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)

The effect of euglycemic hyperinsulinism on branched-chain amino acids (BCAA; valine, isoleucine and leucine) was evaluated in five obese subjects and five controls. A continuous intravenous insulin infusion raised plasma insulin to a steady-state level. An artificial endocrine pancrease that infused glucose was used to sustain euglycemia. Basal and steady-state insulin levels were significantly higher in the obese subjects than in the controls. The amount of glucose infused to maintain euglycemia and its ratio to steady-state insulin levels was significantly lower in the obese subjects, suggesting an impaired insulin action on glucose metabolism. Basal BCAA levels were similar in the two groups of subjects. During insulin infusion the decremental areas of BCAA below basal levels were significantly lower in the obese patients (63 +/- 5 nmol/mL X min v 143 +/- 8 nmol/mL X min, P less than 0.001), as was the ratio of the decremental areas of BCAA to the incremental areas of insulin (1.11 +/- 0.05 nmol/microU v 3.30 +/- 0.24 nmol/microU, P less than 0.001). Our data suggest that insulin resistance in obesity reduces hormonal effects on glucose as well as on BCAA metabolism.
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PMID:Insulin-dependent metabolism of branched-chain amino acids in obesity. 636 75

The ratio of plasma concentrations of tryptophan to the sum of neutral amino acids (valine, isoleucine, leucine, phenylalanine and tyrosine) was found to be significantly lower in formula-fed infants as compared to breast-fed infants and to newborns at birth. This tryptophan to neutral amino acids ratio in the blood is thought to control the synthesis of serotonin in the brain. Serotonin deficiency in the developing brain based on a decreased plasma tryptophan to neutral amino acids ratio may contribute to developmental obesity and/or permanent changes of mental capacity and social adaptability as observed in human subjects who had been formula-fed as compared to those who had been breast-fed in neonatal life.
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PMID:Changes of the plasma tryptophan to neutral amino acids ratio in formula-fed infants: possible effects on brain development. 668 52

A review of some investigations about amino acid absorption before and after intestinal bypass operations for obesity is presented. One common complication following the operation is hepatic damage. Several studies report a relationship between protein malnutrition and liver dysfunction. Hence, determination of amino acid (and peptide) absorption is of particular importance in order to improve our understanding of this complication. A constant finding in several investigations is the postoperative reduction in plasma concentrations and absorption of branched chain amino acids (leucine, isoleucine and valine). However, the absorption of dipeptides containing the branched chain amino acids does not seem to be affected to the same extent. The changes in the uptake of the branched chain amino acids before and after intestinal bypass operation are correlated with the plasma levels of two proteins with a known sensitivity to protein depletion (thyroxine-binding pre-albumin and retinol-binding protein). Plasma concentrations of some amino acids increases following the operation but there is no evidence so far that this could cause any damage to the liver. The significance of the impaired uptake of the branched chain amino acids is discussed.
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PMID:Amino acid absorption after intestinal bypass procedures. 703 Sep 93

Young female obese (ob/ob) and lean mice were allowed to self-select from two diets varying in protein and carbohydrate, protein and fat or carbohydrate and fat for 36 days. Obese and lean mice offered a choice between two diets varying in protein and carbohydrate consumed 35 and 30%, respectively, of energy from protein. When two diets varying in protein and fat were fed, both obese and lean mice initially self-selected a higher percentage of energy from protein than when diets varying in protein and carbohydrate were fed. This pattern was rapidly reversed in lean mice and more gradually reversed in obese mice. By the end of this feeding trial, obese and lean mice were self-selecting 26 and 16%, respectively, of energy from protein. When two diets varying in carbohydrate and fat were fed, young obese mice self-selected only 44 +/- 6% of energy from the high fat diet whereas lean mice self-selected 65 +/- 4% of energy from the high fat diet. The ratio of plasma tryptophan to large neutral amino acids (valine, leucine, isoleucine, phenylalanine and tyrosine) showed a strong inverse relationship to protein intake. In summary, replacement of dietary carbohydrate with fat lowered the percentage of energy self-selected as protein. Obese mice, however, continued to consume more energy and more protein than lean mice.
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PMID:Effect of dietary fat on protein intake regulation in young obese and lean mice. 721 39

