Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020505 (hyperphagia)
 6,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Variations in energy balance, body composition, and nutrient partitioning induced by high-fat feeding, cold exposure or by concomitant high-fat feeding and cold exposure were studied in young Wistar rats. Changes in hepatic metabolism as well as in serum free triiodothyronine and leptin levels were also evaluated. Rats were exposed to either 24 or 4 degrees C and fed either a low- or high-fat diet (10 % or 50 % energy respectively) for 2 weeks. Relative to low-fat feeding at 24 degrees C, both energy intake and expenditure were increased by high-fat feeding or by cold exposure, and these changes were accompanied by increased serum triiodothyronine levels. In response to concomitant high-fat feeding and cold exposure, serum triiodothyronine tended to be further elevated, but no further increases in energy intake or energy expenditure were observed. Independently of diet, the increased energy expenditure in cold-exposed rats was not completely balanced by adaptive hyperphagia, with consequential reductions in protein and fat gain, accompanied by marked decreases in serum leptin. Furthermore, unlike high-fat feeding at 24 degrees C, cold exposure enhanced hepatic mitochondrial oxidative capacity both in the low-fat- and high-fat-fed groups. It is concluded that in this strain of young Wistar rats, despite similarly marked stimulation of energy expenditure by high-fat feeding at 24 degrees C, by cold exposure and by concomitant high-fat feeding and cold exposure, an increased hepatic oxidative capacity occurred only in the presence of the cold stimulus.
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PMID:Effect of cold exposure on energy balance and liver respiratory capacity in post-weaning rats fed a high-fat diet. 1122 37

Leptin deficiency results in a complex obesity phenotype comprising both hyperphagia and lowered metabolism. The hyperphagia results, at least in part, from the absence of induction by leptin of melanocyte stimulating hormone (MSH) secretion in the hypothalamus; the MSH normally then binds to melanocortin-4 receptor expressing neurons and inhibits food intake. The basis for the reduced metabolic rate has been unknown. Here we show that leptin administered to leptin-deficient (ob/ob) mice results in a large increase in peripheral MSH levels; further, peripheral administration of an MSH analogue results in a reversal of their abnormally low metabolic rate, in an acceleration of weight loss during a fast, in partial restoration of thermoregulation in a cold challenge, and in inducing serum free fatty acid levels. These results support an important peripheral role for MSH in the integration of metabolism with appetite in response to perceived fat stores indicated by leptin levels.
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PMID:Integrated control of appetite and fat metabolism by the leptin-proopiomelanocortin pathway. 1125 69

Mice homozygous for the Leprdb3J (db3J) mutation are null for all known isoforms of the leptin receptor (LEPR). These animals are obese, hyperphagic, cold intolerant, insulin resistant, and infertile. Mice homozygous for the Leprdb (db) mutation (lacking the B isoform only) have the same phenotype as db3J animals. To better understand the function(s) of the LEPR isoforms in vivo, we generated db3J/db3J and db/db mice bearing a transgene (neuron-specific enolase [NSE]-Rb) expressing the B isoform of LEPR, the isoform capable of activating the signal transducer and activator of transcription (STAT) pathway, under the control of the neuron-specific enolase enhancer/promoter. The NSE-Rb transgene was expressed in the brain, with low levels of expression in adrenals, testis, and white adipose tissue. LEPR-B transgene expression in NSE-Rb db3J/db3J mice partially corrected the increased fat mass, hyperphagia, and glucose intolerance while restoring fertility in males and rescuing the cold intolerance in both sexes. The body weights of NSE-Rb transgenic mice that possessed the full complement of short LEPR isoforms (NSE-Rb db/db mice) were similar to those of NSE-Rb db3J/db3J mice, suggesting that the short LEPR isoforms play little role in body weight regulation. Based on quantitative analysis of hypothalamic neuropeptide gene expression in the transgenic animals, we infer full restoration of leptin sensitivity to proopiomelanocortin (POMC) neurons, partial correction of leptin sensitivity in agouti gene-related protein (AGRP)/neuropeptide Y (NPY) neurons, and a lack of effect on leptin sensitivity of melanin concentrating hormone neurons. Thus, hypothalamic POMC and AGRP/NPY neurons are primary candidates as the mediators of the effects of the NSE-Rb transgene on energy homeostasis, ingestive behavior, the neuroendocrine system, and glucose metabolism.
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PMID:Transgenic complementation of leptin-receptor deficiency. I. Rescue of the obesity/diabetes phenotype of LEPR-null mice expressing a LEPR-B transgene. 1127 57

