Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sequential cleavage of the precursor protein pre-pro-opiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) alpha, beta and gamma as well as the opioid-receptor ligand beta-endorphin. While a few cases of isolated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far. Recent studies in animal models elucidated a central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor (MC4-R; refs 3-5) and the linkage of human obesity to chromosome 2 in close proximity to the POMC locus, led to the proposal of an association of POMC with human obesity. The dual role of alpha-MSH in regulating food intake and influencing hair pigmentation predicts that the phenotype associated with a defect in POMC function would include obesity, alteration in pigmentation and ACTH deficiency. The observation of these symptoms in two probands prompted us to search for mutations within their POMC genes. Patient 1 was found to be a compound heterozygote for two mutations in exon 3 (G7013T, C7133delta) which interfere with appropriate synthesis of ACTH and alpha-MSH. Patient 2 was homozygous for a mutation in exon 2 (C3804A) which abolishes POMC translation. These findings represent the first examples of a genetic defect within the POMC gene and define a new monogenic endocrine disorder resulting in early-onset obesity, adrenal insufficiency and red hair pigmentation.
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PMID:Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. 962 Jul 71

Melanocortins are derived from posttranslational processing of the precursor protein pro-opiomelanocortin (POMC). The central melanocortinergic system consists of endogenous agonist alpha-melanocyte-stimulating hormone, the naturally occurring antagonist Agouti-related protein (AGRP), and two melanocortin receptors (MC3R, MC4R). Activation of central melanocortin receptors inhibits feeding and leads to weight loss, whereas blockade of the central melanocortin signaling pathway increases food consumption and promotes weight gain. This review will focus on the role of central melanocortin signaling in eating behavior and will evaluate studies of the neural pathways of POMC and AGRP systems, the effects of the central melanocortinergic system on food intake and body weight, and the regulation of hypothalamic POMC and AGRP neurons in response to altered feeding state and energy balance. In addition, this review will explore what is known about the interplay between the central melanocortinergic system and peripheral signals of energy homeostasis, i.e., leptin and glucocorticoids. Furthermore, evidence will be presented that genetic defects within the melanocortin signaling system are involved in determining susceptibility to obesity and anorexia in humans, and the therapeutic potential of melanocortin agonists and antagonists in the treatment of these disorders will be discussed.
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PMID:Role of central melanocortin signaling in eating disorders. 1239 56

Unsaturated fatty acids play an important role in the prevention of human diseases such as diabetes, obesity, cancer, and neurodegeneration. However, their oxidation in vivo by acyl-CoA dehydrogenases (ACADs) that catalyze the first step of each cycle of mitochondrial fatty acid beta-oxidation is not entirely understood. Recently, a novel ACAD (ACAD-9) of unknown function that is highly homologous to human very-long-chain acyl-CoA dehydrogenase was identified by large-scale random sequencing. To characterize its enzymatic role, we have expressed ACAD-9 in Escherichia coli, purified it, and determined its pattern of substrate utilization. The N terminus of the mature form of the enzyme was identified by in vitro mitochondrial import studies of precursor protein. A 37-amino acid leader peptide was cleaved sequentially by two mitochondrial peptidases to yield a predicted molecular mass of 65 kDa for the mature subunit. Submitochondrial fractionation studies found native ACAD-9 to be associated with the mitochondrial membrane. Gel filtration analysis indicated that, like very-long-chain acyl-CoA dehydrogenase, ACAD-9 is a dimer, in contrast to the other known ACADs, which are tetramers. Purified mature ACAD-9 had maximal activity with long-chain unsaturated acyl-CoAs as substrates (C16:1-, C18:1-, C18:2-, C22:6-CoA). These results suggest a previously unrecognized role for ACAD-9 in the mitochondrial beta-oxidation of long-chain unsaturated fatty acids. Because of the substrate specificity and abundance of ACAD-9 in brain, we speculate that it may play a role in the turnover of lipid membrane unsaturated fatty acids that are essential for membrane integrity and structure.
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PMID:Human acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial beta-oxidation of unsaturated fatty acids. 1602 May 46

In humans, mice, and other mammals, the melanocortin system consists of four peptide hormones with a core amino acid sequence of histidine-phenylalanine-arginine-tryptophan and five melanocortin receptors. Both the melanocortin hormones and their receptors are produced in diverse tissues throughout the body. The ligand of primary interest for treatment of insulin resistance is alpha-melanocyte-stimulating hormone (alpha-MSH), which is derived, as are all melanocortins, from tissue-specific post-translational proteolytic processing of the pro-opiomelanocortin (POMC) precursor protein. Recent results have shown that alpha-MSH is the complement of leptin in the endocrine circuit, regulating bodyweight, food intake, and metabolic rate. alpha-MSH can decrease bodyweight, weight gain, and food intake in mice with diet-induced and genetic obesity. As obesity is a major risk factor for type 2 diabetes mellitus, it was reasonable to investigate the endocrine agents involved in obesity for their involvement in diabetes. alpha-MSH analogs have also been shown to affect blood glucose levels in some mouse models of obesity. For instance, the POMC null mouse is extremely sensitive to insulin in an insulin tolerance test, while being otherwise euglycemic. The results from rodent studies with alpha-MSH suggest reciprocal effects: alpha-MSH appears to increase sensitivity to insulin when present in the CNS, while alpha-MSH in the periphery is necessary for insulin resistance. Should these trends be validated in humans, alpha-MSH-based therapeutics specifically active in the CNS or peripheral circulation may be promising for the treatment of type 2 diabetes.
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PMID:The role of melanocyte-stimulating hormone in insulin resistance and type 2 diabetes mellitus. 1639 14

