Melatonin is rhythmically secreted by both the pineal gland and retina in a circadian fashion, with its peak synthesis occurring during the night. Once synthesized, melatonin exerts its effects by binding to two specific G-protein coupled receptors-melatonin receptor type 1(MT1) and melatonin receptor type 2(MT2). Recent studies suggest the involvement of MT1 and MT2 in the regulation of glucose homeostasis; however the ability of melatonin signaling to impart timing cues on glucose metabolism remains poorly understood. Here we report that the removal of MT1 or MT2 in mice abolishes the daily rhythm in blood glucose levels. Interestingly, removal of melatonin receptors produced small effects on the rhythmic expression patterns of clock genes within skeletal muscle, liver, and adipose tissue. Taken together, our data suggest that the loss of the daily rhythm in blood glucose observed in MT1(-/-) and MT2(-/-) mice does not occur as a consequence of 'disrupted' clocks within insulin sensitive tissues. Finally our results highlight a diurnal contribution of melatonin receptor signaling in the daily regulation of blood glucose levels.

The incidence of obesity and type 2 diabetes mellitus (T2DM) has risen to epidemic proportions. The pathophysiology of T2DM is complex and involves insulin resistance, pancreatic β-cell dysfunction and visceral adiposity. It has been known for decades that a disruption of biological rhythms (which happens the most profoundly with shift work) increases the risk of developing obesity and T2DM. Recent evidence from basal studies has further sparked interest in the involvement of daily rhythms (and their disruption) in the development of obesity and T2DM. Most living organisms have molecular clocks in almost every tissue, which govern rhythmicity in many domains of physiology, such as rest/activity rhythms, feeding/fasting rhythms, and hormonal secretion. Here we present the latest research describing the specific role played by the molecular clock mechanism in the control of glucose metabolism and speculate on how disruption of these tissue clocks may lead to the disturbances in glucose homeostasis.

The mammalian biological clock, located in the hypothalamic suprachiasmatic nuclei (SCN), imposes its temporal structure on the organism via neural and endocrine outputs. To further investigate SCN control of the autonomic nervous system we focused in the present study on the daily rhythm in plasma glucose concentrations. The hypothalamic paraventricular nucleus (PVN) is an important target area of biological clock output and harbors the pre-autonomic neurons that control peripheral sympathetic and parasympathetic activity. Using local administration of GABA and glutamate receptor (ant)agonists in the PVN at different times of the light/dark-cycle we investigated whether daily changes in the activity of autonomic nervous system contribute to the control of plasma glucose and plasma insulin concentrations. Activation of neuronal activity in the PVN of non-feeding animals, either by administering a glutamatergic agonist or a GABAergic antagonist, induced hyperglycemia. The effect of the GABA-antagonist was time dependent, causing increased plasma glucose concentrations only when administered during the light period. The absence of a hyperglycemic effect of the GABA-antagonist in SCN-ablated animals provided further evidence for a daily change in GABAergic input from the SCN to the PVN. On the other hand, feeding-induced plasma glucose and insulin responses were suppressed by inhibition of PVN neuronal activity only during the dark period. These results indicate that the pre-autonomic neurons in the PVN are controlled by an interplay of inhibitory and excitatory inputs. Liver-dedicated sympathetic pre-autonomic neurons (responsible for hepatic glucose production) and pancreas-dedicated pre-autonomic parasympathetic neurons (responsible for insulin release) are controlled by inhibitory GABAergic contacts that are mainly active during the light period. Both sympathetic and parasympathetic pre-autonomic PVN neurons also receive excitatory inputs, either from the biological clock (sympathetic pre-autonomic neurons) or from non-clock areas (para-sympathetic pre-autonomic neurons), but the timing information is mainly provided by the GABAergic outputs of the biological clock.

The delivery rate of amino acids to an organism significantly affects protein anabolism. The rate can be controlled by the type and the timing of feeding. Our aim was to bring new insights to the way they may act.