Intracerebroventricular injections of 10-20-microg orexin-A induce food intake in rats for about 30 min, or enhance fasting-induced hyperphagia. In thermoregulatory studies, an amount of 2 microg of the peptide causes hypometabolism and hypothermia in the same period. The thermoregulatory reaction can be demonstrated at moderately cool environments, mainly after slight food deprivation. Both the ingestive and the thermoregulatory reactions are more pronounced in cold-adapted animals. Pretreatment with D-Tyr27,36,D-Thr32-NPY(27-36), a peptide-antagonist of NPY, prevents the hypothermia. It is concluded that, probably through NPY activation, orexin-A is involved primarily in the regulation of energy status of the body (as an anabolic agent), and not simply in the regulation of either food intake or body temperature. This anabolic response is followed by a late and more sustained catabolic phase characterized by absence of food intake, increased metabolism and dose-dependent hyperthermia, which hyperthermia cannot be suppressed by the NPY-antagonist. In contrast to orexin-A, neither hyperphagia nor suppression of refeeding hyperphagia, but dose-dependent hyperthermia follows injections of orexin-B, suggesting that this peptide has neither coordinated anabolic nor coordinated catabolic effects on energy balance.
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PMID:Effects of orexins on energy balance and thermoregulation. 1183 Feb 76

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.
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PMID:Analysis of energy expenditure at different ambient temperatures in mice lacking DGAT1. 1238 46

Energy homeostasis is regulated by a complex network involving peripheral and central signals that determine food intake and energy expenditure. Melanin-concentrating hormone (MCH) plays an essential role in this process. Animals treated with MCH develop hyperphagia and obesity. Ablation of the prepro-MCH gene leads to a lean phenotype, as does ablation of the rodent MCH receptor, MCHR-1. MCH is overexpressed in the leptin-deficient ob/ob mouse, and we hypothesized that ablation of MCH in this animal would lead to attenuation of its obese phenotype. Compared with ob/ob animals, mice lacking both leptin and MCH (double null) had a dramatic reduction in body fat. Surprisingly, the hyperphagia of the ob/ob mouse was unaffected. Instead, leanness was secondary to a marked increase in energy expenditure resulting from both increased resting energy expenditure and locomotor activity. Furthermore, double-null mice showed improvements in other parameters impaired in ob/ob mice. Compared with ob/ob mice, double-null animals had increased basal body temperature, improved response to cold exposure, lower plasma glucocorticoid levels, improved glucose tolerance, and reduced expression of stearoyl-CoA desaturase 1 (SCD-1). These results highlight the importance of MCH in integration of energy homeostasis downstream of leptin and, in particular, the role of MCH in regulation of energy expenditure.
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PMID:Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype. 1289 41

Signal transducer and activator of transcription (STAT)3 is widely expressed in the CNS during development and adulthood. STAT3 has been implicated in the control of neuron/glial differentiation and leptin-mediated energy homeostasis, but the physiological role and degree of involvement of STAT3 in these processes is not defined and controversial because of the lack of a direct genetic model. To address this, we created mice with a neural-specific disruption of STAT3 (STAT3(N-/-)). Surprisingly, homozygous mutants were born at the expected Mendelian ratio without apparent developmental abnormalities but susceptible to neonatal lethality. Mutants that survived the neonatal period were hyperphagic, obese, diabetic, and infertile. Administering a melanocortin-3/4 receptor agonist abrogated the hyperphagia and hypothalamic immunohistochemistry showed a marked reduction in proopiomelanocortin with an increase in neuropeptide Y and agouti-related protein. Mutants had reduced energy expenditure and became hypothermic after fasting or cold stress. STAT3(N-/-) mice are hyperleptinemic, suggesting a leptin-resistant condition. Concomitant with neuroendocrine defects such as decreased linear growth and infertility with accompanying increased corticosterone levels, this CNS knockout recapitulates the unique phenotype of db/db and ob/ob obese models and distinguishes them from other genetic models of obesity. Thus, STAT3 in the CNS plays essential roles in the regulation of energy homeostasis and reproduction.
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PMID:Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. 1507 Jul 74

