Genetic obesity in rats. II. The effect of food restriction on the metabolism of adipose tissue

The metabolism of adipose tissue from genetically obese rats (Fatty) and lean animals was studied in two experiments. In the first experiment, food intake was regulated at three levels in Fatty rats. One group ate ad lib., a second group was pair fed to lean controls, and the third group received two-thirds of the food eaten by the lean rats. Serum insulin was reduced by restricting food intake. Fat cells were largest in the ad lib.-fed Fatties and smallest in the lean rats. Lipolysis, as measured by glycerol release, was comparable in lean and Fatty rats. Several lipolytic drugs were as effective in fat from the obese as the lean animals. Metabolism of ¹⁴C-glucose with or without insulin was reduced in the tissue from Fatty rats and was not corrected by restricting food intake. In the second experiment, lipolysis and lipogenesis were studied by serial biopsies during starvation-induced weight loss. Rats were allowed to eat for 3 days before each biopsy. Reduction of fat cells to the same size as normals did not restore lipogenesis or lipolysis to normal. Reesterification of fatty acids remained high in all experiments with tissues from Fatty rats.     

Regulation of bile acid pool size and plasma lipid levels in the SHR/N-corpulent rat: influence of the level of caloric intake

In the obese progeny of the SHR/N-cp strain of the rat the bile acid pool was at least twice as large as that in their lean littermates even when only 6 weeks old. The composition of the pool remained unchanged in the obese females, but in their male counterparts the proportion of cholic acid was significantly increased. Cholestyramine feeding reduced the pool size by 26% in the obese rats, but a similar effect also occurred in the lean animals. The obese rats consumed about 60% more food per day than their lean littermates. When obese females were pair-fed to the intake of their lean controls from 6 to 11 weeks of age, the bile acid pool remained significantly enlarged, although not to the same extent as in the obese rats fed ad lib. Plasma cholesterol levels were reduced but remained significantly higher than the levels in the lean animals. The marked hypertriglyceridemia exhibited by the obese rats fed ad libitum did not develop in their pair-fed counterparts. In contrast, there was a comparatively smaller reduction in plasma cholesterol and triglyceride levels in the obese rats fed cholestyramine. Hepatic steatosis persisted in the pair-fed animals as well as in those given cholestyramine. Restricting caloric intake significantly reduced the body weight gain of the obese rats but had little effect on the extent of their corpulence. These studies show that at least some of the characteristics of this congenic strain, including hypertriglyceridemia and hepatic and intestinal hypertrophy, are due mainly to excess dietary intake.(ABSTRACT TRUNCATED AT 250 WORDS)     

Leptin responsiveness in chronically decerebrate rats

Peripheral infusions of physiological doses of leptin decrease body fat mass, but it is not known whether this results from direct effects on peripheral tissue or activation of central leptin receptors. In this study, we infused chronically decerebrate (CD) rats, in which the forebrain was surgically isolated from the caudal brainstem, with 60 microg leptin/d or PBS for 14 d from ip mini-osmotic pumps. The CD rats were tube fed an amount of food equivalent to the intake of ad libitum-fed intact controls or 75% of this amount to account for their reduced energy expenditure. Control rats fed ad libitum or tube fed 75, 100, or 125% of their ad libitum intake also were peripherally infused with leptin or PBS. CD rats had a lower serum testosterone, energy expenditure, and lean body mass compared with controls but had increased levels of adiponectin and leptin and were obese. Leptin increased body fat and decreased energy expenditure during the light period in 100%-fed CD rats, but not 75%-fed CD rats. Leptin decreased body fat of ad libitum- and 100%-fed but not 75%-fed or 125%-fed intact controls. Energy expenditure did not change in any control group. These results show that leptin can change body fat independent of a change in food intake or energy expenditure, that the forebrain normally prevents leptin from inhibiting energy expenditure through mechanisms initiated in the caudal brainstem or peripheral tissues, and that the leptin response in both intact and CD rats is determined by the energy status of the animal.     

