rats to determine the metabolic effect of genetic obesity on whole body cholesterol homeostasis. Lean and obese mature Zucker rats were studied during intake of either a chow diet or a semisynthetic diet containing 10% corn oil; in addition growing animals were studied during constant body weight gain on a chow diet. Under all conditions the obese Zucker rats had significantly higher levels of total plasma cholesterol and triglyceride; however, measurements of the specific activity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase and of the rate of whole body cholesterol synthesis by sterol balance techniques demonstrated that the lean and obese animals did not differ in their endogenous rates of cholesterol synthesis. When sterol balance data were calculated per kilogram body weight, lean male Zucker rats synthesized a greater amount of cholesterol per day than obese animals. These studies demonstrate that the obese male Zucker rat, in many ways a model of human obesity, does not overproduce cholesterol and thus fails to exhibit one of major characteristics of the obese human.     

Growth hormone treatment reduces total body fat accumulation in Zucker obese rats

Lean and obese Zucker rats were injected daily intraperitoneally with high doses (5-10 mg/kg) of human growth hormone (GH) for 3 weeks. In the obese rats after GH treatment, carcass lipid was decreased by 50 percent, and bone weight increased to levels of lean controls. During the last two weeks of GH treatment, food intake was increased in lean rats and not significantly affected in obese rats. Loss of body weight in obese animals was masked by water retention. Serum insulin concentrations were doubled in obese animals but unchanged in lean phenotypes after GH treatment. Hepatic fatty acid oxidation in obese animals was stimulated 5-fold by treatment, while hepatic lipid synthesis was stimulated 2-fold and adipose lipid synthesis was reduced 3-fold. These results suggest that growth hormone induces a partitioning of nutrients in obese rats which results in less lipid accumulation.     

Lipoprotein and apolipoprotein distribution in Zucker rats following an endurance running program

We examined the response to 12 weeks of endurance running of the obese Zucker rat and its lean littermate with regard to changes in serum lipids, lipoproteins and apoproteins. The obese Zucker rat is hyperlipoproteinemic, characterized by elevated serum triglyceride and cholesterol levels primarily associated with the very low density lipoprotein (VLDL) fraction. In lean Zucker rats, training did not affect the concentrations of serum lipids or apolipoproteins. In marked contrast, obese Zucker rats that were trained had significant decreases in serum concentrations of triglycerides, free and esterified cholesterol, and apolipoprotein B compared to their sedentary counterparts. Training obese rats caused an increase in the serum concentration of apolipoprotein E (HDL fraction). In contrast, training did not affect the concentration of Apo E in lean rats. The VLDL fraction was most affected by training obese rats showing marked 50-65% decreases in VLDL triglyceride and VLDL cholesterol. HDL cholesterol was unchanged in lean rats whereas training prompted a 29% increase in obese rats. These data show that exercise training altered the metabolic abnormalities of obese Zucker rats which are responsible for the accumulation in serum of VLDL, lipids and apolipoproteins.     

Increased hypothalamic content of preproneuropeptide Y messenger ribonucleic acid in genetically obese Zucker rats and its regulation by food deprivation

Neuropeptide Y (NPY) is a potent orexigenic agent capable of producing hyperphagia and obesity. NPY-containing neurons project from the hypothalmic arcuate nucleus to the paraventricular nucleus, an area known to be sensitive to the orexigenic effects of NPY. In this study we investigated the possibility that preproNPY messenger RNA (mRNA) content may be altered in obese Zucker rats compared to that of their lean littermates. Total RNA was isolated from hypothalamic dissections from male and female, obese and lean Zucker rats. RNA was also isolated from dissections of: olfactory bulb, entorhinal cortex, hippocampus, and striatum of female obese and lean rats. PreproNPY mRNA content was determined by solution hybridization-RNase protection analysis. The results revealed a 2- to 3-fold increase in preproNPY mRNA levels in the hypothalamus of obese animals compared to lean. The increase was observed in both sexes and was specific to the hypothalamus. In situ hybridization localized this increase to the arcuate nucleus. An additional RNase protection study was pursued to investigate the effects of 72 h food deprivation on hypothalamic preproNPY mRNA levels in lean and obese animals. Lean animals displayed an approximate 2-fold increase in preproNPY mRNA content, whereas obese animals showed no significant increase after food deprivation. These data are consistent with the hypothesis that NPY projections within the hypothalamus are involved in regulating feeding behavior and weight gain, and that disturbed regulation of hypothalamic NPY expression may play a role in the etiology of obesity in the genetically obese Zucker rat.     