Obesity-associated hyperaminoacidemia is traditionally interpreted as a consequence of insulin resistance. We performed two different experiments to investigate the effects of both obesity-associated insulin resistance and the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM) on amino acid metabolism. In the first experiment, we measured postabsorptive amino acid concentrations and their decline in response to an oral carbohydrate load in 19 obese nondiabetic women and 19 normal-weight nondiabetic controls. Obese subjects were more resistant to insulin with respect to its effects on glucose metabolism than normal-weight controls, as calculated by the method described by Matthews. However, postabsorptive plasma concentrations of the so-called large neutral amino acids (LNAA), namely phenylalanine, tyrosine, valine, leucine, and isoleucine, and their decrease in response to carbohydrate consumption were similar in both groups. In the second experiment, we compared the decrease of plasma concentrations of LNAA during a euglycemic, hyperinsulinemic clamp in obese subjects with and without NIDDM. Peripheral glucose uptake (PGU) was more impaired in NIDDM subjects compared with obese controls. Furthermore, hepatic glucose production (HGP) was less attenuated by insulin infusion in NIDDM than in control subjects. Postabsorptive plasma LNAA concentrations were not different in the two groups. Values obtained in either group were not different from the postabsorptive concentrations in the normal-weight control subjects of experiment 1. All amino acid levels decreased substantially in response to insulin infusion. The magnitude of the decrease was not significantly different in the two groups, except for a slightly greater decrease of the plasma isoleucine concentration in obese control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin-induced decline of plasma amino acid concentrations in obese subjects with and without non-insulin-dependent diabetes. 817 54

Mice homozygous for the fat mutation exhibit marked hyperpro-insulinemia and develop late onset obesity. The fat mutation was recently mapped to the gene encoding carboxypeptidase E (CpE), a processing enzyme involved in trimming C-terminal paired basic residues from prohormone-derived peptides. The mutation resulted in a loss of CpE activity that correlated with aberrant proinsulin processing. Neurotensin (NT) and melanin-concentrating hormone (MCH) are two neuropeptides that, among other central effects, inhibit food intake. Here, using RIA techniques coupled to reverse phase HPLC, we analyzed the processing products derived from the NT and MCH precursors in the brain of +/fat and fat/fat mice. Compared to control hypothalamic and brain extracts, fat/fat extracts had markedly reduced levels (>80%) of NT and neuromedin N (NN), another active pro-NT-derived peptide. In contrast, they exhibited high concentrations of biologically inactive NT-KR and NN-KR (NT and NN with a C-terminal Lys-Arg extension), two peptides that were undetectable in control extracts. MCH, which is located at the C-terminus of its precursor, was present in 2- to 3-fold higher amounts in fat/fat than in +/fat hypothalamus. Neuropeptide-Glu-Ile, another pro-MCH-derived neuropeptide separated from MCH by an Arg-Arg sequence, was present in amounts similar to those of MCH in control extracts. In contrast, neuropeptide-Glu-Ile was more than 10 times less abundant than MCH in extracts from obese mice. Our data are consistent with a deficit in CpE activity affecting the maturation of both pro-NT and pro-MCH. This suggests that abnormal neuropeptide and hormone precursor processing is a general phenomenon in fat/fat mice and supports the idea that defects in the production of neuropeptide involved in the control of feeding might lead to the development of obesity in these animals.
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PMID:Impaired processing of brain proneurotensin and promelanin-concentrating hormone in obese fat/fat mice. 877 Sep 19

Disruption of the melanocortin-4 (MC-4) receptor gene in mice results in maturity-onset obesity, hyperinsulinaemia and hyperglycaemia. These phenotypes are characteristic of human obesity that frequently accompanies non-insulin-dependent diabetes. It is therefore possible that human MC-4 receptor gene mutations contribute to human obesity. To test this possibility, we examined by DNA sequencing the entire coding region of the human MC-4 receptor gene in 40 morbidly obese (BMI > 35 kg/m2) white British males and examined the 5'- and 3'-flanking regions in 20 out of these obese subjects. We also sequenced all these regions in 10 lean (BMI < 18 kg/m2) white British males for a reference. We identified a single nucleotide substitution that replaces valine with isoleucine at codon 103, in two obese subjects in the heterozygous state. No other nucleotide alterations were found. The prevalence of this missense variant was studied in 322 white British males (190 with BMI > 28 kg/m2 and 132 with BMI < 22 kg/m2) selected from a population-based epidemiological survey. In these subjects, no homozygotes for the isoleucine allele were found. The frequency of heterozygotes was similar (4.2 vs 4.5%) in the two groups and there was no significant difference in BMI, total skinfold thickness, plasma insulin and glucose levels between heterozygotes and codon-103 valine homozygotes in either group. These results suggest that coding sequence mutations in the MC-4 receptor gene are unlikely to be a major cause of human obesity, at least in white British males.
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PMID:Molecular screening of the human melanocortin-4 receptor gene: identification of a missense variant showing no association with obesity, plasma glucose, or insulin. 926 95

