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PubMed2003

Decreased hypothalamic concentration of neuropeptide Y correlates with onset of hyperphagia in fa/fa rats on postnatal day 12.

An increased action of hypothalamic neuropeptide Y (NPY) has been proposed as a major factor in the pathophysiology of the obesity syndrome in Zucker (fa/fa) rats. Using a developmental strategy to test this hypothesis, we showed previously that significantly more arcuate NPY was expressed in fa/fa pups than in lean littermates on postnatal day (P) 2 and throughout the preweaning period [Physiol. Behav. 67 (1999) 521], and that hyperphagia first appeared on P12 [Am. J. Physiol. 275 (1998) R1106]. To test the hypothesis further, we used a specific radioimmunoassay to measure the concentration of hypothalamic NPY peptide in lean (+/+ and +/fa) and obese fa/fa Zucker rat pups on P9, P10, and P12. The concentration of NPY in fa/fa pups was not significantly different from that of the other genotypes. There was, however, a significant decrease in NPY concentration from P9 to P12 in fa/fa pups, but not in lean pups. The combination of increased NPY message and decreasing concentration of NPY peptide in fa/fa pups with age is consistent with, but does not prove, increased release of hypothalamic NPY in fa/fa pups just before and on P12 when hyperphagia emerges. These results provide further support for the importance of hypothalamic NPY in the phenotypic expression of hyperphagia in the fa/fa pups during the second postnatal week.

Aging↗
PubMed1997

Effects of fluvoxamine on food intake during rebound hyperphagia in rats.

We examined the effects of fluvoxamine on food intake during rebound hyperphagia induced by a time-restricted feeding schedule in rats. Rats were allowed access to food for only 2 h daily for 7 days, and then had free access to food for 7 consecutive days. The daily food intake of the rats was dramatically increased, by 42.5% (rebound hyperphagia), for 7 days of the free-feeding period. Intraperitoneal injection of fluvoxamine decreased food intake significantly in a dose-dependent manner for the first 3 h of feeding during 7 days. When rats were allowed access to one of the standard, carbohydrate-, fat-, or protein-rich diets in the free-feeding period following the time-restricted feeding schedule, fluvoxamine significantly decreased food intakes of standard, carbohydrate- and fat-rich diets on all days, and the protein-rich diet after the 2nd day of the free-feeding period. These results indicate that fluvoxamine, irrespective of the diet composition, suppresses rebound hyperphagia induced by a time-restricted feeding schedule, but that its effect is short-lived.

Animals↗
PubMed2001

Agouti-related protein is a mediator of diabetic hyperphagia.

To explore the role of agouti-related protein (AGRP) in diabetic hyperphagia changes in hypothalamic AGRP mRNA levels were examined in diabetic rats. Rats rendered diabetic by streptozotocin displayed marked hyperglycemia (blood glucose 456.0+/-8.4 mg/dl versus 71.8+/-1.9 mg/dl) and hyperphagia (36.9+/-1.0 g/day versus 22.0+/-0.4 g/day), that was associated with a 286.6+/-4.4% increase in hypothalamic AGRP mRNA and a 178.9+/-13.5% increase in hypothalamic NPY mRNA. Insulin treatment of diabetic rats partially corrected blood glucose (147.4+/-13.1 mg/dl) and ameliorated hyperphagia (26.6+/-2.0 g/day). Insulin replacement was also associated with a return of hypothalamic AGRP mRNA (111.7+/-8.3% of controls) and NPY mRNA (125.0+/-8.9% of controls) from the elevated levels that were observed in untreated diabetic rats. In contrast to insulin treated rats, sodium orthovanadate treated diabetic rats remained significantly hyperglycemic (361.5+/-12.5 mg/dl). However, despite their persistent hyperglycemia, orthovanadate treated diabetic rats were still observed to have a significant reduction of hypothalamic AGRP mRNA (138.7+/-11.4%) and NPY mRNA (129.9+/-9.8%). Simultaneous measurement of serum leptin revealed suppressed levels in both untreated diabetic (0.5+/-0.1 ng/ml) and sodium orthovanadate treated rats (0.5+/-0.1 ng/ml) compared to non-diabetic controls (2.1+/-0.1 ng/ml). These data indicate that AGRP is a mediator of diabetic hyperhpagia and suggest that insulin can directly influence hypothalamic AGRP and NPY mRNA expression.

