glycogen and Hyperphagia

Constitutional thinness (CT) is a nonpathological state of underweight. The current study aimed to explore skeletal muscle energy storage in individuals with CT and to further characterize muscle phenotype at baseline and in response to overfeeding. Thirty subjects with CT (15 females, 15 males) and 31 normal-weight control subjects (16 females, 15 males) participated in the study. Histological and enzymological analyses were performed on muscle biopsy specimens before and after overfeeding. In the skeletal muscle of CT participants compared with controls, we observed a lower content of intramuscular triglycerides for type I (-17%,

Topics: Adaptation, Physiological; Adult; Body Weight; Dietary Supplements; Energy Intake; Female; Glycogen; Humans; Hyperphagia; Male; Muscle Fibers, Skeletal; Muscle, Skeletal; Thinness; Triglycerides; Weight Gain; Young Adult

Hyperthyroidism is known to increase food intake and central administration of thyroid hormone shows acute orexigenic effects in rodents. We investigated whether T3 influences appetite and glucose homeostasis by modulating circulating ghrelin, an important orexigenic hormone, in Zucker fatty rats. The acute anorectic effects of T3 and ghrelin mimetic MK-0677 were studied in rats trained for fasting induced food intake. The serum concentration of T3, ghrelin, glucose, triglycerides, and liver glycogen were estimated. The involvement of sympathetic nervous system was evaluated by conducting similar experiments in vagotomized rats. T3 increased food intake and glucose in rats over 4 h, with increase in serum T3 and decrease in liver glycogen. T3 treatment was associated with increase in serum ghrelin. An additive effect on appetite and glucose was observed when T3 (oral) was administered with central (intracerebroventricular) administration of a ghrelin mimetic, MK-0677. Ghrelin antagonist, compound 8a, antagonized the hyperglycemic and hyperphagic effects of T3. In vagotomized rats, T3 did not show increase in appetite as well as glucose. Serum ghrelin levels were unchanged in these animals after T3 treatment. However, T3 showed increase in serum triglyceride levels indicating its peripheral lipolytic effect, in vagotomized as well as sham treated animals. To conclude, acute orexigenic and hyperglycemic effects of T3 are associated with ghrelin secretion and activity. This effect seems to be mediated via vagus nerves, and is independent of glucoregulatory hormones.

Topics: Animals; Appetite Regulation; Blood Glucose; Disease Models, Animal; Eating; Feeding Behavior; Ghrelin; Glycogen; Homeostasis; Hyperphagia; Hyperthyroidism; Indoles; Injections, Intraperitoneal; Injections, Intraventricular; Liver; Male; Rats, Zucker; Spiro Compounds; Time Factors; Triglycerides; Triiodothyronine; Vagotomy; Vagus Nerve

Dietary trans-fatty acids are associated with increased risk of cardiovascular disease and have been implicated in the incidence of obesity and type 2 diabetes mellitus (T2DM). It is established that high-fat saturated diets, relative to low-fat diets, induce adiposity and whole-body insulin resistance. Here, we test the hypothesis that markers of an obese, prediabetic state (fatty liver, visceral fat accumulation, insulin resistance) are also worsened with provision of a low-fat diet containing elaidic acid (18:1t), the predominant trans-fatty acid isomer found in the human food supply. Male 8-week-old Sprague-Dawley rats were fed a 10% trans-fatty acid enriched (LF-trans) diet for 8 weeks. At baseline, 3 and 6 weeks, in vivo magnetic resonance spectroscopy (1H-MR) assessed intramyocellular lipid (IMCL) and intrahepatic lipid (IHL) content. Euglycemic-hyperinsulinemic clamps (week 8) determined whole-body and tissue-specific insulin sensitivity followed by high-resolution ex vivo 1H-NMR to assess tissue biochemistry. Rats fed the LF-trans diet were in positive energy balance, largely explained by increased energy intake, and showed significantly increased visceral fat and liver lipid accumulation relative to the low-fat control diet. Net glycogen synthesis was also increased in the LF-trans group. A reduction in glucose disposal, independent of IMCL accumulation was observed in rats fed the LF-trans diet, whereas in rats fed a 45% saturated fat (HF-sat) diet, impaired glucose disposal corresponded to increased IMCLTA. Neither diet induced an increase in IMCLsoleus. These findings imply that trans-fatty acids may alter nutrient handling in liver, adipose tissue, and skeletal muscle and that the mechanism by which trans-fatty acids induce insulin resistance differs from diets enriched with saturated fats.