Body composition and in vitro lipid metabolism of overfed hypophysectomized rats

Hypophysectomized (hypox) rats were fed ad libitum or were tube-fed increasing levels of their normal food intake. Sham operated (sham) rats were tube-fed to maintain their normal rate of growth or were fed 150 percent of their ad libitum food intake. This was equivalent to the highest intake of hypox rats. Overfeeding continued for 20 days. Overfeeding hypox rats increased body weight almost entirely by hypertrophy and hyperplasia of body fat depots. Overfeeding did not promote growth of lean tissue in hypox rats. Serum insulin increased with higher levels of food intake and extreme overfeeding resulted in hyperinsulinemia and hyperglycemia in hypox rats. Serum thyroid hormones and corticosterone were lower in hypox than sham rats and were not significantly changed by overfeeding. Adipose and hepatic fatty acid synthesis and esterification and adipose glycerol release were measured in vitro. Although serum insulin increased, peripheral tissue of overfed hypox rats remained insulin resistant. Rates of hepatic and adipose lipid synthesis and adipose lipolysis appeared to be determined by nutrient availability rather than being dependent upon pituitary factors.     

Aging and dietary modulation of rat skeleton and parathyroid hormone

Studies were carried out on SPF F344 male rats to evaluate the effects of aging and life-prolonging food restriction, without malnutrition, on rat skeleton and circulating PTH. Six-week-old F344 rats were divided into five groups. Group 1 rats were fed ad libitum a diet that contained 21% protein. Group 2 rats were fed 60% of the mean food intake of group 1 rats from 6 weeks of age for the rest of their lives. Group 3 rats were fed 60% of the ad libitum food intake until 6 months of age and then switched to ad libitum feeding. Group 4 rats were fed ad libitum until 6 months of age, and then switched to 60% of the ad libitum food intake. Group 5 rats were fed ad libitum a diet that contained only 12.6% protein so that these animals ingested the same amount of protein per day as the group 2 rats. In group 1 animals, bone length, weight, density, and calcium content increased rapidly with age and plateaued at about 12 months of age. There was no evidence of bone loss in these animals until about 24 months of age, but by 27 months, the animals had lost appreciable amounts of bone. The circulating immunoreactive PTH levels of the animals increased with advancing age, with a marked rise at 27 months. The age-related changes in bone and serum PTH levels of rats in groups 3 and 5 were similar to those of group 1 animals, except that a terminal increase in serum PTH did not occur in group 5 rats. In the groups 2 and 4 animals which were food restricted for the longest period, bone growth and maturation were slowed down, but the animals did not experience senile bone loss or marked terminal increase in circulating PTH. The salutary effects of food restriction were, therefore, not due specifically to the restriction of protein intake or to restricting food intake only during the period of rapid growth.     

Undernutrition potentiates melatonin effects in maturing female rats

Prepubertal (21-22 days) female Sprague-Dawley rats were caged singly in either long (LP; 14:10 LD) or short (SP; 8:16 LD) photoperiod and fed ad libitum or underfed (1/2 the food intake of controls). Additionally, a fed and underfed group in LP received a daily sc injection of saline or 100 micrograms melatonin at 1700 h. Food restriction delayed vaginal opening and resulted in a reduction in body weight and in the weights of the pituitary, ovary and uterus in all underfed groups. Melatonin treatment (but not SP exposure) significantly enhanced the reduction in pituitary, ovarian and uterine weight compared to the underfed saline-treated controls. Thyroid weights were significantly increased in underfed LP and SP groups compared to their respective controls where melatonin treatment in either fed or underfed animals was ineffective. Underfeeding caused a significant rise in pituitary LH (except for SP-underfed group) and FSH concentrations and a fall in pituitary prolactin concentrations and plasma T3 levels. Melatonin injections in underfed rats significantly increased pituitary LH and FSH and decreased prolactin concentrations compared to underfed saline-treated animals. Plasma prolactin levels increased after melatonin administration in both fed and underfed rats. These observations emphasize that environmental influences such as undernutrition can alter the physiological status of immature animals and enhance the sensitivity of the neuroendocrine axis to the pineal and one of its hormones, melatonin.     