During young and adult ages, when food supply is liberal, subjects can adapt to various modes of protein feeding. However, during food restriction, protein anabolism is favored when the delivery of amino acids is evenly distributed over the day, either with frequent meals, or through the use of slowly absorbed proteins like casein. In contrast, during aging, quickly absorbed protein sources become more efficient. During recovery after exercise, the timing of protein feeding after the end of exercise may or may not influence its anabolic effect, depending on the subject's age and the type of exercise.

The synchronization of variations in anabolic capability with amino acid supply partly explains the effects of the type and timing of protein feeding. This effect is modulated by the amount of amino acids required to increase whole-body proteins and by the signaling properties of some amino acids to stimulate protein synthesis. Indeed, the anabolic effect of amino acids is determined by their interaction with other anabolic factors (other nutrients or physiological factors, whose efficiency is mainly related to their effect on protein degradation). It is clear that benefits can be obtained from adapted protein feeding patterns.

The daily rhythm in feeding activity in mammals, as driven by the biological clock, largely determines the daily fluctuations in basal concentrations of glucose and insulin. To investigate a possible direct impact of the suprachiasmatic nucleus (SCN) on these parameters, we subjected intact rats and SCN-lesioned rats to a fasting regimen of 36 h, or to a scheduled feeding regimen of six identical meals equally distributed over the light:dark-cycle. Plasma profiles of glucose and insulin in rats during the final 24 h of the 36 h of fasting, and in rats subjected to the scheduled feeding regimen were compared to profiles in rats fed ad libitum. In rats fed ad libitum, in fasted rats and in rats subjected to a scheduled feeding regimen basal glucose concentrations showed a pronounced 24-h rhythm that was not found in rats that had been SCN-lesioned. Basal insulin levels showed a 24-h rhythm in 50% of the rats fed ad libitum and in 50% of the rats subjected to a scheduled feeding regimen; neither rhythms were present in SCN-lesioned rats. However, none of the fasted rats showed a 24-h rhythm in basal insulin concentrations. These data provide clear evidence that the SCN directly controls basal glucose concentrations independent of its influence on feeding activity. At the same time, we found no consistent evidence for a strong impact of the SCN on basal insulin concentrations.

To investigate whether there is a circadian regulation of insulin secretion, rats were adapted to a feeding regimen of six meals equally distributed over 24 h. Under these conditions basal glucose and insulin levels increased during the light phase and decreased during the dark phase. Maximal blood glucose responses were fairly similar during the six different meals, but glucose increments were clearly delayed during the last two meals consumed during the light period. Insulin increments were highest during the dark phase and clearly diminished during the second half of the light phase. This situation was reversed when the scheduled meals were replaced by i.v. glucose infusions, i.e., no significant differences were detected between insulin responses, whereas glucose increments were reduced during the dark period. These results show that there is a circadian regulation of basal blood glucose and feeding-induced insulin responses, which is independent of the temporal distribution of feeding activity.

Although hypothalamic injections of neuropeptide Y (NPY) induce robust feeding, there is little information about the patterns of feeding elicited by this peptide. To reveal these patterns, NPY (0, 8, 24, 78, 235 pmol/10 nl) was injected into the perifornical hypothalamus (PFH) of satiated adult male rats and their subsequent food intake was monitored every minute for 24 h. For comparison, feeding patterns were similarly observed following fasts of 0, 3, 6, 9, 12, and 24 h. The results demonstrated that NPY and food deprivation both produced dose- or deprivation-dependent increases in food intake that were most evident in the first 6 h. The increased intakes induced by NPY were characterized by combinations of increased meal size and frequency, with the predominant effects being increases in the size of and decreased latency to eat the first meal. Similarly, fasting progressively increased food intake by combinations of increased meal size and frequency, with the predominant effects being increases in the size of and decreased latency to eat the first meal. These similarities between NPY-induced and food deprivation-induced feeding are consistent with a stimulatory role for endogenous NPY in deprivation-induced feeding. These findings also suggest that NPY may increase eating by acting on mechanisms of both meal initiation and of meal termination.

