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

In response to moderately increased dietary fat content, melanocortin-4 receptor-null mutant (MC4R-/-) mice exhibit hyperphagia and accelerated weight gain compared to wild-type mice. An increased feed efficiency (weight gain/kcal consumed) argues that mechanisms in addition to hyperphagia are instrumental in causing weight gain. We report two specific defects in coordinating energy expenditure with food intake in MC4R-/- mice. Wild-type mice respond to an increase in the fat content of the diet by rapidly increasing diet-induced thermogenesis and by increasing physical activity, neither of which are observed in MC4R-/- mice. Leptin-deficient and MC3R-/- mice regulate metabolic rate similarly to wild-type mice in this protocol. Melanocortinergic pathways involving MC4-R-regulated neurons, which rapidly respond to signals not requiring changes in leptin, thus seem to be important in regulating metabolic and behavioral responses to dietary fat.
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PMID:Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. 1136 41

Identifying the role of the melanocortin system in regulating energy homeostasis has relied on both genetic and pharmacological studies. The key findings included 1) that the coat color phenotype in the lethal yellow (A(Y)/a) mouse is due to antagonism of the melanocortin-1 receptor (MC1R) by the agouti gene product; 2) the MC3R and MC4R are expressed in CNS centers involved in energy homeostasis, and 3) the combined results of pharmacological studies showing that agouti is an antagonist of the MC4R and transgenic studies showing that inhibition or loss of the MC4R recapitulate the lethal yellow phenotype. Pro-opiomelanocortin (POMC), MC3R, and MC4R knockouts are obese and are now being used to further analyze melanocortin receptor function. The obesity phenotype observed in the MC3R and MC4R knockouts (KO) differ markedly. MC4RKO mice are hyperphagic, do not regulate pathways that increase energy expenditure (diet-induced thermogenesis) and physical activity in response to hyperphagia, and can develop type 2 diabetes. In contrast, MC3R deficient mice are not hyperphagic, have a normal metabolic response to increased energy consumption, and do not develop diabetes. The mechanism underlying the increased adiposity in the MC3R knockout remains unclear, but might be related to changes in nutrient partitioning or physical activity.
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PMID:The melanocortin receptors: lessons from knockout models. 1235 99

Proopiomelanocortin (POMC) is expressed in the arcuate nucleus of the hypothalamus (ARC) and the commissural nucleus of the solitary tract (cNTS). Post-translational processing of POMC produces two melanocortin receptor ligands, alpha- and gamma-melanocyte-stimulating hormone (MSH). Two melanocortin receptors (MC3R, MC4R) are expressed in brain regions receiving projections of POMC fibers, most of which also receive projections from a population of ARC neurons that co-express neuropeptide Y (NPY) and the MC3R/MC4R antagonist agouti-related peptide (AgRP). MC4R haploinsufficient humans and MC4R knockout (MC4RKO) mice exhibit increased adiposity and linear growth. MC4RKO mice exhibit hyperleptinemia and hyperinsulinemia and sometimes, but not always, develop type 2 diabetes (T2D). Individually housed MC4RKO mice fed low-fat diets are not hyperphagic when food intake is corrected for lean mass, whereas hyperphagia is observed after the introduction of diets with increased fat content. POMC knockout (POMCKO) mice are similar in that the severity of hyperphagia increases with the introduction of high-fat diets. By contrast, targeted deletion of the MC3R in the mouse results in increased adiposity despite the absence of hyperphagia. MC3RKO mice also exhibit reduced linear growth and lean mass; while MC3RKO mice are hyperleptinemic and hyperinsulinemic, the development of T2D has not been reported. The MC4R, but not the MC3R, is required for the stimulation of energy expenditure in response to melanocortin agonists and voluntary hyperphagia. Evidence for altered physical activity has also been reported for both knockout models. Analysis of MC4RKO mice indicates that this receptor is involved in rapidly coordinating energy consumption with energy expenditure through diet-induced thermogenesis and activity.
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PMID:Knockout studies defining different roles for melanocortin receptors in energy homeostasis. 1285 22

