Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

White adipose tissue (WAT) plays a critical role in the development of insulin resistance via secretion of free fatty acids (FFA) and adipocytokines. Muscle-specific insulin receptor knockout (MIRKO) mice do not develop insulin resistance or diabetes under physiological conditions despite a marked increase in adiposity and plasma FFA. On the contrary, WAT of MIRKO is sensitized to insulin action during a euglycemic clamp, and WAT glucose utilization is dramatically increased. To get insight into the potential antidiabetic role of MIRKO adiposity, we have studied insulin action in WAT during a euglycemic, hyperinsulinemic clamp, and we have characterized the morphology and biology of WAT. During the clamp, there is no alteration in the expression or activation in the insulin signaling molecules involved in glucose transport through the phosphoinositide 3-kinase/Akt and CAP/Cbl pathways in WAT from MIRKO. The 53% increase in WAT mass results from a 48% increase in adipocyte number (P < 0.05) without alteration in cell size and contemporary to a 300% increase in mRNA levels of the adipogenic transcription factor CCAAT enhancer binding protein-alpha (C/EBP-alpha) (P < 0.05). There is a 39.5% increase in serum adiponectin (P < 0.01) without modification in serum leptin, resistin, and TNF-alpha. In conclusion, the MIRKO mouse displays muscle insulin resistance, visceral obesity, and dyslipidemia but does not develop hyperinsulinemia or diabetes. There is an accelerated differentiation of small insulin sensitive adipocytes, an increased secretion of the insulin sensitizer adiponectin, and maintenance of leptin sensitivity. The MIRKO mouse confirms the importance of WAT plasticity in the maintenance of whole body insulin sensitivity and represents an interesting model to search for new secreted molecules that positively alter adipose tissue biology.
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PMID:Cellular and molecular mechanisms of adipose tissue plasticity in muscle insulin receptor knockout mice. 1468 12

Prader-Willi syndrome (PWS) is a genetic disorder characterized by mild mental retardation, short stature, abnormal body composition, muscular hypotonia and distinctive behavioural features. Excessive eating causes progressive obesity with increased cardiovascular morbidity and mortality. In the PWS genotype loss of one or more normally active paternal genes in region q11-13 on chromosome 15 is seen. It is supposed that the genetic alteration leads to dysfunction of several hypothalamic centres and growth hormone (GH) deficiency (GHD) is common. PWS is well described in children, in whom GH treatment improves body composition, linear growth, physical strength and agility. Few studies have focused on adults. We examined a cohort of 19 young adults with clinical PWS (13 with positive genotype) and mean BMI of 35 kg/m2. At baseline the activity of the GH-insulin-like growth factor-I (IGF-I) system was impaired with low GH values, low total IGF-I and in relation to the obesity low levels of free IGF-I and non-suppressed IGF-binding-protein-1 (IGFBP-1). 2/3 were hypogonadal. Bone mineral density (BMD) was low. Four patients had impaired glucose tolerance and nine patients high homeostasis model assessment (HOMA) index, indicating insulin resistance. Seven patients had a moderate dyslipidemia. The 13 patients with the PWS genotype were shorter and had significantly lower IGF-I. Seventeen (9 men and 8 women), subsequently completed a 12 months GH treatment trial, and GH had beneficial effects on body composition without significant adverse effects. The effects were more pronounced in the patients with the PWS genotype. Analysis of peptides involved in appetite regulation showed that leptin levels were high reflecting obesity and as a consequence NPY levels were low. In relation to the patients obesity circulating oxytocin levels were abnormally low and ghrelin levels abnormally high. Thus, oxytocin and ghrelin might be involved in the hyperphagia. NPY, leptin and ghrelin did not change during GH treatment. In conclusion this pilot study showed that adults with PWS have a partial GH deficiency, and GH treatment has beneficial effects on body composition in adult PWS without significant side-effects. Larger and longer term studies on the effect of GH replacement in adult PWS are encouraged.
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PMID:Endocrine and metabolic aspects of adult Prader-Willi syndrome with special emphasis on the effect of growth hormone treatment. 1470 May 52