Obesity is a disorder of energy balance, indicating a chronic disequilibrium between energy intake and expenditure. Recently, the mouse ob gene, and subsequently its human and rat homologues, have been cloned. The ob gene product, leptin, is expressed exclusively in adipose tissue, and appears to be a signalling factor regulating body-weight homeostasis and energy balance. Because the level of ob gene expression might indicate the size of the adipose depot, we suggest that it is regulated by factors modulating adipose tissue size. Here we show that ob gene exhibits diurnal variation, increasing during the night, after rats start eating. This variation was linked to changes in food intake, as fasting prevented the cyclic variation and decreased ob messenger RNA. Furthermore, refeeding fasted rats restored ob mRNA within 4 hours to levels of fed animals. A single insulin injection in fasted animals increased ob mRNA to levels of fed controls. Experiments to control glucose and insulin independently in animals, and studies in primary adipocytes, showed that insulin regulates ob gene expression directly in rats, regardless of its glucose-lowering effects. Whereas the ob gene product, leptin, has been shown to reduce food intake and increase energy expenditure, our data demonstrate that ob gene expression is increased after food ingestion in rats, perhaps through a direct action of insulin on the adipocyte.

Hypothalamic injection of neuropeptide Y (NPY) can elicit eating in satiated rats, and the perifornical hypothalamus (PFH) is the site where this effect is most pronounced (48). Additionally, there is a well-documented circadian rhythm of spontaneous eating behavior. Our objective was to determine whether there are daily rhythms of sensitivity to NPY in the PFH that might contribute to this behavioral rhythm. To accomplish this, the effectiveness in eliciting eating of PFH injection of NPY was examined at six different time points in the light-dark cycle. Neuropeptide Y (78 pmol/10 nl) or vehicle (10 nl) were injected through chronically implanted guide cannulas into the PFH of satiated adult male rats and food intake was measured 1, 2, and 4 h later. In animals on 12-12 h light-dark cycles, these injections were given 1 h before and after the onset of the light and dark phases, and in the middle of these phases. Additionally, dose-response effects of NPY were examined at two points: the first hour of both the dark and the light phases. The results show that NPY was effective at every time tested, and that the magnitude of the peptide-elicited intakes was primarily additive to the underlying patterns of spontaneous intake, with only a modest daily cycle of sensitivity to NPY. Consistent with this, NPY dose-dependently increased intake in the early light and in the early dark, and the magnitude of these effects across doses was similar at these times. This suggests that the sensitivity of the PFH system mediating NPY eating exhibits only a modest daily cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Food intake was studied in 339 French children, aged 7-12 years. Daily energy consumption and distribution of intake over the waking hours estimated from dietary histories were compared in children of five corpulence categories. The categories (lean, slim, average, fat, obese) were defined on the basis of the weight/height2 index. No difference in estimated daily energy intake was observed between corpulence groups; however, the reported distribution of intake over the waking hours varied. Obese and fat children ate less at breakfast and more at dinner than leaner peers. The traditionally larger meals of the day (lunch and dinner) represented higher proportions of daily intake in fat and obese children; the energy value of breakfast and afternoon snack was inversely related to corpulence. Although these effects do not rule out hyperphagia or increased 'externality' in some overweight subjects, the results suggest a possible contribution of disturbed metabolic and/or behavioral daily cycles in the development of overweight. This hypothesis, which should be investigated further, suggests prevention strategies.

Circadian rhythms of plasma lipids and lipoproteins, lipoprotein lipase activities and VLDL secretion rates were studied in fed and food-deprived (12 h) male rats after a light/dark synchronization of 14 days. In ad libitum fed rats, a circadian rhythm of plasma triacylglycerol, blood glucose and liver glycogen was clearly identified. A rhythm was also identified for plasma cholesterol, but not phospholipids. The peak of plasma triacylglycerol occurred 2 h after the beginning of the light period (7.00 a.m.), and the nadir, 2 h after the beginning of the dark period (7.00 p.m.). The differences of plasma triacylglycerol at these two circadian stages were even more pronounced in food-deprived rats and were confined to the very-low-density lipoprotein (VLDL) fraction. Plasma post-heparin and heart and muscle lipoprotein lipase activities were 50-100% higher at 7.00 p.m., the time when plasma triacylglycerol were lowest, as compared to 7.00 a.m. Plasma post-heparin hepatic lipase and adipose tissue lipoprotein lipase activities, in contrast, did not change. VLDL secretion rates were somewhat higher at 7.00 a.m. compared to 7.00 p.m., but this difference was not significant. It is concluded that physiological variation of heart and muscle lipoprotein lipase together with small differences of VLDL secretion rates are responsible for normal range oscillations of plasma VLDL triacylglycerol levels.