In several hyperphagic models, including lactation, in which hypothalamic melanocortin signaling is reduced, a novel expression of NPY mRNA in the dorsomedial hypothalamus (DMH) has been observed, suggesting that melanocortin signaling and the induced NPY in the DMH may constitute unique neurocircuitry in mediating energy balance. Using lactating rats as a model, the present study first showed that in the DMH abundant alpha-MSH and agouti-related protein fibers are in close apposition to NPY-positive cells. However, no NPY and MC4R (a melanocortin receptor) double-labeled neurons were observed. These data suggested that melanocortin input may synapse on presynaptic terminals that then synapse on DMH NPY cells. To study the function of DMH MC4Rs in energy balance, an MC3/4R-selective agonist, melanotan II (MTII), was injected bilaterally into the DMH. MTII injection significantly suppressed feeding induced by 24 hr fasting or suckling-induced hyperphagia. Furthermore, MTII treatment greatly attenuated suckling-induced NPY expression in the DMH. MTII treatment also stimulated uncoupling protein 1 activity in the brown adipose tissue of suckling female rats, indicative of increased sympathetic outflow. In summary, the present study demonstrated that the melanocortin system in the DMH not only plays an important role in inducing NPY expression in the DMH of lactating rats but also in regulating energy homeostasis, at least in part, by modulating appetite and energy expenditure.
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PMID:Melanocortin 4 receptor-mediated hyperphagia and activation of neuropeptide Y expression in the dorsomedial hypothalamus during lactation. 1517 78

To address whether defective melanocortin activation is one element of leptin resistance with age, we infused centrally the melanocortin agonist, MTII and antagonist, SHU9119 in young and old rats. Food intake, energy expenditure, adiposity, BAT UCP1, and leptin expression in white fat as well as hypothalamic expressions of MC3R, MC4R, POMC, AgRP and NPY were assessed. The MTII-evoked anorexia was transient whereas the SHU9119-induced hyperphagia was sustained in young and old. MTII elevated oxygen consumption in both ages. The oxygen consumption waned gradually in young but increased continuously in aged following MTII infusion. The MTII-mediated induction in BAT UCP1 was similarly robust in both ages as was the SHU9119-mediated suppression in UCP1. POMC and MC3/4 receptor expressions were unaltered with age. These findings demonstrate the effectiveness of MTII to bypass leptin resistance in aged-obese rats. The equally strong orexigenic response to SHU9119 coupled with unaltered POMC expression and food intake in the young versus old suggest that melanocortin tone is unchanged with age despite impaired melanocortin activation by leptin.
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PMID:Aged-obese rats exhibit robust responses to a melanocortin agonist and antagonist despite leptin resistance. 1546 33

We tested whether MC4R null mice display altered gustatory function relative to wild-type controls that may contribute to the characteristic hyperphagia and obesity associated with this gene deletion. Mice were tested for their licking responses to prototypical taste solutions (sucrose, NaCl, quinine, citric acid) in series of daily 30-min sessions in which a range of concentrations of each tastant was available in randomized blocks of 5-s trials. Notwithstanding some minor deviations, the concentration-response functions of the MC4R null and wild-type mice were basically the same for all of the prototypical compounds tested here. Thus, taste-based appetitive and avoidance behavior is expressed in the absence of the MC4 receptor, demonstrating that this critical component in the melanocortin system is not required for normal affective gustatory function to be maintained.
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PMID:Melanocortin-4 receptor-null mice display normal affective licking responses to prototypical taste stimuli in a brief-access test. 1599 83