Agouti-Related Protein↗
PubMed1985

Hyperphagia: a necessary precondition to obesity?

Weight-gain is generally attributed to a caloric imbalance resulting from hyperphagia. However, this attribution is often made without observing caloric intakes during the initial accumulation of fat stores. Instead, this conclusion is drawn because many obese organisms overeat, and overconsumption is sufficient to cause weight-gain. The literature is reviewed, specifically those studies on the onset of caloric overconsumption relative to weight-gain and the accumulation of fat during food restriction, which suggests that hyperphagia is not necessary for animals prone to obesity to become fatter and heavier. It is observed that animals with genetically- and surgically-induced obesity often become fat prior to hyperphagia and continue to gain even if food restricted to subnormal levels. Overconsumption does speed this gain.

Animals↗
PubMed1997

Poststarvation hyperphagia and body fat overshooting in humans: a role for feedback signals from lean and fat tissues.

An increase in the sensation of hunger and overeating after a period of chronic energy deprivation can be part of an autoregulatory phenomenon attempting to restore body weight. To gain insights into the role of fat and lean tissue depletion as determinants of such a hyperphagic response in humans, we reanalyzed the individual data on food intake and body composition available for the 12 starved and refed men in the classical Minnesota Experiment after a shift from a 12-wk period of restricted refeeding to an ad libitum refeeding period of 8 wk. For each individual, the following were determined: 1) the total hyperphagic response during the ad libitum refeeding period, calculated as the energy intake in excess of that during the prestarvation (control) period; 2) the degree of fat recovery and that of fat-free-mass (FFM) recovery before ad libitum refeeding, calculated as the deviation in fat and FFM from their respective prestarvation values (ie, the amount of fat or FFM before ad libitum refeeding as a percentage of fat or FFM during the control period); and 3) the deficit in energy intake before ad libitum refeeding, calculated as the difference between the energy intake during the period of restricted refeeding and that during the control period. The results indicate that 1) the total hyperphagic response is inversely correlated with the degree of fat recovery (r = -0.6) as well as with that of FFM recovery (r = -0.5), 2) the correlation between hyperphagia and FFM recovery persists after adjustment for fat recovery, and 3) the correlations between hyperphagia and fat recovery or FFM recovery persist after adjustment for the variance in the energy deficit during the preceding period of restricted refeeding. Taken together, these results in humans suggest that poststarvation hyperphagia is determined to a large extent by autoregulatory feedback mechanisms from both fat and lean tissues. These findings, which have implications for both the treatment of obesity and for nutritional rehabilitation after malnutrition and cachexia, have been integrated into a compartmental model of autoregulation of body composition, and can be used to explain the phenomenon of poststarvation overshoot in body fat.

Adipose Tissue↗
PubMed1997

The involvement of 5-HT1B receptors in the inhibitory effects of nitric oxide synthase inhibitor on 2-deoxy-D-glucose-induced hyperphagia in rats.

We found previously that the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) significantly reduced 2-deoxy-D-glucose (2-DG)-induced hyperphagia in rats. To clarify the involvement of 5-HT, we investigated the effects of 5-HT receptor antagonists on inhibitory effects of L-NAME on 2-DG-induced hyperphagia. The effects of L-NAME on 2-DG-induced hyperphagia were inhibited by the 5-HT1B receptor antagonist metergoline. However, the 5-HT2 receptor antagonist ritanserin had no such effect. These results suggest that the anorectic effects of L-NAME may be related to serotonergic mechanisms.

Analysis of Variance↗
PubMed2004

Net digestive absorption and adaptive hyperphagia in adult short bowel patients.