The vgf gene has been identified as an energy homeostasis regulator. Vgf encodes a 617-aa precursor protein that is processed to yield an incompletely characterized panel of neuropeptides. Until now, it was an unproved assumption that VGF-derived peptides could regulate metabolism. Here, a VGF peptide designated TLQP-21 was identified in rat brain extracts by means of immunoprecipitation, microcapillary liquid chromatography-tandem MS, and database searching algorithms. Chronic intracerebroventricular (i.c.v.) injection of TLQP-21 (15 mug/day for 14 days) increased resting energy expenditure (EE) and rectal temperature in mice. These effects were paralleled by increased epinephrine and up-regulation of brown adipose tissue beta2-AR (beta2 adrenergic receptor) and white adipose tissue (WAT) PPAR-delta (peroxisome proliferator-activated receptor delta), beta3-AR, and UCP1 (uncoupling protein 1) mRNAs and were independent of locomotor activity and thyroid hormones. Hypothalamic gene expression of orexigenic and anorexigenic neuropeptides was unchanged. Furthermore, in mice that were fed a high-fat diet for 14 days, TLQP-21 prevented the increase in body and WAT weight as well as hormonal changes that are associated with a high-fat regimen. Biochemical and molecular analyses suggest that TLQP-21 exerts its effects by stimulating autonomic activation of adrenal medulla and adipose tissues. In conclusion, we present here the identification in the CNS of a previously uncharacterized VGF-derived peptide and prove that its chronic i.c.v. infusion effected an increase in EE and limited the early phase of diet-induced obesity.
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PMID:TLQP-21, a VGF-derived peptide, increases energy expenditure and prevents the early phase of diet-induced obesity. 1698 76

Compelling evidence indicates that excess consumption of sugar-sweetened beverages plays an important role in the epidemic of obesity, a major risk factor for type 2 diabetes mellitus. Type 2 diabetes mellitus has been associated with a higher incidence of Alzheimer disease (AD). High fat diets promote AD-like pathology in mice. It is not known whether consumption of excess sugar as in calorically sweetened beverages with an otherwise normal diet affects the development of AD. In the present study, we provided 10% sucrose-sweetened water to a transgenic mouse model of AD with a normal rodent diet. Compared with the control mice with no sucrose added in the water, the sucrose group gained more body weight and developed glucose intolerance, hyperinsulinemia, and hypercholesterolemia. These metabolic changes were associated with the exacerbation of memory impairment and a 2-3-fold increase in insoluble amyloid-beta protein levels and deposition in the brain. We further showed that the levels of expression and secretase-cleaved products of amyloid-beta precursor protein were not affected by sucrose intake. The steady-state levels of insulin-degrading enzyme did not change significantly, whereas there was a 2.5-fold increase in brain apoE levels. Therefore, we concluded that the up-regulation of apoE accelerated the aggregation of Abeta, resulting in the exacerbation of cerebral amyloidosis in sucrose-treated mice. These data underscore the potential role of dietary sugar in the pathogenesis of AD and suggest that controlling the consumption of sugar-sweetened beverages may be an effective way to curtail the risk of developing AD.
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PMID:Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. 1794 1

1. Ghrelin is a multifunctional peptide hormone that affects various processes, including growth hormone and insulin release, appetite regulation, gut motility, metabolism and cancer cell proliferation. Ghrelin is produced in the stomach and in other normal and pathological cell types. It may act as an endocrine or autocrine/paracrine factor. 2. The present article reviews recent findings in the study of ghrelin and its receptor that suggest that the ghrelin gene locus may give rise to a number of functional molecules (peptides and RNA transcripts) in addition to ghrelin. 3. The ghrelin gene encodes a precursor protein, preproghrelin, from which ghrelin and other potentially active peptides are derived by alternative mRNA splicing and/or proteolytic processing. The metabolic role of the peptide obestatin, derived from the preproghrelin C-terminal region, is contentious. However, obestatin has direct effects on cell proliferation. 4. The regulation of ghrelin expression and the mechanisms through which the peptide products arise are unclear. We have recently re-examined the organization of the ghrelin gene and identified several novel exons and transcripts. One transcript, which lacks the ghrelin-coding region of preproghrelin, contains the coding sequence of obestatin. 5. Furthermore, we have identified an overlapping gene on the antisense strand of ghrelin, namely GHRLOS, which generates transcripts that may function as non-coding regulatory RNAs or code for novel, short bioactive peptides. 6. The identification of these novel ghrelin-gene related transcripts and peptides raises critical questions regarding their physiological function and their potential role in obesity, diabetes and cancer.
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PMID:Ghrelin gene-related peptides: multifunctional endocrine / autocrine modulators in health and disease. 1956 30

