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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hormone insulin remains the cornerstone of diabetic therapy since it is required for almost all cases of Type 1 and many cases of Type 2 diabetes. Since the discovery of insulin in 1921, much has been learned about its chemistry, structure and action as well as its production in the beta cell. Insulin is formed through a series of precursors, beginning with preproinsulin, the protein encoded in the insulin gene. These precursors direct the prohormone into the secretory pathway and ultimately into the secretory granules where it is converted into insulin and C-peptide. These products are stored and secreted together in a highly regulated manner in response to glucose and other stimuli. This review focuses on the recently discovered prohormone convertases, PC2 and PC3 (PC1), the enzymes responsible for the endoproteolytic processing of proinsulin to insulin and C-peptide in the beta cell as well as for the selective processing of proglucagon to glucagon in the alpha cell or GLP1 in intestinal L-cells. PC2 and PC3 are calcium-dependent serine proteases related to the bacterial enzyme subtilisin. They cleave selectively at Lys-Arg or Arg-Arg sites in precursors, generating products with C-terminal basic residues that are then removed by carboxypeptidase E, an exopeptidase. All 3 enzymes are expressed mainly in secretory granules of neuroendocrine cells throughout the body and in the brain. Inherited defects affecting the prohormone-processing enzymes have recently been found in association with unusual syndromes of obesity and other metabolic disorders.
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PMID:The role of prohormone convertases in insulin biosynthesis: evidence for inherited defects in their action in man and experimental animals. 879 89

Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse. We have previously described a women with extreme childhood obesity (Fig. 1), abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism and elevated plasma proinsulin and pro-opiomelanocortin (POMC) concentrations but a very low insulin level, suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 (PC1; ref. 4). We now report this proband to be a compound heterozygote for mutations in PC1. Gly-->Arg483 prevents processing of proPC1 and leads to its retention in the endoplasmic reticulum (ER). A-->C+4 of the intro-5 donor splice site causes skipping of exon 5 leading to loss of 26 residues, a frameshift and creation of a premature stop codon within the catalytic domain. PC1 acts proximally to CPE in the pathway of post-translational processing of prohormones and neuropeptides. In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents.
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PMID:Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. 920 82

Proopiomelanocortin (POMC) is a precursor to various, bioactive peptides including ACTH, beta LPH, alpha MSH, and beta endorphin (beta END). Processing of POMC at dibasic residues is tissue-specific and is performed by either PC1 alone (resulting in ACTH and beta LPH, anterior pituitary corticotrophes) or by a combination of PC1 and PC2 (yielding alpha MSH and beta END, pituitary neurointermediate lobe and hypothalamus). The PC2-specific binding protein 7B2 is intimately involved in the zymogen activation of proPC2 into PC2. Structure-function studies of these enzymes demonstrated the presence of N- and C-terminal domains, as well as specific amino acids within the catalytic segment that influence the degree of activity of each enzyme and the interaction of PC2 with 7B2. The tissue distribution, plasticity of expression, and the multiple precursors that are differentially cleaved by PC1 and/or PC2, predict a wide array of combinatorial activities of these convertases within the endocrine and neuroendocrine system. The phenotypic consequences of the absence of genetic expression of either PC1 or PC2 are now explored using knockout mice and in human patients suffering from obesity and diabetes.
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PMID:The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1. 1081 41

A spontaneous point mutation in the coding region of the carboxypeptidase E (CPE) gene results in a loss of CPE activity that correlates with the development of late onset obesity (Nagert, J. K., Fricker, L. D., Varlamov, O., Nishina, P. M., Rouille, Y., Steiner, D. F., Carroll, R. J., Paigen, B. J., and Leiter, E. H. (1995) Nat. Genet. 10, 135-142). Examination of the level of neuropeptides in these mice showed a decrease in mature bioactive peptides as a result of a decrease in both carboxypeptidase and prohormone convertase activities. A defect in CPE is not expected to affect endoproteolytic processing. In this report we have addressed the mechanism of this unexpected finding by directly examining the expression of the major precursor processing endoproteases, prohormone convertases PC1 and PC2 in Cpe(fat) mice. We found that the levels of PC1 and PC2 are differentially altered in a number of brain regions and in the pituitary. Since these enzymes have been implicated in the generation of neuroendocrine peptides (dynorphin A-17, beta-endorphin, and alpha- melanocyte-stimulating hormone) involved in the control of feeding behavior and body weight, we compared the levels of these peptides in Cpe(fat) and wild type animals. We found a marked increase in the level of dynorphin A-17, a decrease in the level of alpha-melanocyte-stimulating hormone, and an alteration in the level of C-terminally processed beta-endorphin. These results suggest that the impairment in the level of these and other peptides involved in body weight regulation is mainly due to an alteration in carboxypeptidase and prohormone convertase activities and that this may lead to the development of obesity in these animals.
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PMID:Impaired prohormone convertases in Cpe(fat)/Cpe(fat) mice. 1103 63