BACKGROUND AND AIMS: Intestinal adaptation after small bowel resection in humans is debated. We have quantified in adult short bowel (remnant small bowel length <2 m) patients oral intake and net digestive absorption and their evolution over time. PATIENTS AND METHODS: Oral intake and faecal output were studied over three days in 90 patients (39 and 51 without or with parenteral nutrition, respectively) and in 14 patients in early (<6 months) and late (>6 months) periods after digestive continuity. Nitrogen and fat output were measured using chemiluminescence and Van de Kamer techniques, respectively. RESULTS: In the whole group, 81% of patients had hyperphagia (spontaneous oral intake >1.5 x resting energy expenditure), independently and negatively related to fat absorption (p<0.01) and body mass index (p<0.001) but not braked by the presence of parenteral nutrition. Protein and fat absorption were related to small bowel length. We observed, in the late in comparison with the early period after digestive continuity: an increase in oral intake (1.6 v 2.3 resting energy expenditure), decrease in stool weight/oral intake ratio, no reduction in per cent fat absorption, and protein absorption improvement associated with a significant increase in the amount of protein absorbed (40 v 64 g/day; p<0.05), both being correlated with remnant small bowel length (p<0.01). CONCLUSIONS: This study confirms an adaptive hyperphagia in adult short bowel patients. Over time, hyperphagia and amount of protein absorbed increased, the latter being related to remnant small bowel length, indicating a behavioural adaptation that allows expression of intestinal absorptive adaptation.

Adaptation, Physiological↗
PubMed1989

Energy expenditure and diet-induced thermogenesis in presence and absence of hyperphagia induced by insulin.

The influence of experimental hyperinsulinemia on energy intake, energy expenditure, and body composition was investigated in rats treated chronically with high doses of insulin. Energy balance studies, each of 2-wk duration, were conducted with two different long-acting insulins (Protamine and Monotard), administered in the morning (IM), the late afternoon (IA), or both (IMA) and in animals of three different ages, namely in 4-, 8-, and 12-wk-old rats. The results indicate that the level of hyperphagia induced by insulin was markedly influenced by the type of long-acting insulin (P less than 0.001; Protamine greater than Monotard), by age (P less than 0.001; 12 greater than 8 greater than 4 wk), as well as by the timing of insulin administration (P less than 0.002, IMA greater than IM or IA). Body protein deposition was unaltered, but body fat and energy expenditure increased in parallel to the level of hyperphagia. Regression analysis shows a strong linear correlation (r = 0.963) between the change in energy expenditure and the change in energy intake in response to insulin and indicates that approximately 50% of the excess calories consumed was dissipated as heat. In the absence of hyperphagia, however, insulin administration had no effect on energy expenditure nor on energy partitioning. Similarly, the influence of altered meal pattern, induced by administering insulin at different times of the day, was also found to have no impact on energy expenditure. The current investigations therefore refute the notion that high doses of insulin via hyperinsulinemia and/or altered meal pattern have an inhibitory influence on whole body thermogenesis. In contrast, our data demonstrate that the adaptive phenomenon that tends to minimize the accumulation of excess caloric intake, i.e., diet-induced thermogenesis, persists in the hyperinsulinemic state.

Animals↗
PubMed2006

Hyperphagia, lower body temperature, and reduced running wheel activity precede development of morbid obesity in New Zealand obese mice.

Among polygenic mouse models of obesity, the New Zealand obese (NZO) mouse exhibits the most severe phenotype, with fat depots exceeding 40% of total body weight at the age of 6 mo. Here we dissected the components of energy balance including feeding behavior, locomotor activity, energy expenditure, and thermogenesis compared with the related lean New Zealand black (NZB) and obese B6.V-Lep(ob)/J (ob/ob) strains (11% and 65% fat at 23 wk, respectively). NZO mice exhibited a significant hyperphagia that, when food intake was expressed per metabolic body mass, was less pronounced than that of the ob/ob strain. Compared with NZB, NZO mice exhibited increased meal frequency, meal duration, and meal size. Body temperature as determined by telemetry with implanted sensors was reduced in NZO mice, but again to a lesser extent than in the ob/ob strain. In striking contrast to ob/ob mice, NZO mice were able to maintain a constant body temperature during a 20-h cold exposure, thus exhibiting a functioning cold-induced thermogenesis. No significant differences in spontaneous home cage activity were observed among NZO, NZB, and ob/ob strains. When mice had access to voluntary running wheels, however, running activity was significantly lower in NZO than NZB mice and even lower in ob/ob mice. These data indicate that obesity in NZO mice, just as in humans, is due to a combination of hyperphagia, reduced energy expenditure, and insufficient physical activity. Because NZO mice differ strikingly from the ob/ob strain in their resistance to cold stress, we suggest that the molecular defects causing hyperphagia in NZO mice are located distal from leptin and its receptor.