Topics: Adiposity; Animals; Blood Glucose; Diet, Fat-Restricted; Energy Intake; Energy Metabolism; Glucose Clamp Technique; Glycogen; Hyperphagia; Insulin; Insulin Resistance; Intra-Abdominal Fat; Liver; Magnetic Resonance Spectroscopy; Male; Metabolic Syndrome; Muscle, Skeletal; Obesity; Oleic Acid; Oleic Acids; Prediabetic State; Rats; Rats, Sprague-Dawley; Time Factors; Trans Fatty Acids

Changes in dietary macronutrient composition and/or central nervous system neuronal activity can underlie obesity and disturbed fuel homeostasis. We examined whether switching rats from a diet with high carbohydrate content (HC; i.e., regular chow) to diets with either high fat (HF) or high fat/high protein content at the expense of carbohydrates (LC-HF-HP) causes differential effects on body weight and glucose homeostasis that depend on the integrity of brain melanocortin (MC) signaling. In vehicle-treated rats, switching from HC to either HF or LC-HF-HP feeding caused similar reductions in food intake without alterations in body weight. A reduced caloric intake (-16% in HF and LC-HF-HP groups) required to maintain or increase body weight underlay these effects. Chronic third cerebroventricular infusion of the MC receptor antagonist SHU9119 (0.5 nmol/day) produced obesity and hyperphagia with an increased food efficiency again observed during HF (+19%) and LC-HF-HP (+33%) feeding. In this case, however, HF feeding exaggerated SHU9119-induced hyperphagia and weight gain relative to HC and LC-HF-HP feeding. Relative to vehicle-treated controls, SHU9119 treatment increased plasma insulin (2.8-4 fold), leptin (7.7-15 fold), and adiponectin levels (2.4-3.7 fold), but diet effects were only observed on plasma adiponectin (HC and LC-HF-HP

Topics: Animals; Body Composition; Body Weight; Brain; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Glucose Tolerance Test; Glycogen; Homeostasis; Hormones; Hyperphagia; Liver; Male; Melanocyte-Stimulating Hormones; Rats; Rats, Wistar; Receptors, Corticotropin; Receptors, Melanocortin; Signal Transduction

Mice lacking acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in triglyceride synthesis, have increased energy expenditure and therefore are resistant to obesity. Because ambient temperature can significantly affect energy expenditure in mice, we undertook these studies to determine the effects of different ambient temperatures on energy expenditure, food intake, and thermoregulation in DGAT1-deficient [Dgat1(-/-)] mice. Dgat1(-/-) mice had increased energy expenditure irrespective of changes in the ambient temperature. Although core temperature was normal, surface temperature was increased in Dgat1(-/-) mice, most likely reflecting an active mechanism to dissipate heat from increased thermogenesis. Dgat1(-/-) mice had increased food intake at baseline, and this hyperphagia became more pronounced upon exposure to cold. When fasted in a cold environment, Dgat1(-/-) mice developed hypothermia, which was associated with hypoglycemia. These results suggest that the hyperphagia in Dgat1(-/-) mice is a secondary mechanism that compensates for the increased utilization of fuel substrates. Our findings offer insights into the mechanisms of hyperphagia and increased energy expenditure in a murine model of obesity resistance.

