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Query: UMLS:C0020505 (hyperphagia)
 6,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gold-thioglucose (GTG) induces lesions in the ventromedial nucleus of the hypothalamus, resulting in hyperphagia and obesity. To identify genes involved in the hypothalamic regulation of energy homeostasis, we used a screen for genes that are dysregulated in GTG-induced obese mice. We found that GPR7, the endogenous G protein-coupled receptor for the recently identified ligands neuropeptide B and neuropeptide W, was down-regulated in hypothalamus after GTG treatment. Here we show that male GPR7-/- mice develop an adult-onset obese phenotype that progressively worsens with age and was greatly exacerbated when animals are fed a high-fat diet. GPR7-/- male mice were hyperphagic and had decreased energy expenditure and locomotor activity. Plasma levels of glucose, leptin, and insulin were also elevated in these mice. GPR7-/- male mice had decreased hypothalamic neuropeptide Y RNA levels and increased proopiomelanocortin RNA levels, a set of effects opposite to those evident in ob/ob mice. Furthermore, ob/ob GPR7-/- and Ay/a GPR7-/- double mutant male mice had an increased body weight compared with normal ob/ob or Ay/a male mice, suggesting that the obesity of GPR7-/- mice is independent of leptin and melanocortin signaling. Female mice did not show any significant weight increase or associated metabolic defects. These data suggest a potential role for GPR7 and its endogenous ligands, neuropeptide B and neuropeptide W, in regulating energy homeostasis independent of leptin and melanocortin signaling in a sexually dimorphic manner.
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PMID:Targeted disruption of GPR7, the endogenous receptor for neuropeptides B and W, leads to metabolic defects and adult-onset obesity. 1292 42

Seventy unwed pregnant patients in states of mild to moderate depression evidenced by one or more symptoms (tenseness, "nervousness," crying spells, listlessness, fatigue, nausea and vomiting, insomnia and overeating), received informal psychotherapy and a sustained-release capsule combining d-amphetamine sulfate and amobarbital.Forty-eight patients had complete or substantial relief of symptoms, 15 had partial relief, seven had slight or no relief. Use of the preparation seemed to make tense, "nervous" patients more communicative and amenable to counseling, but was less effective in listless, easily fatigued patients. Because of its direct mood-alleviating action and its ability to facilitate psychotherapy, the d-amphetamine sulfate-amobarbital combination proved a very effective treatment for mild and moderate depression accompanying pregnancy.
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PMID:Prepartum depression; a study of seventy unwed mothers treated with d-amphetamine sulfate and amobarbital. 1352 17

Obesity has reached epidemic proportions and has become one of the major health problems in developed countries. Current theories consider obesity a result of overeating and sedentary life style and most efforts to treat or prevent weight gain concentrate on exercise and food intake. This approach does not improve the situation as may be seen from the steep increase in the prevalence of obesity. This encouraged us to reanalyse existing information and look for biochemical basis of obesity. Our approach was to ignore current theories and concentrate on experimental data which are described in scientific journals and are available from several databases. We developed and applied a Knowledge Discovery in Databases procedure to analyse metabolic data. We began with the contradictory information: in obesity, more calories are consumed than used up, suggesting that obese people should have excess energy. On the other side, obese people experience fatigue and decreased physical endurance that indicates diminished energy supply in the body. The result of our work is a chain of metabolic events leading to obesity. The crucial event is the inhibition of the TCA cycle at the step of aconitase. It disturbs energy metabolism and results in ATP deficiency with simultaneous fat accumulation. Further steps in obesity development are the consequences of diminished energy supply: inhibition of beta-oxidation, leptin resistance, increase in appetite and food intake and a decrease in physical activity. Thus, our theory shows that obesity does not have to be caused by overeating and sedentary life-style but may be the result of the "obese" change in metabolism which is forcing people to overeat and save energy to sustain metabolic functions of cells. This "obese" change is caused by environmental factors that activate chronic low-grade inflammatory process in the body linking obesity with the environment of developed countries.
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PMID:Decreased energy levels can cause and sustain obesity. 1455 57