Lactate dehydrogenase and isoenzyme changes in rats with experimental thiamine deficiency.

Heat and liver lactate dehydrogenase (LDH) and isoenzyme distributions were studied in rats with experimental thiamine deficiency. No change in total heart LDH activity was observed on days 24 and 40 of a thiamine deficient diet. At the time of symptoms (average 53 days on diet), total heart muscle LDH was slightly decreased in thiamine deficient rats (248 +/- 12 U/g tissue, Mn +/- SE) compared to ad lib fed controls (293 +/- 12, p less than 0.05), but did not differ from pair fed controls (273 +/- 15). Heart muscle LDH isoenzyme distribution showed a relative increase in the H4 band and a decrease in the H2M2 and HM3 bands in thiamine deficiency on day 24. This pattern became more promient by day 40. Calculated total M-LDH activity of heart muscle in thiamine deficient rats was significantly decreased at day 40 (44 +/- 3) compared to pair fed controls (57 +/- 5, p less than 0.05) and ad lib fed controls (85 +/- 7 p less than 0.001). Further changes were not observed in the symptomatic stage. Total H-LDH in heart muscle did not change during the period of study, while total liver LDH activity was reduced in thiamine deficient rats at the symptomatic stage (137 +/- 15) compared with pair fed controls (193 +/- 12, p less than 0.05) and ad lib fed controls (407 +/- 50, p less than 0.01). Liver isoenzyme electrophoresis showed an almost 100% distribution to the M4 band. The present investigation demonstrates a decrease in cardiac muscle M-LDH in experimental thiamine deficiency. Differences in LDH isoenzyme distribution in chronic hypoxia and thiamine deficiency are discussed.     

Lifelong dietary modulation of calcitonin levels in rats

Studies were carried out on specific pathogen-free rats to evaluate the effects of aging and dietary manipulation on serum and thyroid calcitonin (CT) levels. Male Fischer 344 rats were randomized at 6 weeks of age to six dietary groups and subsequently maintained on the following dietary regimens. Group 1 rats were fed ad libitum throughout life; group 2 rats were fed 60% of the ad libitum food uptake, but received the same amounts of calcium, phosphorus, and vitamin D; group 3 rats were fed as the group 2 animals until 6 months of age and from then on were fed ad libitum; group 4 rats were fed ad libitum until 6 months of age and then switched to 60% food restriction; group 5 rats were fed ad libitum on food isocaloric with that of group 1 rats, but containing only 60% of the protein. Group 6 rats were killed at 6 weeks of age to serve as baseline controls. Ten rats were killed in each of the remaining five groups 15 h postprandial at 6-month intervals. The following observations were made. Serum CT increased with age similarly in the ad libitum fed group 1 and 5 rats. Food restriction markedly inhibited the increase in serum CT, and the effect was more profound in animals whose food intake was restricted after 6 months of age (group 4) than in animals on lifelong food restriction (group 2). In rats switched from food restriction to ad libitum feeding (group 3) at 6 months of age, serum CT increased with age to levels identical with those of lifelong ad libitum fed group 1 animals. Thyroid CT showed a similar pattern of age-dependent and dietary modulated changes. In contrast, aging and dietary modulation had no appreciable effect on serum calcium levels, except at 27 months of age when the serum calcium level of group 1 animals increased dramatically from the level for 24-month-old animals. There was a weak positive correlation between serum calcium and serum CT (r = 0.627; P = 0.02) and a highly significant positive correlation between serum CT and thyroid CT (r = 0.917; P = 0.001). These findings indicate that elective and therapeutic restriction of food intake might also attenulate CT levels in humans, with potentially adverse implications for skeletal homeostasis.     