Pancreatic hypersensitivity to glucose by young obese Zucker rats (fa/fa)

Insulin secretory response to glucose was investigated in 5- to 6-week-old male Zucker obese (fa/fa) and lean (Fa/Fa) rats using a pancreatic perfusion procedure. Blood glucose response to fasting was studied in lean and obese animals over 24 hours. Plasma glucose was slightly elevated in pentobarbital-anesthetized obese rats. However, plasma insulin was 4.6 times greater than that of leans. A hypoglycemic glucose stimulus (75 mg/dL) caused pancreata from obese animals to release 6 times more insulin than lean animals. Stimuli of 125 mg/dL (normoglycemic) and 600 mg/dL (hyperglycemic) caused hypersecretion of 8 and 5 times, respectively. Hypersecretion was not accounted for solely by the twofold increase in pancreatic insulin content. Obese animals had steeper decreases in plasma glucose than lean controls during seven to 13 hours of fasting. Hypersecretion by pancreata from young obese rats to physiological levels of glucose may result in hyperphagia in order to maintain normoglycemia.     

Endogenous opioids modulate ventilation in the obese Zucker rat

This study evaluated the modulatory role of endogenous opioids on ventilation in young and mature, lean and obese male Zucker rats. Naloxone, an opioid receptor antagonist, and saline (control) were administered subcutaneously to awake rats, and ventilation in air and in response to an hypoxic and an hypercapnic gas challenge measured. In response to naloxone young,obese but not lean rats exhibited a marked increase of ventilation in all three conditions. Older obese Zucker rats that were morbidly obese breathed at a frequency of over 200 breaths per minute and showed only a modest increase of ventilation in response to naloxone. Older lean rats increased ventilation with naloxone only when exposed to hypercapnia. Unlike the stimulatory effects hypoxia and hypercapnia had on ventilation in older, lean rats, the ventilatory responses of the obese, older rats to hypoxia and to hypercapnia were blunted. We conclude that the obese Zucker rat may be a good animal model to assess how chest wall loading and endogenous opioids interact in the development of ventilatory control abnormalities.     

Metabolic consequences of fasting in old lean and obese Zucker rats

The effects of fasting on lipid and carbohydrate metabolism and plasma insulin and glucagon levels were compared in lean and obese Zucker rats. Sixteen-month-old female and male rats were fasted for periods of 2, 4, 6 and 12 days. Fasting produced significant decreases in hepatic rates of lipid, cholesterol, and glycogen synthesis, as well as circulating levels of triglycerides, cholesterol, phospholipids, and insulin. Significant increases in hepatic lipid levels and serum free fatty acids were noted. When compared to lean rats, obese rats had elevated rates of hepatic lipid and glycogen synthesis, hepatic lipid and glycogen stores, serum triglycerides, cholesterol, phospholipids, and plasma insulin. Lean rats had higher plasma glucagon levels. Sex differences in several parameters were observed. Females demonstrated higher levels of lipid and cholesterol synthesis and serum free fatty acids, whereas serum cholesterol levels and hepatic glycogen stores were higher in males. Following a 12-day fast, carcass fat and protein content were decreased in both lean and obese rats, but the obese animals maintained an obese body composition. It is concluded that fasting results in qualitatively similar metabolic and hormonal changes in both lean and obese rats, but that abnormalities in carbohydrate and lipid metabolism persist in obese rats even after a 12-day fast.