Uncoupling proteins (UCPs) are a proton transporter family located in the mitochondrial inner membrane. The molecular expression and activity of UCPs in brown adipose tissue and skeletal muscle are regulated by factors as diverse as chronic overeating and cold exposure, suggesting roles in energy expenditure and heat production. Although UCP2, UCP4 and brain mitochondrial carrier protein-1 (BMCP-1, i.e. UCP5) mRNAs are expressed in the central nervous system, their central function is unknown. This study presents the first evidence on localization and quantitative expression of UCPs in the rat inner ear by real-time PCR and immunohistochemistry. Real-time PCR studies revealed that UCP2 mRNA was expressed in the vestibular and spiral ganglia more abundantly than any other UCP. Neocortex, by contrast, contained UCP2 and UCP4 equally. Notably, UCP3 and UCP4 mRNAs were expressed in inner ear ganglia, but brain UCP3 mRNA expression level was undetectable by simple PCR. Immunohistochemical studies confirmed that both UCP2- and UCP3-like immunoreactivities were detected in vestibular and spiral ganglion cells and co-localized with a mitochondrial marker, MitoFluorGreen. According to previous reports, UCP2 and UCP3 are thermogenic in yeast and brain UCP2 has been suggested to modulate pre- and post-synaptic events by axonal thermogenesis. It has also been reported recently that UCP2 and UCP3 responses to superoxide application may be an antioxidant protective mechanism. Therefore, it is suggested that mitochondrial UCPs (UCP2, UCP3, UCP4) may play both a protective role against oxidative damage and a thermal signaling role in the eighth nerve.
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PMID:Localization of the mitochondrial uncoupling protein family in the rat inner ear. 1546

Pten is an important phosphatase, suppressing the phosphatidylinositol-3 kinase/Akt pathway. Here, we generated adipose-specific Pten-deficient (AdipoPten-KO) mice, using newly generated Acdc promoter-driven Cre transgenic mice. AdipoPten-KO mice showed lower body and adipose tissue weights despite hyperphagia and enhanced insulin sensitivity with induced phosphorylation of Akt in adipose tissue. AdipoPten-KO mice also showed marked hyperthermia and increased energy expenditure with induced mitochondriagenesis in adipose tissue, associated with marked reduction of p53, inactivation of Rb, phosphorylation of cyclic AMP response element binding protein (CREB) and increased expression of Ppargc1a, the gene that encodes peroxisome proliferative activated receptor gamma coactivator 1 alpha. Physiologically, adipose Pten mRNA decreased with exposure to cold and increased with obesity, which were linked to the mRNA alterations of mitochondriagenesis. Our results suggest that altered expression of adipose Pten could regulate insulin sensitivity and energy expenditure. Suppression of adipose Pten may become a beneficial strategy to treat type 2 diabetes and obesity.
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PMID:Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice. 1593 75

Secretion of leptin from adipose tissue communicates body energy status to the neuroendocrine system by activating the long form of the leptin receptor (LRb). Lack of leptin or LRb (as in db/db mice) results in obesity that stems from the combined effects of hyperphagia and decreased energy expenditure. We have previously generated mice in which LRb is replaced with a mutant LRb (LRbS1138) that specifically disrupts LRb-->STAT3 (signal transducer and activator of transcription-3) signaling; mice homozygous for this mutant (s/s) display increased feeding and are obese. We have now examined energy expenditure in s/s and db/db mice. Consistent with the increased lean body mass of s/s animals, locomotor activity and acute cold tolerance (partly a measure of shivering thermogenesis) in s/s mice were modestly but significantly improved compared with db/db mice, although they were decreased compared with wild-type mice. Total and resting metabolic rates were similarly depressed in s/s and db/db mice, however. Indeed, s/s and db/db mice display similar reductions in thyroid function and brown adipose tissue expression of uncoupling protein-1, which is regulated by sympathetic nervous system (SNS) tone. Thus, the LRb-->STAT3 signal is central to both the control of energy expenditure by leptin and the neuroendocrine regulation of the SNS and the thyroid axis.
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PMID:LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin. 1556 35


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