Effects of oral and parenteral quinine on rats with ventromedial hypothalamic knife-cut obesity

The addition of quinine to the food reversed the obesity in rats with hypothalamic hyperphagia induced by knife cuts. Similarly, the injection of quinine into rats with hypothalamic knife cuts reduced food intake and body weight but the effects were smaller than those observed when quinine was added to the diet. Urinary quinine excretion was similar by the oral and parenteral routes. The food intake of the knife-cut animals receiving quinine gradually fell to the same level as in the sham-operated animals receiving quinine by either route. The weights of retroperitoneal fat pads were related to the weights of the animals and were reduced in the quinine-treated groups. Plasma insulin concentrations were significantly higher in the knife-cut animals and were reduced toward control levels by quinine treatment. Gluconeogenesis, measured by incorporation of radioactivity from labeled bicarbonate into glucose, was unaffected by treatment with quinine or by knife cuts. Lipogenesis from tritiated water in vivo was not different between treatment groups in the liver or retroperitoneal fat pads. However, in vivo lipogenesis was reduced in knife-cut rats fed ad libitum compared with quinine-treated rats. The response of lipogenesis to insulin in vitro was also not different between treatment groups. These data suggest that a major part of the reduction in food intake in hyperphagic rats eating a quinine-adulterated diet is due to postingestional events.     

Thermogenic drugs for the treatment of obesity: screening using obese rats and mice

The thermogenic activity of ephedrine, ethinyloestradiol and triiodothyronine were compared by incorporating the drugs into the diets fed to groups of adult rats and mice. The animals used were normal lean mice, hypothalamic obese mice, dietary-induced obese mice and rats, and genetically obese mice and rats. Food intake and body weight were monitored throughout and oxygen consumption measurements were made. Finally, the animals were killed and their carcasses analysed. Generally, ethinyloestradiol reduced body weight by causing anorexia. Triiodothyronine increased oxygen consumption but also increased food intake such that in most cases body weight did not change; it killed the genetically obese animals, but reduced fat in the hypothalamic and dietary induced obese animals. The animals treated with ephedrine lost body weight and body fat without increasing food intake, and had elevated oxygen consumptions. This experiment not only demonstrated marked differences between the various laboratory animal models of obesity, but also that ephedrine is a potential slimming agent. It is relatively safe and has been used by us to obtain successful breeding using the genetically obese male animals which are normally sterile.     

Effect of chronic feeding of ethanol diet of “average” fat content on rat pancreas

The present study was done to determine the influence of dietary fat on the effect of ethanol on pancreatic macromolecular content and secretion. Weight-matched groups of Sprague-Dawley rats were divided into controls fed Rodent-Blox ad libitum; American Institute of Nutrition-76 (AIN-76) diet containing 12% calories as fat with 36% of carbohydrate calories replaced with 5% (weight/volume) concentration of ethanol fed ad libitum pair fed with animals given isocaloric amounts of AIN-76 diet for three to six months. Compared with Rodent-Blox fed controls, tissue content of trypsinogen, chymotrypsinogen, amylase, and lipase; specific activity and concentration of trypsinogen, chymotrypsinogen; and concentration of amylase were decreased at six months in AIN-76 fed controls. These changes did not result from diminished food intake, but were due to adaptation to the liquid diet. Animals fed AIN-76 diet plus ethanol did not show significant difference in the total content, specific activity, concentration, and secretion of digestive enzymes compared with those animals pair fed isocaloric amounts of AIN-76 diet. Activation of trypsinogen by exogenous trypsin was lower in rats fed AIN-76 diet and a similar change was observed in animals fed AIN-76 diet with ethanol for six months. These findings are in contrast to increased secretion of proteases and decreased trypsin inhibitor observed previously in animals fed ethanol in a diet containing "high" fat. These data indicate that ethanol effect on the pancreas is modified by dietary intake of fat and/or carbohydrates.     