The disturbance of very low density lipoprotein (VLDL) metabolism that occurs as a result of intensive insulin treatment and during a euglycaemic clamp have been investigated in a rat model. Normal rats were maintained with fed blood glucose levels below 5 mmol l-1 for 8 weeks by subcutaneous insulin injections (normal fed levels 5.8 +/- 0.4 (SD) mmol l-1). Glucose requirement to maintain a glucose clamp was significantly reduced (116 +/- 3 mumol min-1 kg-1 (SE) vs. 173 +/- 5 mumol min-1 kg-1, P less than 0.001), compared with weight-matched normal control rats. In the fasting state (blood glucose 3.5 +/- 0.2 mmol l-1 vs. 3.9 +/- 0.1 mmol l-1, NS) plasma non-esterified fatty acid levels were reduced. Fasting VLDL-triglyceride turnover, measured by bolus injection of 14C-VLDL, was also lower (3.17 +/- 0.12 mumol min-1 kg-1 vs. 3.50 +/- 0.07 mumol min-1 kg-1, P less than 0.05). Despite decreased turnover, insulin over-treated rats had normal plasma triglyceride concentrations indicating a removal defect. At the end of a 3-h euglycaemic clamp, plasma triglyceride concentrations and VLDL-triglyceride turnover were decreased in both normal control and insulin over-treated animals, and turnover remained significantly lower in the insulin over-treated rats (2.59 +/- 0.13 mumol min-1 kg-1 vs. 3.08 +/- 0.10 mumol min-1 kg-1, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Literature data on the diurnal rhythms of blood glucose, liver glycogen levels and key hepatic enzyme activities of glycolysis, gluconeogenesis, glycogen metabolism and lipogenesis in animals are reviewed. Materials on the diurnal rhythms of the activities of other enzymes involved in carbohydrate metabolism and related pathways such as the equilibrium glycolytic enzymes are also given. Interspecies comparison and analysis of the results and their interpretation are given.

In an attempt to assess pancreatic glucagon's efficacy at repeatedly reducing food ingestion during differing circadian periods, three groups of 8 rats each were randomly assigned to 4-hr food deprivations beginning at 0800, 1200 or 1600 with light off at 2000. Subjects were then refed following injections of pancreatic glucagon (400 micrograms/kg b.wt. dissolved in DMSO) or vehicle alone every third day (no injection on intervening day). Food intake was measured at 1 and 20 hr following each injection. Following 3 cycles of the above procedure, each animal was again food deprived at the appropriate time, stunned and sacrificed by decapitation. The liver was sampled and glycogen determinations were made. Glucagon suppressed food intake when injected at 1200 (49.6%) and at 1600 (43.1%) but not when given at 2000 (-2.2%). Glycogen content measured after similar deprivation ending at these times was 5.6, 3.9 and 2.0%, respectively. With repeated glucagon injections, the hormone lost its ability to reduce food intake. In a second study, designed to evaluate the role of insulin in glucagon's action, three groups of 6 rats each were given atropine plus glucagon or glucagon or atropine injections alone; food ingestion was then measured one hr later. Atropine alone somewhat decreased eating, however, in combination with glucagon (given 10 min following atropine), no significant decrements in ingestion were achieved. Glucagon injected after saline produced a significant reduction in food intake (62.5%). Since glucagon stimulates insulin release and hyperglycemia; perhaps insulin release is necessary for glucagon's satiety effect.