A national epidemiological study undertaken in November 1995 recensed the data of 2563 patients admitted to 373 Intensive Care Units for acute myocardial infarction. There were 1827 men and 736 women with an average age of 67 years. Seventeen per cent of patients had left ventricular ejection fration (LVEF) < or = 35%. The mortality rate at 5 days was 7.7%. Clinical heart failure (Killip > 1) was observed in 34.4% of patients. 63% of patients were admitted before the 6th hour. Forty-six per cent of patients underwent early revascularisation by thrombolysis and/or angioplasty. The most widely used drugs in the first 5 days were heparin (96%), aspirin (89%), betablockers (65%), and angiotension converting enzyme inhibitors (46%). The influence of region on the demographical features, morbidity, mortality and therapeutic practice was studied. France was divided into 6 regions. In the Centre, the patients were older, with increased morbidity and mortality compared with the national average. Patients in the North East were similar and had a higher incidence of obesity. In the Ile de France, patients were generally younger with a higher incidence of tobacco consumption and their infarcts were generally less severe. Finally, in the South East, the mortality was particularly low. In multivariate analysis living in this region was good prognostic factor whereas low LVEF (< or = 35%) and age > or = 65 years were poor prognostic factors. This study, for the first time in France, describes the clinical features of myocardial infarction admitted to the Intensive Care Unit with respect to criteria of severity (LVEF, Killip) and region of origin of the patients. Its confirms large regional variations in the severity of acute myocardial infarction.
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PMID:[Epidemiology of myocardial infarction in France. Regional specificities]. 953 25

Increased body mass index (BMI) has been correlated with increased blood pressure in human populations. To examine the role of the leptin gene (OB) in essential hypertension in African Americans, we performed affected sib pair analysis on a set of 103 hypertensive African American sibships using four highly polymorphic markers at the human leptin locus. No evidence of linkage was detected between these markers and the phenotype of essential hypertension either in these sibships or in a severely obese subset of 46 sibships in which each sibling had a BMI > or = 85th percentile for the US population. Using BMI rather than hypertension as a quantitative trait, we found significant linkage for the marker D7S504 (P=0.029) but not for the other markers. Significance strengthened in the overweight subset of sibships for this marker (P=0.001), and there was a trend of lower P values for the other three markers. However, multipoint analysis with the use of all four markers simultaneously to estimate linkage between BMI and the leptin locus did not demonstrate a statistically significant relationship. Analysis of the coding region of the leptin gene (exons 2 and 3) by single-strand conformational polymorphism revealed a rare Ile-Val polymorphism at amino acid 45 but revealed no other alterations. These results suggest that the OB gene is not a major contributor to the phenotype of essential hypertension in African Americans, although a minor contribution to the phenotype of extreme obesity in this group cannot be ruled out.
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PMID:Genetic markers at the leptin (OB) locus are not significantly linked to hypertension in African Americans. 962 34

The melanocortin-4 receptor gene (MC4-R) has been implicated in weight regulation. Recently, two independent groups reported frameshift mutations associated with a dominant form of obesity (1, 2). We screened the coding region of the MC4-R in 306 extremely obese children and adolescents (mean body mass index: BMI 34.4 +/- 6.6 kg/m2), 25 healthy underweight students (mean BMI 17.1 +/- 0.8 kg/m2), 52 normal weight individuals (mean BMI 22.0 +/- 1.0 kg/m2), 51 inpatients with anorexia nervosa (AN, DSM IV criteria, mean BMI 14.3 +/- 1.5 kg/m2) and 27 patients with bulimia nervosa (BN, DSM IV criteria, mean BMI 21.7 +/- 5.8 kg/m2) by single strand conformation polymorphism analysis (SSCP). Several mutations were identified, including the frameshift mutation described (1). The mutations were as follows: a) The deletion of 4 bp (delta of CTCT at codon 211) results in a frameshift, thus rendering a truncated protein. This mutation has been assumed to be associated with dominantly-inherited morbid obesity in humans (1). Both the index patient (BMI 42.06 kg/m2, height 171 cm, age 19.6 years) and her mother (BMI 37.55 kg/m2, height 164 cm, age 42.5 years) were heterozygous for the deletion. b) A nonsense mutation at position 35 of the MC4-R was detected in two obese probands (BMI 31.29 kg/m2 and BMI 45.91 kg/m2). This mutation leads to a truncated protein that encompasses the N-terminal extracellular domain. Both carriers additionally showed (c) a missense mutation (Asp-37-Val). In both of these cases Tyr-35-Stop and Asp-37-Val were maternally transmitted, thus these variations form a haplotype. d) e) A male obese proband harbored two missense mutations (Ser-30-Phe, Gly-252-Ser). f)-i) Four different missense mutations (Pro-78-Leu, Thr-112-Met, Arg-165-Trp, Ile-317-Thr) were detected in four different male probands, respectively. All of these mutations (a to i) were found solely in extremely obese individuals whose BMIs were all above the 99th percentile. j) A silent mutation (C-579-T, Val-193-Val) was detected in a male underweight individual. k) A previously described polymorphism (Val-103-Ile; 3) was detected with similar frequencies in all different study groups. 1) We identified a novel polymorphism (Ile-251-Leu) with similar allele frequencies in all groups under study. In conclusion, our data indicate that mutations in the MC4-R are not uncommon. Whereas our data support the evidence for dominantly inherited obesity as revealed by the three obese probands with haplo-insufficiency, the functional significance of the missense mutations remains to be determined.
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PMID:Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. 1019


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