Body composition of lean and obese Zucker rats in parabiosis

Parabiosis is the surgical union of two animals to produce a chronic blood exchange. This model has previously been used to demonstrate the involvement of a blood-borne factor in the feedback control of food intake and regulation of energy balance. It has been hypothesized that obese rats produce a humoral agent that acts centrally to inhibit food intake and accumulation of fat. In this study 50-day-old male or female Zucker rats were joined in either lean-lean pairs or lean-obese pairs. They ate ad libitum until 152 days of age when body composition was determined. Parabiosis inhibited growth in all rats compared with single controls. Lean partners of obese rats had reduced carcass weights, the same percent body protein but less fat than members of lean-lean pairs. Female rats showed larger changes in body composition than did males. These results suggest that obese Zucker rats produce the hypothesized regulatory signal but do not respond to it.     

Effect of food intake on intestinal absorption and mucosal hydrolases in alloxan diabetic rats

The relation between food intake and enzyme activity of the small intestine and rate of intestinal absorption were studied in rats 15 days after induction of alloxan diabetes. Diabetic rats were given an ad lib. semisynthetic diet or a restricted diet on the basis of either daily intake or body weight. The rates of absorption of 5mM D-galactose and L-valine were determined in vitro by the everted sac method. The rates of absorption of the substances, expressed per unit weight or per length of intestine, were higher in diabetic rats than in controls, regardless of the amount of food consumed. Maltase and sucrase activities were significantly increased in diabetic rats, regardless of the amount of food consumed. The activity of intestinal alkaline phosphatase was increased in diabetic rats fed ad lib., but not in those on a restricted diet. These findings suggest that in alloxan diabetic rats the increased disaccharidase activity in the small intestine is due to insulin deficiency, and that the increased activity of alkaline phosphatase is only a secondary effect of insulin deficiency, caused by increased food intake resulting from insulin deficiency.     

Recurrent intermittent restraint delays fed and fasting hyperglycemia and improves glucose return to baseline levels during glucose tolerance tests in the Zucker diabetic fatty rat--role of food intake and corticosterone

Short-term elevations of stress hormones cause an increase in glycemia. However, the effect of intermittent stress on development of type 2 diabetes mellitus is unclear. We hypothesized that recurrent intermittent restraint stress would deteriorate glycemia. Male, prediabetic Zucker diabetic fatty (ZDF) rats were restrained 1 hour per day, 5 days per week for 13 weeks and compared with unstressed, age-matched diabetic controls and lean nondiabetic rats. To differentiate the effects of recurrent restraint stress per se vs restraint-induced inhibition of food intake, a pair-fed group of rats was included. Surprisingly, recurrent restraint and pair feeding delayed fed and fasting hyperglycemia, such that they were lowered 50% by restraint and 30% by pair feeding after 13 weeks. Rats that were previously restrained or pair fed had lower glucose levels during a glucose tolerance test, but restraint further improved the return of glucose to baseline compared to pair feeding (P<.05). This was despite pair-fed rats having slightly lowered food intake and body weights compared with restrained rats. Restraint and pair feeding did not alter insulin responses to an intraperitoneal glucose tolerance test (IPGTT) or fasting insulin, and did not lower plasma lipids. Interestingly, restraint normalized basal corticosterone to one third that in control and pair-fed rats, prevented increases in pretreatment corticosterone seen with pair feeding, and led to habituation of restraint-induced corticosterone responses. After 13 weeks of treatment, multiple regression analysis showed that elevations in basal corticosterone could explain approximately 20% of the variance in fed glucose levels. In summary, intermittent restraint and its adaptations delayed hyperglycemia and improved glucose control in Zucker diabetic fatty rats. These benefits can be partially explained by restraint-induced lowering of food intake, but additional improvements compared to pair feeding may involve lower overall corticosterone exposure with repeated restraint. Paradoxically, these novel investigations suggest some types of occasional stress may limit development of diabetes.     

Decreased food intake does not completely account for adiposity reduction after ob protein infusion.