Amyloid precursor protein (APP) has been characterized as an adipocyte-secreted protein that might contribute to obesity-related insulin resistance, inflammation, and dementia. In the current study, regulation of APP by the proinflammatory and insulin resistance-inducing cytokine tumor necrosis factor (TNF) alpha was determined in 3T3-L1 adipocytes. Interestingly, APP protein synthesis and mRNA expression were significantly increased by TNFalpha in a time-dependent manner with maximal induction observed after 24 h of treatment. Furthermore, TNFalpha induced APP mRNA expression dose-dependently with maximal 6.4-fold upregulation seen at 100 ng/ml effector. Moreover, inhibitor experiments suggested that TNFalpha-induced APP expression was mediated by nuclear factor kappa B. Taken together, we show for the first time a potent upregulation of APP by TNFalpha suggesting a potential role of this adipocyte-secreted protein in TNFalpha-induced insulin resistance and inflammatory disease.
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PMID:Amyloid precursor protein expression is induced by tumor necrosis factor alpha in 3T3-L1 adipocytes. 1986

Several studies have demonstrated increases in acylation stimulating protein (ASP), and precursor protein C3 in obesity, diabetes and dyslipidemia, however the nature of the regulation is unknown. To evaluate chronic hormonal and pharmaceutical mediated changes in ASP and potential mechanisms, 3T3-L1 adipocytes were treated with physiological concentrations of relevant hormones and drugs currently used in treatment of metabolic diseases for 48 h. Medium ASP production and C3 secretion were evaluated in relation to changes in adipocyte lipid metabolism (cellular triglyceride (TG) mass, non-esterified fatty acid (NEFA) release and real-time FA uptake). Chylomicrons increased ASP production (up to 411 +/- 133% P < 0.05), while leptin, triiodothyronine, and beta-blockers atenolol and propranolol had no effect. Dexamethasone, lovastatin, rosiglitazone and rimonabant decreased ASP production (-53 to -85%, P < 0.05), associated with a decrease in the precursor protein C3 (-37% to -65%, P < 0.01). By contrast, epinephrine, progesterone, testosterone, angiotensin II and metformin also decreased ASP (-54% to -100%, P < 0.05), but without change in precursor protein C3, suggesting a direct effect on convertase activity, possibly mediated by interference (except metformin) due to marked increases in NEFA (5.6-31-fold, increased P < 0.05). Both lovastatin and metformin induced decreases in ASP were also associated with decreased TG mass (maximal -60%, P < 0.05) and real-time FA uptake (maximum -75%, P < 0.05), suggesting a change in adipocyte differentiation status. These in vitro results are consistent with in vivo ASP profiles in subjects, and suggest that ASP may be regulated through precursor C3 availability, convertase activity and differentiation status.
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PMID:Hormone and pharmaceutical regulation of ASP production in 3T3-L1 adipocytes. 2006 51

Nesfatin-1 is a recently identified anorexigenic peptide derived from its precursor protein, nonesterified fatty acid/nucleobindin 2 (NUCB2). Although the hypothalamus is pivotal for the maintenance of energy homeostasis, adipose tissue plays an important role in the integration of metabolic activity and energy balance by communicating with peripheral organs and the brain via adipokines. Currently no data exist on nesfatin-1 expression, regulation, and secretion in adipose tissue. We therefore investigated NUCB2/nesfatin-1 gene and protein expression in human and murine adipose tissue depots. Additionally, the effects of insulin, dexamethasone, and inflammatory cytokines and the impact of food deprivation and obesity on nesfatin-1 expression were studied by quantitative RT-PCR and Western blotting. We present data showing NUCB2 mRNA (P < 0.001), nesfatin-1 intracellular protein (P < 0.001), and secretion (P < 0.01) were significantly higher in sc adipose tissue compared with other depots. Also, nesfatin-1 protein expression was significantly increased in high-fat-fed mice (P < 0.01) and reduced under food deprivation (P < 0.01) compared with controls. Stimulation of sc adipose tissue explants with inflammatory cytokines (TNFalpha and IL-6), insulin, and dexamethasone resulted in a marked increase in intracellular nesfatin-1 levels. Furthermore, we present evidence that the secretion of nesfatin-1 into the culture media was dramatically increased during the differentiation of 3T3-L1 preadipocytes into adipocytes (P < 0.001) and after treatments with TNF-alpha, IL-6, insulin, and dexamethasone (P < 0.01). In addition, circulating nesfatin-1 levels were higher in high-fat-fed mice (P < 0.05) and showed positive correlation with body mass index in human. We report that nesfatin-1 is a novel depot specific adipokine preferentially produced by sc tissue, with obesity- and food deprivation-regulated expression.
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PMID:Identification of nesfatin-1 in human and murine adipose tissue: a novel depot-specific adipokine with increased levels in obesity. 2042 81


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