Adiposity↗
PubMed2002

Role of ghrelin in streptozotocin-induced diabetic hyperphagia.

Ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptor, was originally purified from the rat stomach. We have previously reported that central administration of ghrelin increases food intake and body weight. To investigate the role of ghrelin in the hyperphagic response to uncontrolled diabetes, adult male rats were studied 14 days after administration of streptozotocin (STZ) or vehicle. STZ-treated diabetic rats were markedly hyperphagic. This hyperphagia was accompanied by hyperglycemia, hypoinsulinemia, and reduced plasma GH levels. Treatment of diabetic rats with insulin reversed these changes. Plasma ghrelin concentrations in untreated diabetic rats were significantly higher than in control rats and were normalized by insulin treatment. The ghrelin gene expression in the stomach was also higher in STZ diabetic rats than in control rats, but this difference was not significant. In contrast, plasma leptin was markedly reduced in STZ diabetic rats. This reduction in plasma leptin levels was reversed by insulin treatment. In addition, hypothalamic NPY mRNA levels were increased in STZ-treated diabetic rats and were reversed by insulin treatment. Furthermore, the hyperphagia was partially reversed by the administration of a ghrelin-receptor antagonist. Therefore, we conclude that the elevated plasma ghrelin levels, along with decreased plasma leptin levels, could contribute to the diabetic hyperphagia in part by increasing hypothalamic NPY. This is the first report to show the pathophysiological significance of ghrelin in diabetes.

Animals↗
PubMed2006

Role of endogenous ghrelin in the hyperphagia of mice with streptozotocin-induced diabetes.

Ghrelin is an orexigenic peptide involved in the regulation of energy homeostasis. To investigate the role of ghrelin in the hyperphagia associated with uncontrolled streptozotocin-induced diabetes, food intake was followed in diabetic ghrelin knockout (ghrelin(-/-)) and control wild-type (ghrelin(+/+)) mice and diabetic Naval Medical Research Institute noninbred Swiss mice treated with either saline or the ghrelin receptor antagonist, D-Lys3-GH-releasing peptide-6 (D-Lys3-GHRP-6) for 5 d. In diabetic ghrelin(-/-) mice, hyperphagia was attenuated, and the maximal increase in food intake was 50% lower in mutant than in wild-type mice. The increased food intake observed during the light period (1000-1200 h) in ghrelin(+/+) mice was abolished in mutant mice. Diabetic ghrelin(-/-) mice lost 12.4% more body weight than ghrelin(+/+) mice. In diabetic ghrelin(+/+) mice, but not in ghrelin(-/-) mice, the number of neuropeptide Y (NPY)-immunoreactive neurons was significantly increased. Diabetic Naval Medical Research Institute noninbred Swiss mice were hyperphagic and had increased plasma ghrelin levels. Treatment with D-Lys3-GHRP-6 reduced daily food intake by 23% and reversed the increased food intake observed during the light period. The change in the number of NPY- (2.4-fold increase) and alpha-MSH (1.7-fold decrease)-immunoreactive hypothalamic neurons induced by diabetes was normalized by D-Lys3-GHRP-6 treatment. Our results suggest that enhanced NPY and reduced alpha-MSH expression are secondary to the release of ghrelin, which should be considered the underlying trigger of hyperphagia associated with uncontrolled diabetes.

Animals↗
PubMed2006

Combined deletion of Y1, Y2, and Y4 receptors prevents hypothalamic neuropeptide Y overexpression-induced hyperinsulinemia despite persistence of hyperphagia and obesity.