Feeding at the beginning of the night is probably dependent on the rat's immediate energy requirements while feeding at the end may have an anticipatory function. This latter feeding peak may be mainly controlled by a circadian pacemaker. The aim of this study was to investigate the relative contribution of satiety signals and circadian pacemakers in the control of feeding behavior. Food intake was monitored after infusion of liquid food into the stomach during several parts of the day-night cycle to prevent a possible influence of oral sensations. It is demonstrated that intragastric infusion is more effective in suppressing intake during daytime and the first half of the dark phase than during the second half of the dark phase. Suppressions of food intake are mainly due to delaying the first occurrence of food ingestion, whereas the size of that meal is less affected. During the last period of the night no significant delay could be brought about. These experiments suggest that in the rat a circadian pacemaker dominates feeding motivation during the end of the night thereby strongly interacting with caloric control of feeding behavior.

The present study was undertaken to investigate the effects of short-term fasting periods up to 24 hr on insulin secretory responses of the B-cell to glucose and the consequences for FFA and glucose availability in the circulation. Conscious male rats provided with permanently implanted heart catheters received glucose infusions at midday, lasting for 20 min, in the nearly ad lib condition (i.e., 6 hr of non feeding during daytime) and after extending the fasting period to 12, 18 and 24 hr. Basal preinfusion insulin levels and insulin responses to glucose decreased gradually during these fasting periods. Basal blood glucose dropped only significantly after 24 hr of fasting whereas basal FFA levels increased gradually from 6 hr of fasting onwards. After prolonged fasting insulin released during glucose infusion became more effective in suppressing plasma FFA levels. While our data suggest that the sensitivity to the antilipolytic action of insulin is increased, the decreased responsiveness of the B-cell after moderate fasting periods may result in a drop of basal insulin levels. This facilitates the switch from glucose to FFA metabolism for most tissues already, when the first meals are missed. The results suggest that this physiological process is important to save the glycogen stores as long as possible as fuel for the central nervous system, and also to support basic energy requiring processes adequately.

1. Studies of whole-body balances of non-metabolizable base (NB) and several minerals, and of relevant acid-base quantities in blood and urine, were carried out in two 6-month-old ruminating Holstein X Friesian bull calves fed on fixed rations containing 500 g barley straw/kg diet (group A) to examine the quantitatively important components of the balance of NB and determine the rates of mineral and NB retention associated with normal body growth. 2. Parallel balance studies were conducted in six other bull calves given fixed rations containing 500 g alkali-treated barley straw/kg diet to evaluate the effects of long-term alkali-straw feeding on the rates of body growth and skeletal mineral and NB deposition and the renal control of extracellular electrolyte and acid-base status. The straw component was treated either with 50 g sodium hydroxide/kg dry matter (DM) (group B; two calves), or with 50 g or 100 g NaOH/kg DM and subsequently neutralized with hydrochloric acid (groups C and D, two calves per group). In all groups the animals were given free access to tap water. 3. Throughout the total 105 d experiment, all animals remained healthy and gained weight. Normal body growth group A) was associated with a positive balance of NB (1-2 mmol/kg live weight (LW) per d) due to continuing deposition of dietary NB in 'new tissue', largely in the developing skeleton. 4. During 105 d alkali-straw feeding, the animals showed a remarkable ability to cope with dietary loads of NAOH or sodium chloride, up to about 30 mmol/kg LW per d, without any significant disturbance of extracellular acid-base and electrolyte status or body growth rate. The surplus mineral and NB loads were absorbed and subsequently excreted in an increased volume of urine. Rates of mineral and NB retention were not significantly different from the reference values of group A and remained within the range of values reported from similar studies. In all groups, maintenance of normal whole blood and plasma acid-base and electrolyte status was accounted for by efficient renal control of the composition of the extracellular fluid compartment.