The cloning of five rodent obesity genes has constituted a major advance in our understanding of body weight homeostasis. Breakthroughs in human molecular genetics have identified mutations disrupting either rodent homologue/analogue genes or genes involved in the same pathways in obese patients. Three rare cases of human morbid obesity of early onset associated with hypogodatropic hypogodanism are due to mutations in the leptin and the leptin receptor genes. These studies have confirmed that leptin plays not only a crucial role in the control of body weight in the human but also in several endocrine functions. Other Human obesity syndromes are linked to mutations in the genes encoding brain-expressed targets of leptin, particularly some key components of the melanocortin system. Patients compound heterozygous for mutations in the POMC gene display severe obesity of early onset, congenital adrenal insufficiency and red hair. Another genetic cause of obesity is due to mutation in the Proconvertase gene (PC1), the enzyme required for the cleavage of POMC into ACTH and alpha MSH, and also of Proinsulin to insulin. The subject compound heterozygous for the PC1 mutation displays besides obesity, a partial ACTH deficiency, elevated POMC and late post absorptive hypoglycemia due to the accumulation of high pro-insulinemia. Contrasting largely with these rare syndromic forms of obesity, several mutations located in the melanocortin 4 receptor gene have been showed to cause an early onset dominant form of obesity with no other associated abnormalities indifferent populations. These mutations in MC4-R could represent a "frequent" cause of common monogenic forms of obesity in human. More generally, these researches into human obesity have opened new exciting understandings in some of the pathways regulating body fat mass.
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PMID:[Monogenic forms of obesity: from mice to human]. 1114 35

Hypogonadotropic hypogonadism is characterized by failure of gonadal function secondary to deficient gonadotropin secretion, resulting from either a pituitary or hypothalamic defect, and is commonly seen in association with structural lesions or functional defects affecting this region. Although the genetic basis for idiopathic hypogonadotropic hypogonadism is largely unknown, mutations in several genes involved in the hypothalamo-pituitary-gonadal axis development and function have recently been implicated in the pathogenesis of this condition. Genes currently recognized to be involved include KAL-1 (associated with X-linked Kallmann Syndrome), gonadotropin-releasing hormone (GnRH) receptor, gonadotropins, pituitary transcription factors (HESX1, LHX3, and PROP-1), orphan nuclear receptors (DAX-1, associated with X-linked adrenal hypoplasia congenital, and SF-1), and three genes also associated with obesity (leptin, leptin receptor, and prohormone convertase 1 [ PC1]). Study of these mutations provides an important contribution in the understanding of the different stages of the reproductive axis development and physiology. Treatment options currently available for puberty induction, maintenance replacement therapy, and fertility induction are considered here. Gametogenesis can be induced with either exogenous gonadotropin or pulsatile GnRH therapy, depending on the etiology.
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PMID:Hypogonadotropic hypogonadism. 1253 56

Genetic susceptibility modulates the impact of obesity on the risk for type 2 diabetes. One candidate gene predisposing to type 2 diabetes is ENPP1/PC1. A common polymorphism in this protein, K121Q, is associated with insulin resistance and increased susceptibility to type 2 diabetes in Caucasian, Afro-Caribbean, and South Asian populations. The goal of this study was to evaluate differences in the prevalence of the ENPP1 121Q variant in the Caucasian, African-American, and Hispanic populations in Dallas county and to establish a population-based estimate of gene variant prevalence for future investigations. We also evaluated the association between the ENPP1 121Q variant and diabetes. The Dallas Heart Study (DHS) is a multiethnic probability-based sample of the Dallas county population in which African-Americans were systematically oversampled so that the final sample was 50% African-Americans. We performed ENPP1/PC1 genotyping in 1038 non-Hispanic Whites (544 women, 494 men), 1815 African-Americans (1052 women and 763 men), and 597 Hispanics (347 women, 250 men). The frequency of ENPP1/PC1 K121Q was higher in both African-Americans (78.5%) and Hispanics (21.9%) than in the non-Hispanic White group (13.2%). The former two groups also have a higher prevalence of type 2 diabetes (African-Americans, 14.1%, and Hispanics, 11.7%) compared to non-Hispanic Whites (6.8%). Logistic regression analysis revealed significant interactions between the ENPP1 genotype, age, and body mass index within each ethnic group. After adjustment for these variables and their interactions, ENPP1 Q allele predicted diabetes when a recessive model was tested. Ethnic differences in ENPP1 121Q allele frequency may contribute to the increased susceptibility to type 2 diabetes observed in US minority groups.
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PMID:Ethnic differences in the frequency of ENPP1/PC1 121Q genetic variant in the Dallas Heart Study cohort. 1749 46