The effects of recombinantly produced ob protein were compared to those of food restriction in normal lean and genetically obese mice. Ob protein infusion into ob/ob mice resulted in large decreases in body and fat-depot weight and food intake that persisted throughout the study. Smaller decreases in body and fat-depot weights were observed in vehicle-treated ob/ob mice that were fed the same amount of food as that consumed by ob protein-treated ob/ob mice (pair feeding). In lean mice, ob protein infusion significantly decreased body and fat-depot weights, while decreasing food intake to a much lesser extent than in ob/ob mice. Pair feeding of lean vehicle-treated mice to the intake of ob protein-treated mice did not reduce body fat-depot weights. The potent weight-, adipose-, and appetite-reducing effects exerted by the ob protein in ob protein-deficient mice (ob/ob) confirm hypotheses generated from early parabiotic studies that suggested the existence of a circulating satiety factor of adipose origin. Pair-feeding studies provide compelling evidence that the ob protein exerts adipose-reducing effects in excess of those induced by reductions in food intake.     

Effect of a glucosidase inhibitor on the metabolic response of diabetic rats to a high carbohydrate diet,consisting of starch and sucrose,or glucose

The metabolic consequences of the addition of BAY-g-5421 to a diet whose caloric value included 67% carbohydrate, comprising wheat starch (diet A), equal quantities of wheat starch and sucrose (diet B) or glucose (diet C) were studied in lean diabetic and non-diabetic rats. BAY-g-5421 led to a significant (30%) reduction in daily food intake of diabetic and non-diabetic rats fed diets A and B, respectively. In diabetic rats fed diets A and B with BAY-g-5421, daily urinary glucose was diminished ten-fold, while the post-prandial plasma glucose excursions were almost halved. Serum cholesterol, but not triglyceride concentrations, were reduced after five days, by the addition of BAY-g-5421 to diets A or B in non-diabetic rats, and in diabetic rats when the animals fed diets A and B were combined. BAY-g-5421 did not significantly alter the food intake, urinary glucose excretion, post-prandial plasma glucose excursions nor serum lipids in diabetic and non-diabetic rats fed diet C. These findings illustrate the therapeutic potential of BAY-g-5421 as an adjunct to the dietary management of diabetes mellitus.     

Effect of caloric restriction on basal insulin levels and the in vivo lipogenesis and glycogen synthesis from glucose in the Koletsky obese rat

Fasting plasma immunoreactive insulin levels increased with age in hyperinsulinemic Koletsky obese rats, being almost four times as high as in lean siblings at 3 mo (40 ± 5 μU/ml) and rising steadily to 82 ± 4 μU/ml at 6 mo (about seven times higher than lean siblings). Restricting the food intake of the obese rats markedly reduced but did not normalize the hyperinsulinemia, which in these rats was accompanied by normal plasma glucose concentrations. The incorporation in vivo of D-U-¹⁴C-glucose into tissue lipids and glycogen was measured 1 hr after the intravenous injection of 1 g glucose (containing 100 μCi D-U-¹⁴C-glucose) per kg body weight in obese rats eating ad libitum, obese rats after 3 mo on a restricted food intake, and lean siblings. All tissues (heart, diaphragm, skeletal muscle, and adipose tissues and liver) of obese rats exhibited a significantly greater lipogenesis from glucose than those of lean siblings. Dietary restriction of the obese rats reduced the ¹⁴C incorporation into lipid to levels not significantly different from lean controls in all tissues except skeletal muscle and liver, where, although greatly reduced, lipogenesis was still significantly higher than in lean rats. Glycogen synthesis tended to be greater in all tissues of obese rats than in lean animals. Dietary restriction of obese rats did not greatly affect glycogen synthesis.     

Different levels of food restriction have opposite effects on adipocyte cellularity and lipoprotein-lipase activity in obese rats