The expressed and total activities of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase (EC 1.1.1.34) were measured in microsomal fractions prepared from cold-clamped liver samples [Easom & Zammit (1984) Biochem. J. 220, 733-738] from control or insulin-treated diabetic animals. Streptozotocin-induced diabetes resulted in a marked decrease in total activity of HMG-CoA reductase and in the fraction of the enzyme in the active form, but appreciable effects were only observed in the liver of animals in which the blood glucose was above 20 mM. Intravenous infusion of insulin into diabetic rats resulted in a rapid (less than 20 min) and total dephosphorylation of the enzyme in vivo without any change in total activity. Longer-term (4 h) treatment with insulin (injected intraperitoneally) produced a rapid increase in expressed/total HMG-CoA reductase activity ratio to about 90%, followed, after a lag of 2-3 h, by a 5-6-fold increase in total activity. These observations are discussed with respect to the possible role of insulin in generating and maintaining the respective diurnal rhythms in total and in expressed/total HMG-CoA reductase activity ratio observed for normal animals in vivo [Easom & Zammit (1984) Biochem. J. 220, 739-745].

The stability of tryptophan was evaluated in several different food model systems using a chemical method (high pressure liquid chromatography after alkaline-hydrolysis) and rat assays. Losses of tryptophan were compared with the losses of lysine and methionine. Whey proteins stored in the presence of oxidizing lipids showed large losses of lysine and extensive methionine oxidation but only minor losses of tryptophan as measured chemically. The observed decrease in bioavailable tryptophan was explained by a lower protein digestibility. Casein treated with hydrogen peroxide to oxidize all methionine to methionine sulphoxide showed a 9% loss in bioavailable tryptophan. When casein was reacted with caffeic acid at pH 7 in the presence of monophenol monooxygenase (tyrosinase; EC 1.14.18.1), no chemical loss of tryptophan occurred, although fluorodinitrobenzene-reactive lysine fell by 23%. Tryptophan bioavailability fell 15%, partly due to an 8% reduction in protein digestibility. Alkali-treated casein (0.15 M-sodium hydroxide, 80 degrees, 4 h) did not support rat growth. Chemically-determined tryptophan, available tryptophan and true nitrogen digestibility fell 10, 46 and 23% respectively. Racemization of tryptophan was found to be 10% (D/(D+L)). In whole-milk powder, which had undergone "early' or "advanced' Maillard reactions, tryptophan, determined chemically or in rat assays, was virtually unchanged. Extensive lysine losses occurred. It was concluded that losses of tryptophan during food processing and storage are small and of only minor nutritional importance, especially when compared with much larger losses of lysine and the more extensive oxidation of methionine.

The consequences of reactions between protein and oxidizing lipids on the nutritional quality of food proteins have been investigated using a whey protein-methyl linolenate-water model system. In rat assays, significant reductions were observed in protein efficiency ratio, net protein ratio, net protein utilization, biological value and true nitrogen digestibility, especially when the reaction had taken place at high moisture content, high temperature and in the presence of excess oxygen. The losses of bioavailable lysine and tryptophan as measured by rat assays followed a similar pattern. The chemical value of each amino acid multiplied by the true N digestibility closely resembled the rat assay value. In general, the reaction products of lysine and tryptophan formed during lipid oxidation were biologically unavailable. The bioavailabilities of methionine and of 'methionine plus cyst(e)ine' were determined in separate assays. Cyst(e)ine was calculated as 'methionine plus cyst(e)ine' minus methionine. In whey protein which had reacted with oxidizing methyl linolenate, the bioavailable methionine content was not significantly reduced even though 82% of the methionine residues were present as methionine sulphoxide. In hydrogen peroxide-treated casein in which all methionine residues were oxidized to the sulphoxide, methionine sulphoxide was found to be 96% as utilizable as a methionine source to the rat. Free methionine sulphoxide was 87% utilizable. Cyst(e)ine appeared to be as sensitive as lysine to reactions with lipid oxidation products. In whey protein which had reacted with oxidizing methyl linolenate, the bioavailabilities of cyst(e)ine, lysine, tryptophan and methionine were reduced by 28, 24, 11 and 8% respectively and true N digestibility by 9%. These results are discussed in relation to food products.