The incidence of obesity has increased dramatically in recent years, making it one of the most pressing public health concerns worldwide. Obesity is commonly associated with comorbid conditions, most notably diabetes, coronary artery disease, and hypertension, and the coexistence of these diseases has been termed the Metabolic Syndrome. The identification of the hormone leptin provided a molecular link to obesity. Leptin is recognized as the central mediator in an endocrine circuit regulating energy homeostasis. Leptin administration leads to hypophagia, increased energy expenditure, and weight loss, while leptin deficiency enacts an adaptive response to starvation manifested by hyperphagia, decreased energy expenditure, and suppression of the neuroendocrine axis. While elucidation of leptin's role has permitted a more detailed view of the biology underlying energy homeostasis, most obese individuals are leptin resistant. A more complete understanding of the molecular components of the leptin pathway is necessary to develop effective treatment for obesity and the Metabolic Syndrome. The identification and role of one such component, stearoyl-CoA desaturase-1 (SCD-1), is reviewed here. Leptin's actions are not due to its anorectic effects alone. Leptin also mediates specific metabolic effects, including the potent depletion of triglyceride from liver and other peripheral tissues. To explore the molecular basis by which leptin depletes hepatic lipid, we used oligonucleotide arrays to identify genes in liver whose expression was modulated by leptin treatment. An algorithm was created that identified and ranked genes specifically repressed by leptin. The gene ranking at the top of this list was SCD-1, the rate limiting enzyme in the biosynthesis of monounsaturated fats. SCD-1 was specifically repressed during leptin-mediated weight loss, and mice lacking SCD-1 showed markedly reduced adiposity on both a lean and ob/ob background (ab(J)/ab(J); ob/ob), despite higher food intake. ab(J)/ab(J); ob/ob mice also showed a complete correction of the hypometabolic phenotype and hepatic steatosis of ob/ob mice, suggesting that fatty acid oxidation is enhanced in the absence of SCD-1. These findings indicate that pharmacologic manipulation of SCD-1 may be of benefit in the treatment of obesity, diabetes, hepatic steatosis, and other components of the Metabolic Syndrome.
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PMID:Stearoyl-CoA desaturase-1 and the metabolic syndrome. 1468 58

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

Food restriction and weight loss result in reduced plasma leptin, which is associated with a pleiotropic biologic response. However, because weight loss itself is also associated with changes in numerous other humoral and metabolic signals, it can be difficult to determine the precise features of the biologic response to acute leptin deficiency. To study this response in the absence of changes in nutritional state, we have developed a protocol that allows such analysis in normal, non-food-restricted animals. Wild-type mice are treated with high-dose leptin until fat mass is depleted and, as a consequence, endogenous leptin production is reduced. At this point, exogenous leptin is abruptly withdrawn, thus inducing a state of leptin deficiency in otherwise normal mice. Leptin deficiency is sustained by feeding the animals only as much as they consumed voluntarily before leptin withdrawal. The biologic response to leptin deficiency induced in this manner includes altered neuropeptide levels, decreased energy expenditure, and impaired reproductive and immune function. Replacement of leptin at physiological concentrations after withdrawal of high-dosage leptin blunts, but does not completely block, the hyperphagia and weight regain caused by acute leptin deficiency, nor does it correct the resulting reproductive and immune dysfunction. This suggests that high-dosage leptin treatment induces a state of partial leptin resistance. In aggregate, these studies establish the role of acute hypoleptinemia in regulating energy balance, the immune system, and reproductive function, and further suggest that high-dosage leptin treatment can induce a state of acquired leptin resistance.
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PMID:Acute leptin deficiency, leptin resistance, and the physiologic response to leptin withdrawal. 1569 32

There is much more seasonal difference in higher latitudes than in lower latitudes. In a significant portion of the population of the northern United States, the shorter days of fall and winter precipitate a syndrome that can consist of depression, fatigue, hypersomnolence, hyperphagia, carbohydrate craving, weight gain, and loss of libido. If these symptoms persist in the winter, abate as the days grow longer, and disappear in the summer, the diagnosis of seasonal affective disorder (SAD) can be made. Many hypotheses exist regarding the biochemical mechanisms behind the predisposition toward this disease, including circadian phase shifting, abnormal pineal melatonin secretion, and abnormal serotonin synthesis. Although the mechanism(s) behind this disease is not fully known, one treatment appears to address each of the theories. Light therapy is a natural, non-invasive, effective, well-researched method of treatment for SAD. Various light temperatures and times of administration of light therapy have been studied, and a combination of morning and evening exposure appears to offer the best efficacy. Other natural methods of treatment have been studied, including L-tryptophan, Hypericum perforatum (St. John's wort), and melatonin.
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PMID:Epidemiology, etiology, and natural treatment of seasonal affective disorder. 1577 58