Topics: Acyltransferases; Animals; Blood Glucose; Body Temperature; Body Temperature Regulation; Carrier Proteins; Cold Temperature; Diacylglycerol O-Acyltransferase; Eating; Energy Metabolism; Fasting; Female; Gene Expression; Glycogen; Hyperphagia; Hypoglycemia; Hypothermia; Ion Channels; Liver; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Muscle, Skeletal; Obesity; Temperature; Uncoupling Protein 1; Weight Loss

To clarify the role of the neuropeptide Y (NPY) Y5 receptor subtype in energy homeostasis, the effect of the intracerebroventricular infusion of a selective Y5 agonist, D-Trp(34)NPY, was investigated in C57BL/6J mice. Intracerebroventricular infusion of D-Trp(34)NPY (5 and 10 microg/d) produced hyperphagia and body weight gain, accompanied by increased adipose tissue weight, hypercholesterolemia, hyperinsulinemia, and hyperleptinemia. Oral administration of a selective Y5 antagonist at a dose of 100 mg/kg twice a day completely suppressed all of these D-Trp(34)NPY-induced changes, indicating that chronic activation of the Y5 receptor produces hyperphagia and obesity. In addition, D-Trp(34)NPY still resulted in an increase in adipose tissue weight accompanied by hyperleptinemia and hypercholesterolemia, although D-Trp(34)NPY-induced food intake was restricted by pair-feeding. Under the pair-fed condition, D-Trp(34)NPY decreased hormone-sensitive lipase activity in white adipose tissue and uncoupling protein-1 mRNA expression in brown adipose tissue. These findings indicate that Y5-mediated obesity may involve metabolic changes, such as decreased lipolysis and thermogenesis, as well as hyperphagia. Therefore, the Y5 receptor can play a key role in regulating energy homeostasis.

Topics: Animals; Binding, Competitive; Carrier Proteins; CCAAT-Enhancer-Binding Proteins; DNA-Binding Proteins; Drug Administration Schedule; Energy Metabolism; Glycogen; Homeostasis; Hyperphagia; Injections, Intraventricular; Ligands; Lipoprotein Lipase; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; RNA, Messenger; Sterol Esterase; Sterol Regulatory Element Binding Protein 1; Transcription Factors; Triglycerides

Glycogen-targeting subunits of protein phosphatase-1 (PP-1) are scaffolding proteins that facilitate the regulation of key enzymes of glycogen metabolism by PP-1. In the current study, we have tested the effects of hepatic expression of GMDeltaC, a truncated version of the muscle-targeting subunit isoform, in rats rendered insulin-deficient via injection of a single moderate dose of streptozotocin (STZ). Three key findings emerged. First, GMDeltaC expression in liver was sufficient to fully normalize blood glucose levels (from 335 +/- 31 mg/dl prior to viral injection to 109 +/- 28 mg/dl 6 days after injection) and liver glycogen content in STZ-injected rats. Second, this normalization occurred despite very low levels of liver glucokinase expression in the insulin-deficient STZ-injected rats. Finally, the hyperphagia induced by STZ injection was completely reversed by GMDeltaC expression in liver. In contrast to these findings with GMDeltaC, overexpression of another targeting subunit, GL, in STZ-injected rats caused a large increase in liver glycogen stores but only a transient decrease in food intake and blood glucose levels. The surprising demonstration of a glucose-lowering effect of GMDeltaC in the background of depressed hepatic glucokinase expression suggests that controlled stimulation of liver glycogen storage may be an effective mechanism for improving glucose homeostasis, even when normal pathways of glucose disposal are impaired.