The melanocortin family of receptors (MC 1-5R) and their endogenous peptide ligands (alpha, beta, gamma- MSH and ACTH) have been implicated in the control of a wide variety of behavioral and physiological functions including the homeostatic control of food intake and body weight. In rodent models, melanocortin agonists including the nonselective peptide MTII have been shown to decrease food intake and body weight while antagonists such as SHU9119 and AGRP have been shown to stimulate food intake and increase body weight. Deletion of either the MC3R or MC4R in mice was found to be associated with obesity although hyperphagia was only observed in the MC4R deficient mice. Similarly in humans, inactivating mutations of the MC4R have been found in as many as six percent of obese individuals. The suggestion from these findings that activation of MC4Rs would have an anorectic effect in humans has resulted in efforts to produce selective agonists for the treatment of obesity. Over the past decade, efforts to develop MC4R selective small molecule and peptide agonists have been met with fractional success. Many small molecule agonists have been identified; however, few have been shown to have activity in vivo. While their use as therapeutics may have limitations, selective and potent peptide agonists have been shown by several investigators to decrease food intake and body weight in rodent models. The subject of the current review is to examine the progress made to date on producing both small molecule and peptide MC4R agonists as potential therapeutics for obesity.
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PMID:Melanocortin-4 receptor agonists for the treatment of obesity. 1758 32

Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity.
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PMID:The central melanocortin system directly controls peripheral lipid metabolism. 1788 89

The amygdala is rich in melanocortin 4 receptors. Because the reduction in dietary fat intake after enterostatin is injected in the central nucleus of the amygdala (CeA) is blocked by a melanocortin 4 receptor antagonist, we investigated the role of melanocortin activity in the CeA in regulating food intake and macronutrient choice. Sprague-Dawley rats, fitted with CeA cannulas, were fed either chow, a high-fat (HF) diet, or adapted to a two-choice HF or low-fat (LF) diet. Injections of the MC4R agonist melanotan II (MTII) in the CeA had a dose-dependent inhibitory effect on food intake that lasted for at least 24 h. This response was greater in rats fed a HF diet. The inverse agonist agouti-related protein (AgRP) and antagonist SHU-9119 increased food intake in a dose-dependent manner, with the hyperphagia lasting for 60 h. In rats adapted to a two-choice HF/LF diet, MTII decreased HF consumption but had no effect on LF consumption, resulting in a long-lasting decrease in total calorie intake (-35.5% after 24 h, P < 0.05). Total calorie intake increased in both AgRP- and SHU-9119-treated rats (32 and 109% after 24 h, respectively) as the result of increased intake of HF diet. There was no modification of LF consumption with AgRP treatment and a transient nonsignificant decrease with SHU-9119 treatment. Amygdala brain-derived neurotrophic factor expression was increased by AgRP in fed rats. These results identify the amygdala as a site of action for the melanocortin system to control food intake and dietary preferences.
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PMID:Melanocortin activity in the amygdala controls appetite for dietary fat. 1992 60

Following extensive suprasellar operations for excision of hypothalamic tumors, some patients develop morbid obesity, the so-called hypothalamic obesity (HyOb). HyOb complicates disorders related to the hypothalamus, including those that cause structural damage to the hypothalamus, pituitary macroadenoma with suprasellar extension, glioma, meningioma, teratoma, germ cell tumors, radiotherapy, Prader-Willi syndrome, and mutations in leptin, leptin receptor, POMC, MC4R and CART genes. It is conceivable that a subgroup of patients with 'simple obesity' also have HyOb. The hypothalamus regulates body weight by precisely balancing the intake of food, energy expenditure and body fat tissue. Orexigenic and anorexigenic hypothalamic centers (hyperphagia when impaired) play a central role, connecting to adipose tissue by means of an intricate efferent and afferent signals circuit. Other mechanisms by which the brain regulates adipose tissue and beta cells of the pancreas include the sympathetic nervous system, vagally mediated hyperinsulinemia and the endocrine system, namely growth hormone, thyroid-stimulating hormone and the hypothalamo-pituitary-adrenal axis. Corticotropin-releasing hormone, adrenocorticotropic hormone glucocorticoids and the 11beta-HSD-1 shuttle regulate lipolysis both directly and indirectly. All the above mechanisms may be impaired in HyOb. Management of HyOb targets the major manifestations: hyperphagia, autonomic dysfunction, hyperinsulinemia and impaired energy expenditure. Individual variation is considerable. Satisfactory therapy is currently unavailable.
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PMID:Hypothalamic obesity. 1995 67


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