Metabolic depression, an adaptive biological process for energy preservation, is responsible for torpor, hibernation and estivation. We propose that a form of metabolic depression, and not mitochondrial dysfunction, is the process underlying the observed hypometabolism, state-dependent neurobiological changes and vegetative symptoms of major depression in humans. The process of metabolic depression is reactivated via differential gene expression in response to perceived adverse stimuli in predisposed persons. Behavior inhibition by temperament, anxiety disorders, genetic vulnerabilities, and early traumatic experiences predispose persons to depression. The proposed theory is supported by similarities in the presentation and neurobiology of hibernation in bears and major depression and explains the yet unexplained neurobiological changes of depression. Although, gene expression is suppressed in other hibernators by deep hypothermia, bears were chosen because they hibernate with mild hypothermia. Pre-hibernation in bears and major depression with atypical features are both characterized by fat storage through overeating, oversleeping, and decreased mobility. Hibernation in bears and major depression with melancholic features are characterized by withdrawal from the environment, lack of energy, loss of weight from not eating and burning stored fat, changes in sleep pattern, and the following similar neurobiological findings: reversible subclinical hypothyroidism; increased concentration of serum cortisol; acute phase protein response; low respiratory quotient; oxidative stress response; decreased neurotransmitter levels; and changes in cyclic-adenosine monophosphate-binding activity. Signaling systems associated with protein phosphorylation, transcription factors, and gene expression are responsible for the metabolic depression process during pre-hibernation and hibernation. Antidepressants and mood stabilizers interfere with the hibernation process and produce their therapeutic effects by normalizing the fluctuation of activities in the different signaling systems, which are down-regulated during hibernation and depression and up-regulated during exodus from hibernation and the hypomanic or manic phase of mood disorders. The ways individuals cognitively perceive, understand, communicate, and react to the vegetative symptoms of depression, from downregulation in energy production, and in the absence of known medical causes, produce the other characteristics of depression including guilt, helplessness, hopelessness, suicidal phenomena, agitation, panic attacks, psychotic symptoms, and sudden switch to hypomanic or manic episodes. The presence of one or more of these characteristics depends on the person's neuropsychological function, its social status between the others, and the other's response to the person. Neurobiological changes associated with metabolic depression during entrance, maintenance, and exodus from hibernation in bears is suggested as a natural animal model of human depression and mood disorders.
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PMID:Metabolic depression in hibernation and major depression: an explanatory theory and an animal model of depression. 1606 29

An interactive network comprised of neuropeptide Y (NPY) and cohorts is obligatory in the hypothalamic integration of appetite and energy expenditure on a minute-to-minute basis. High or low abundance of NPY and cognate receptors dysregulates the homeostatic milieu engendering hyperphagia, decreased energy expenditure, obesity and attendant metabolic syndrome cluster of dyslipidemia, glucose intolerance, insulin resistance and hyperinsulinemia, risk factors for type II diabetes and cardiovascular diseases. Increasing the supply of the endogenous repressor hormone leptin locally in the hypothalamus with the aid of leptin gene therapy, blocked age-related and dietary obesities, and the sequential development of dyslipidemia, hyperglycemia, and insulin resistance. Thus, sustained repression of NPY signaling with increased leptin selectively in the hypothalamus can avert environmental obesity and the risks of metabolic diseases.
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PMID:Subjugation of hypothalamic NPY and cohorts with central leptin gene therapy alleviates dyslipidemia, insulin resistance, and obesity for life-time. 1638 5

Mutations in the melanocortin-4 receptor (MC4R) are associated with early-onset obesity in humans. Furthermore, a null Mc4r allele in mice leads to severe obesity due to hyperphagia and decreased energy expenditure. As part of independent N-ethyl- N-nitrosourea (ENU) mutagenesis screens, two obesity mutants, Fatboy and Southbeach, were isolated. Mapping revealed linkage to the melanocortin-4 receptor (Mc4r) and sequencing found single amino acid changes in Mc4r for each line. Expression of the mutant receptors in HEK 293 cells revealed defects in receptor signaling. The mutated Fatboy receptor (I194T) shows an increase in the effective concentration necessary for 50% of maximal signaling (EC(50)) when stimulated with alpha-MSH. Based on competitive binding, I194T is expressed on the cell surface at lower levels than the nonmutated receptor. In contrast, Southbeach (L300P) displays minimal receptor signaling when stimulated with the natural ligand alpha-MSH or the synthetic agonist NDP-alpha-MSH. Cell surface binding is absent, which usually indicates a lack of cell surface expression. However, antibody binding to Flag-tagged receptors by flow cytometry analysis and immunofluorescence demonstrates that L300P is translocated to the plasma membrane at a level comparable to the wild-type receptor. These results indicate a correlation with remaining receptor activity and the severity of the obesity in the mice homozygous for the mutations. Southbeach has less receptor activity and becomes more obese. These mutants will serve as good models for the variability in phenotype in humans carrying mutations in the MC4R gene.
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PMID:Point mutations in the melanocortin-4 receptor cause variable obesity in mice. 1714 85


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