Neuropeptide Y (NPY) is a key regulator of energy homeostasis and is implicated in the development of obesity and type 2 diabetes. Whereas it is known that hypothalamic administration of exogenous NPY peptides leads to increased body weight gain, hyperphagia, and many hormonal and metabolic changes characteristic of an obesity syndrome, the Y receptor(s) mediating these effects is disputed and unclear. To investigate the role of different Y receptors in the NPY-induced obesity syndrome, we used recombinant adeno-associated viral vector to overexpress NPY in mice deficient of selective single or multiple Y receptors (including Y1, Y2, and Y4). Results from this study demonstrated that long-term hypothalamic overexpression of NPY lead to marked hyperphagia, hypogonadism, body weight gain, enhanced adipose tissue accumulation, hyperinsulinemia, and other hormonal changes characteristic of an obesity syndrome. NPY-induced hyperphagia, hypogonadism, and obesity syndrome persisted in all genotypes studied (Y1(-/-), Y2(-/-), Y2Y4(-/-), and Y1Y2Y4(-/-) mice). However, triple deletion of Y1, Y2, and Y4 receptors prevented NPY-induced hyperinsulinemia. These findings suggest that Y1, Y2, and Y4 receptors under this condition are not crucially involved in NPY's hyperphagic, hypogonadal, and obesogenic effects, but they are responsible for the central regulation of circulating insulin levels by NPY.

Adipose Tissue↗
PubMed1992

Neuropeptide Y release from the paraventricular nucleus increases in association with hyperphagia in streptozotocin-induced diabetic rats.

We tested the hypothesis that the hyperphagia observed in streptozotocin (STZ)-induced diabetic rats is due to increased release of neuropeptide Y (NPY) in the paraventricular nucleus (PVN) of the hypothalamus. In the first experiment, male rats were injected with STZ or vehicle (control) via the tail vein and 18-20 days later, NPY levels in seven hypothalamic sites and release in vitro from selected hypothalamic sites were evaluated. The results showed that in association with STZ-produced marked hyperglycemia and hyperphagia, NPY concentrations were increased in four hypothalamic sites, including the PVN. Evaluation of NPY release in vitro showed that both basal and KCl-induced release was significantly higher from the micro-dissected PVN of STZ-treated than control rats. A similar augmentation in the NPY efflux in vitro was detected from the median eminence arcuate nucleus, but not from the neighboring ventromedial nucleus of STZ-treated rats. In the second experiment, rats were treated with STZ or vehicle and received permanent push-pull cannula (PPC) in the PVN for evaluation of NPY release in vivo 18-21 days after STZ treatment. The results showed that mean NPY levels in the perfusates collected from the PVN of diabetic rats were significantly higher as compared to control rats. Since NPY is the most potent naturally occurring orexigenic signal and the PVN is an important initial site of NPY action in the stimulatory pathway regulating feeding, our findings of augmented PVN NPY release in vivo and in vitro are in accord with the hypothesis that increased NPY secretion in the PVN may be responsible for hyperphagia in diabetic rats.

Animals↗
PubMed2002

Effects of peripheral administration of 5-hydroxytryptamine (5-HT ) on 2-deoxy-D-glucose-induced hyperphagia in rats.

Effects of peripheral administration of 5-HT (5-hydroxytryptamine, serotonin) on hyperphagia induced by 2-deoxy-D-glucose(2-DG) were studied in rats. It was found that 5-HT i.p. reduced 2-DG-elicited feeding in rats dose-dependently. The 5-HT-induced hypophagia was antagonized by the 5-HT2A receptor antagonist, ketanserin. It is known that 2-DG induces glucoprivation, resulting in hyperphagia and hyperglycemia. However, 5-HT did not affect hyperglycemia induced by 2-DG. These results suggest that peripheral injection of 5-HT reduces 2-DG-induced hyperphagia mediated by the peripheral 5-HT2A receptor and that its effects are not due to enhancement of hyperglycemia.

Animals↗
PubMed2005

Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats.