Topics: Adenoviridae; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Genetic Therapy; Glucokinase; Glycogen; Hyperglycemia; Hyperphagia; Liver; Male; Phosphoprotein Phosphatases; Protein Phosphatase 1; Protein Subunits; Rats; Rats, Wistar; Streptozocin

The metabolic balance method was performed on three men to investigate the fate of large excesses of carbohydrate. Glycogen stores, which were first depleted by diet (3 d, 8.35 +/- 0.27 MJ [1994 +/- 65 kcal] decreasing to 5.70 +/- 1.03 MJ [1361 +/- 247 kcal], 15% protein, 75% fat, 10% carbohydrate) and exercise, were repleted during 7 d carbohydrate overfeeding (11% protein, 3% fat, and 86% carbohydrate) providing 15.25 +/- 1.10 MJ (3642 +/- 263 kcal) on the first day, increasing progressively to 20.64 +/- 1.30 MJ (4930 +/- 311 kcal) on the last day of overfeeding. Glycogen depletion was again accomplished with 2 d of carbohydrate restriction (2.52 MJ/d [602 kcal/d], 85% protein, and 15% fat). Glycogen storage capacity in man is approximately 15 g/kg body weight and can accommodate a gain of approximately 500 g before net lipid synthesis contributes to increasing body fat mass. When the glycogen stores are saturated, massive intakes of carbohydrate are disposed of by high carbohydrate-oxidation rates and substantial de novo lipid synthesis (150 g lipid/d using approximately 475 g CHO/d) without postabsorptive hyperglycemia.

Topics: Adult; Body Composition; Calorimetry, Indirect; Dietary Carbohydrates; Energy Intake; Energy Metabolism; Feeding and Eating Disorders; Glycogen; Humans; Hyperphagia; Lipids; Male; Reference Values

The effect of short-term overnutrition on insulin action for glucose disposal was assessed in 15 Southwest American Indians (mean wt = 74 +/- 6 kg). After two weeks of weight maintenance and again after two weeks of 62% greater caloric intake (constant ratio of fat:carbohydrate:protein), insulin action for glucose disposal was measured using the euglycemic clamp technique with plasma insulin concentrations of about 110 and 1800 uU/mL. Simultaneous indirect calorimetry was used to estimate carbohydrate oxidation and storage rates. Following overnutrition, mean weight gain was 3.0 +/- 0.2 kg, P less than 0.01. Overnutrition induced a decrease in glucose storage at the low and high insulin concentrations: 1.2 +/- 0.3 to 0.2 +/- 0.3, P less than 0.01, and 6.4 +/- 0.3 to 4.3 +/- 0.5, mg/kg FFM min, P less than 0.001. Carbohydrate oxidation was significantly increased at both insulin concentrations. The mean total insulin mediated glucose disposal rate decreased from 11.6 +/- 0.5 to 10.3 +/- 0.7, P less than 0.01, at the high insulin concentration. This decrease was due entirely to the reduction in carbohydrate storage and was correlated with increased fasting insulin concentration (r = 0.7, P less than 0.01). Overnutrition also induced a significant decrease in the percent muscle glycogen synthase active measured fasting and at the end of the high-dose insulin infusion. The results indicate that short-term overnutrition results in reduced insulin action for glucose storage and disposal which is correlated with increased fasting insulin concentrations. Reduced glycogen synthase activity may contribute to the effect of overnutrition on in vivo insulin-mediated glucose storage.

Topics: Adolescent; Adult; Biopsy; Diet, Reducing; Feeding and Eating Disorders; Glucose Tolerance Test; Glycogen; Glycogen Synthase; Humans; Hyperphagia; Indians, North American; Insulin; Male; Muscles; Obesity

In order to test the hypothesis that the enhanced gluconeogenesis of hypothalamic obesity remains responsive to changed in food intake, we have measured gluconeogenesis in two modes of hypothalamic obesity under both hyperphagic and normophagic conditions. The results show that hyperphagia partially decreases gluconeogenesis and fully restores liver glycogen in both modes. The discussion section relates our present findings to the enhanced glucose utilization previously noted after VMH destruction and to the recent hypothesis that hyperphagia is a response to body protein depletion.

Topics: Animals; Carbon Dioxide; Feeding and Eating Disorders; Female; Gluconeogenesis; Glycogen; Humans; Hyperphagia; Hypothalamus; Hypothalamus, Middle; Liver; Obesity; Rats