'Initial' and 'total' activities of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) were measured in cold-clamped samples of liver from rats at 2h intervals throughout the 24h light/dark cycle. Initial activities were obtained in microsomes (microsomal fractions) isolated and assayed in the presence of 100mM-KF, whereas 'total' activities were measured in microsomes prepared from the same homogenates but washed free of KF and incubated with exogenous partially purified rat liver protein phosphatase. The initial/total-activity ratio for HMG-CoA reductase underwent a diurnal cycle, which had a nadir 4h into the light phase (when initial activity was 28% of total activity) and a peak 12h later, i.e. 4h into the dark phase (when initial activity was 80% of total activity). These low and high points of the cycle were separated by gradual steady changes in the ratio. The characteristics of this diurnal cycle were different from those of the cycle observed for total activity, which had a plateau of high activity between 2 and 10h into the dark cycle preceded and succeeded by a very rapid increase and decrease, respectively, in the total activity of HMG-CoA reductase. The combination of the two cycles resulted in the dampening of the resultant cycle for the initial or effective activity of HMG-CoA reductase, such that the changes in initial activity around the beginning and and end of the dark phase were more gradual than would otherwise have been the case if the initial/total-activity ratio for HMG-CoA reductase were constant throughout the diurnal cycle. The physiological implications of the observed diurnal variation in the fraction of hepatic HMG-CoA reductase in the active form are discussed.

The effects of dietary protein on the metabolism of proteins, carbohydrates, and especially, lipids were investigated in genetically obese Zucker rats and their lean siblings. For 40 days the rats received diets containing 15%, 64%, or 82% protein, included at the expense of cornstarch. In the obese animals, the high-protein diets led to decreased food intake and weight gain. While these diets decreased the activities of lipogenic enzymes along with the lipid gain, they did not decrease the final body-fat content. The increase protein intake stimulated hepatic ureogenesis and gluconeogenesis. Lipolysis was stimulated, as demonstrated by an accumulation of ketone bodies in the liver. Blood levels of triacylglycerols, free glycerol, and nonesterified fatty acids were concomitantly decreased, which suggests an accelerated turnover of lipids. Whatever the composition of the diet, total energy retention of the lean rats was always less than that of the obese rats. The changes observed on high-protein diets were essentially the same for the two groups, except that the final body-content of lipids in the lean rats was significantly lower. In the absence of exogenous carbohydrate, the lean rats were barely able to retain nitrogen and to maintain hepatic lipogenesis. Unlike the rats from other strains, the lean Zucker rats could not adapt to a low-carbohydrate diet; this failure may be due to a metabolic disorder.

Glycogen content in the liver, skeletal muscle and heart has been determined in Sprague-Dawley (SD) and Wistar (W) rats and in tricoloured (T) and albino Dunkin Hartley (DH) guinea-pigs. The 12-week-old animals were studied under non-fasted or control conditions (N) and after 48 hr of fast (F48). Hepatic glycogen was higher in DH guinea-pigs (95.6 +/- 3.8 mg g-1) than in W (77.2 +/- 5.3 mg g-1) and SD (80.2 +/- 2.3 mg g-1) rats under N conditions. Mean values for the two strains were slightly higher in guinea-pigs than in rats. After fasting, hepatic glycogen was almost exhausted in the two species but was higher in W (1.5 +/- 0.08 mg g-1) and T (1.5 +/- 0.2 mg g-1) than in SD and DH (0.6 +/- 0.1 mg g-1). The content of glycogen in the anterior muscles of the thigh was comparable in the two strains of rat and guinea-pig, but was twice as high in the guinea-pigs (DH:15.1 +/- 0.6; T: 16.4 +/- 0.7 mg g-1) as in the rats (SD: 8.1 +/- 0.2; W: 7.1 +/- 0.5 mg g-1) under N conditions. In F48 animals, muscular glycogen decreased by 41-46% (rats) and 38-39% (guinea-pigs). Hepatic and extra-liver glycogen stores were calculated and found higher in the guinea-pigs than in the rats. The total utilization during fasting was larger in the guinea-pigs (6140 mg/kg body wt) than in the rats (4500 mg/kg body wt).(ABSTRACT TRUNCATED AT 250 WORDS)