AMP-activated protein kinase (AMPK) acts as a cellular energy sensor, being activated during states of low energy charge. Hypothalamic AMPK activity is altered by hormonal and metabolic signals and mediates the feeding response. To determine the effect of diabetes on hypothalamic AMPK activity, we assayed this activity in streptozotocin (STZ)-induced diabetic rats. Compared with control rats, STZ-induced diabetic rats had significant hyperphagia and weight loss. Hypothalamic AMPK phosphorylation and alpha2-AMPK activity were higher and acetyl-CoA carboxylase activity was lower in diabetic rats than in control rats. Chronic insulin treatment or suppression of hypothalamic AMPK activity completely prevented diabetes-induced changes in food intake as well as in hypothalamic AMPK activity and mRNA expression of neuropeptide Y and proopiomelanocortin. Plasma leptin and insulin levels were profoundly decreased in diabetic rats. Intracerebroventricular administration of leptin and insulin reduced hyperphagia and the enhanced hypothalamic AMPK activity in diabetic rats. These data suggest that leptin and insulin deficiencies in diabetes lead to increased hypothalamic AMPK activity, which contributes to the development of diabetic hyperphagia.

AMP-Activated Protein Kinases↗
PubMed1987

Effect of factors besides hyperphagia on cellularity of adipose tissue in gold thioglucose-induced obese mice.

Whether or not factors besides hyperphagia influence cellularity of adipose tissue in gold thioglucose (GTG)-treated mice was examined. The animals were treated with GTG (800 mg/kg body weight) or saline as control. Control and one of the GTG-treated groups were given a diet ad libitum and another of the GTG-treated groups was pair-fed to control. In GTG-treated group fed ad libitum, hyperphagia and obesity were observed and an enlargement in the parametrial adipose tissue was mainly due to increases both in size and number of adipocytes. The GTG-treated group became obese compared to control even if food intake was comparable. The pair-feeding failed to inhibit completely the increase of both size and number of adipocytes in the fat pads. These results suggest that other factors besides hyperphagia might influence changes of cellularity of the parametrial adipose tissue in the GTG-induced obesity.

Adipose Tissue↗
PubMed1982

Preventing hyperphagia normalizes 3-hydroxy-3-methylglutaryl-CoA reductase activity in small intestine and liver of diabetic rats.

Rats with streptozotocin-induced diabetes stop growing, develop high cholesterol and triacylglycerol levels in plasma, and have decreased activity of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase (EC 1.1.1.34), in liver and increased activity in small intestine. They also eat more than normal. To determine the contribution of hyperphagia to these changes in lipid metabolism, we restricted intake of chow to the amount eaten ad lib by normal rats. Rats were meal-fed for 8 or 22 days from the time diabetes was induced. This regimen normalized reductase activity in both liver and intestine at mid-dark and mid-light, and all but eliminated high plasma cholesterol and triacylglycerol levels, although plasma insulin remained low and glucose remained high. Activation of hepatic reductase by endogenous phosphatase in vitro was reduced in hyperphagic diabetic rats but was normal in diabetic rats eating a normal amount of food. We conclude that hyperphagia, rather than direct effects of insulin deficiency as is usually assumed, is responsible for perturbations of lipid metabolism in chronically diabetic rats. These results support the proposal that hyperphagia increases the input of dietary and newly synthesized cholesterol from the small intestine, and that this increased input raises plasma cholesterol level and inhibits reductase activity in liver.

Animals↗
PubMed1985

Dopaminergic and serotoninergic anorectics differentially antagonize insulin- and 2-DG-induced hyperphagia.

The efficacy of anorectic drugs has been studied in rats made hyperphagic by injection of insulin or of 2-deoxy-d-glucose (2-DG). It was found that anorectics that act through a serotoninergic mechanism, i.e., d- and d-l-fenfluramine, p-chloroamphetamine, quipazine and fluoxetine antagonize both insulin- and 2-DG-induced overeating, while anorectics acting through the dopaminergic system, i.e., d-amphetamine, diethylpropion, lisuride, bromocriptine and mazindol, antagonize the hyperphagia induced by 2-DG but not that induced by insulin. Neither serotoninergic nor dopaminergic anorectics modified insulin-induced hypoglycaemia. The serotonin (5-HT) receptor blocker metergoline did not modify the hyperphagic response to insulin or 2-DG. The present results indicate that there are different neuronal or humoral circuits underlying the hyperphagic responses to insulin and 2-DG. In addition, these results, which show different effectiveness of anorectic drugs depending on what has provoked the hyperphagia, suggest that differences in the etiology of the hyperphagia of obese subjects must be taken into consideration when choosing therapy.

Animals↗