The effects of several levels of chronic energy restriction on epididymal and perirenal adipose tissue cellularity and lipoprotein lipase activity, serum glucose and insulin and hepatic enzyme activities were studied in lean Fa/- and genetically obese fafa rats. The restricted rats were compared to rats fed ad libitum 24/24h or 8/24h. Restricting time of feeding was associated with increases in fat cell number in the lean, increases in perirenal adipose tissue fat cell size and serum insulin in the obese and increases in lipoprotein lipase activity in both phenotypes. Mild food restriction (-25%) had similar effects in the obese: perirenal adipose tissue fat cell size and serum insulin levels were even higher but fat cell hyperplasia was reduced. Restriction by 50% normalized lipoprotein lipase activity and markedly reduced fat cell size in the lean; in the obese, lipoprotein lipase activity and insulin levels were similar to or lower than those of the corresponding ad libitum 24/24h group but fat cell hypertrophy was not particularly affected. Restriction by 75% in the obese prevented adipocyte hyperplasia. Furthermore, lipoprotein lipase activity in adipose tissue was normalized, serum insulin and lipids being within normal limits. However, these animals had large adipocytes and were still fat.     

Hypothalamic obesity in the weanling rat: effect of diet upon hormonal and metabolic alterations

Weanling rats with ventromedial hypothalamic (VMN) lesions were studied on diets varying in carbohydrate and fat content and after 48 hr of starvation to determine dietary effects on the specific endocrine-metabolic alterations associated with this model of experimental obesity. Neither food intake nor the increased carcass fat of VMN rats was affected by diet, though with starvation VMN rats lost more fat and less lean tissue than did controls. Hyperinsulinemia in VMN rats persisted on all diets but disappeared after starvation, at which time moderate hypoglycemia developed. Hypertriglyceridemia was present in VMN rats on fat containing diets but not on a fat-free diet unless the animals were subsequently starved. Increased glucose oxidation and conversion to lipid by adipose tissue of VMN rats was independent of diet and persisted during starvation. The rate of glycogen synthesis was not increased. Palmitate oxidation by VMN adipose tissue was reduced in fed animals but increased in starved animals when compared to similarly treated controls. The observed dissociation of hyperinsulinemia and hypertriglyceridemia as a consequence of dietary alteration and starvation suggests independent pathogenetic mechanisms for these variables. Similarly, persistence of enhanced glucose utilization by adipose tissue during starvation, and selective enhancement of glucose oxidation and lipid but not glycogen synthesis from glucose suggests the presence of a primary defect in VMN adipose tissue metabolism, at least partly independent of hyperinsulinemia.     

Intracerebroventricular infusion of leptin elevates the secretion of luteinising hormone without affecting food intake in long-term food-restricted sheep, but increases growth hormone irrespective of bodyweight

Leptin can act as a satiety factor and exert neuroendocrine effects, but most studies have been performed in fasted animals. We aimed to determine the effect of chronic under-nutrition on the response to a 3-day intracerebroventricular infusion of leptin with regard to food intake and the secretion of pituitary hormones. Ovariectomised ewes (n=6) had a mean (+/-s.e.m. ) bodyweight of 56+/-0.8 kg on a diet available ad libitum (ad lib) or 33.4+/-1 kg on a restricted diet. The differential bodyweight was achieved by dietary means over a period of 6 months prior to the commencement of the study. Leptin (4 microg/h) or vehicle (artificial cerebrospinal fluid (aCSF)) was infused into the third cerebral ventricle for 3 days. Blood samples were taken prior to commencement and on day 3 of infusion for the assay of plasma hormone levels. The experiment was repeated one week later in a cross-over design. Food intake and metabolic status were monitored daily. The luteinising hormone (LH) pulse amplitude was lower (P<0.05) but plasma growth hormone (GH) levels were higher (P<0.05) in the food-restricted animals. Plasma levels of glucose, lactate, insulin, urea and triglycerides were similar in the two groups but non-esterified fatty acid levels were higher (P<0.01) in the animals on an ad lib diet. Leptin reduced (P<0.05) food intake only in the animals fed an ad lib diet. Leptin increased (P<0.05) the secretion of LH in the food-restricted group only and increased (P<0.05) GH irrespective of bodyweight. In conclusion, leptin does not alter food intake in animals on a restricted diet but can increase the secretion of LH in the same animals. The treatment of leptin was not sufficient to reduce plasma GH levels in the food-restricted animals, suggesting that other factors or mechanisms must be involved in the regulation of this axis.