Melanocortin receptors have been implicated in the confounding factors of cardiovascular diseases such as obesity, insulin resistance and salt-sensitive hypertension. The aim of this study was determine how increased dietary salt intake affects the expression profiles of melanocortin system genes in relevant endocrine tissues. Total RNA was isolated from the pituitary and adrenal glands of Wistar Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SP-SHR) and subjected to real-time PCR analysis. Expression levels of pro-opiomelanocortin (POMC), POMC processing enzymes prohormone convertases 1 and 2 (PC1/PC2), melanocortin 3 receptor (MC3R) and melanocortin 5 receptor (MC5R) were not significantly affected by high dietary salt intake in either WKY or SP-SHR tissues. Consistent with known endocrine relationship between the pituitary and adrenal glands, the expression levels of the ACTH receptor, MC2R, were five orders of magnitude higher in adrenal tissues whereas those of POMC were three orders of magnitude higher in the pituitary. MC3R, PC1 and PC2 transcripts were expressed at similar levels in both tissues while MC5R was expressed at a higher level in the adrenal tissues. These results are therefore inconsistent with an endocrine pathway that involves pituitary derived gamma-MSH modulating adrenal function in response to high dietary salt intake.
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PMID:Prevalence of melanocortin system transcripts in rat salt homeostasis endocrine tissues. 1753 Nov 55

In a previous study in 15 inbred mouse strains, we found highest and lowest systolic blood pressures in NZO/HILtJ mice (metabolic syndrome) and C3H/HeJ mice (common lean strain), respectively. To identify the loci involved in hypertension in metabolic syndrome, we performed quantitative trait locus (QTL) analysis for blood pressure with direction of cross as a covariate in segregating F2 males derived from NZO/HILtJ and C3H/HeJ mice. We detected three suggestive main-effect QTLs affecting systolic and diastolic blood pressures (SBP and DBP). We analyzed the first principle component (PC1) generated from SBP and DBP to investigate blood pressure. In addition to all the suggestive QTLs (Chrs 1, 3, and 8) in SBP and DBP, one suggestive QTL on Chr 4 was found in PC1 in the main scan. Simultaneous search identified two significant epistatic locus pairs (Chrs 1 and 4, Chrs 4 and 8) for PC1. Multiple regression analysis revealed three blood pressure QTLs (Bpq10, 100 cM on Chr 1; Bpq11, 6 cM on Chr 4; Bpq12, 29 cM on Chr 8) accounting for 29.4% of blood pressure variance. These were epistatic interaction QTLs constructing a small network centered on Chr 4, suggesting the importance of genetic interaction for development of hypertension. The blood pressure QTLs on Chrs 1, 4, and 8 were detected repeatedly in multiple studies using common inbred nonobese mouse strains, implying substantial QTL independent of development of obesity and insulin resistance. These results enhance our understanding of complicated genetic factors of hypertension in metabolic diseases.
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PMID:Quantitative trait loci associated with blood pressure of metabolic syndrome in the progeny of NZO/HILtJxC3H/HeJ intercrosses. 1764 13

Traditional whole genome linkage scans for obesity were usually performed for a number of correlated obesity related phenotypes separately without considering their correlations. The purpose of this study was to identify quantitative trait loci (QTLs) underlying variations in multiple correlated obesity phenotypes. We performed principal component analysis (PCA) for four highly correlated obesity phenotypes (body mass index [BMI], fat mass, percentage of fat mass [PFM], and lean mass) in a sample of 427 pedigrees (comprising 3,273 individuals) and generated two independent principal components (PC1 and PC2). A whole genome linkage scan (WGS) was then conducted for PC1 and PC2. For PC1, the strongest linkage signal was identified on chromosome 20p12 (LOD = 2.67). For PC2, two suggestive linkages were found on 5q35 (LOD = 2.03) and 7p22 (LOD = 2.18). This study provided evidence supporting several previously identified linkage regions for obesity (e.g., 1p36, 6p23 and 7q34). In addition, our approach by linear combination of highly correlated obesity phenotypes identified several novel QTLs which were not found in genome linkage scans for individual phenotypes.
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PMID:Genomewide linkage scan for combined obesity phenotypes using principal component analysis. 1826 Nov 84


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