Leptin, an adipocyte hormone, when replaced in patients with lipodystrophy, improves insulin resistance, hyperglycemia, dyslipidemia, and hepatic steatosis. Changes in body composition accompany this metabolic improvement. We studied 14 patients (3 men and 11 women); 12 of who had generalized lipodystrophy (7 congenital, 5 acquired), and 2 patients had partial lipodystrophy. Body composition and related parameters were evaluated at baseline and after 4 and 12 months of leptin therapy. Baseline body mass index (BMI) was 21.7 +/- 0.8 kg/m(2), the percent body fat was 9.5% +/- 1.6%, and the serum leptin level was 1.7 +/- 0.3 ng/mL. On treatment, serum leptin levels increased by 10-fold. All patients reported a decrease in appetite on therapy. After 4 months, both daily caloric intake and resting energy expenditure (REE) decreased. The liver volume decreased (baseline = 3,055 +/- 281 cm(3); 4 months = 2,433 +/- 243 cm(3), P =.006). Dual energy x-ray absorptiometry (DEXA) demonstrated significant decreases in fat mass (5.4 +/- 0.8 kg to 5.0 +/- 0.8 kg; P =.003) and lean body mass (51.2 +/- 3.2 kg to 48.3 +/- 3.4 kg; P =.003) at 4 months on therapy. There was no impact of leptin therapy on bone mineral content, mineral density, and metabolism. Changes in body composition occurred during the first 4 months of leptin therapy, but then stabilized and were sustained thereafter.
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PMID:Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy. 1504 1

Retinoids, derivatives of vitamin A, induce hypertriglyceridemia through decreased clearance of very low-density lipoprotein by a lipoprotein lipase (LPL)-dependent pathway. The retinoid X receptor (RXR) gamma isotype, which is highly expressed in skeletal muscle, may be important in mediating the effects of retinoids on skeletal muscle metabolism and triglyceride (TG) clearance. RXRgamma-deficient (-/-) mice had lower fasting plasma TG levels compared with wild-type littermates (33.1 +/- 2.0 vs. 51.7 +/- 6.3 mg/dl, respectively; P < 0.05). Skeletal muscle LPL activity was higher in RXRgamma mice (18.7 +/- 2.2 vs. 13.3 +/- 1.3 nmol free fatty acids/min.g; P = 0.03), but LPL activity was not different in adipose and cardiac tissue, suggesting a specific effect of RXRgamma in skeletal muscle. In addition, when exposed to a 14-wk high-fat diet, RXRgamma -/- mice had less weight gain, which was entirely due to lower fat mass (11.9 +/- 1.8 vs. 14.4 +/- 1.1 g; P = 0.01), and leptin levels were also lower in the RXRgamma -/- mice (17.6 +/- 5.0 vs. 30.9 +/- 6.4 ng/ml; P = 0.03). These data suggest that RXRgamma -/- mice are resistant to gain in fat mass in response to high-fat feeding. This occurs, at least in part, through up-regulation of LPL activity in skeletal muscle. An understanding of the mechanisms governing the role of RXR in TG disposal and metabolism may lead to the rational design of RXR-selective agonists and antagonists that may be useful in common disorders such as dyslipidemia and obesity.
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PMID:Retinoid X receptor gamma-deficient mice have increased skeletal muscle lipoprotein lipase activity and less weight gain when fed a high-fat diet. 1508 32

The bradykinin B2 receptor (B2R) gene is a candidate in the pathogenesis of insulin resistance, which often clusters with other abnormalities in metabolic syndrome. We investigated the distribution of the C-58T B2R gene polymorphism within a population of overweight/obese patients (BMI > or = 25 kg/m2) potentially characterised by different levels of insulin resistance. Patients with type 2 diabetes, dyslipidemia and hypertension were excluded in order to distinguish the effect of obesity on insulin sensitivity from that of confounding factors. Ninety-two unrelated adults (41 men and 51 women, aged 33.7 +/- 11.6 years) were recruited by random sampling from a general population evaluated for cardiovascular risk stratification. Measurements included BMI, waist circumference, body composition, blood pressure, serum leptin, and lipid profile. Insulin sensitivity was calculated according to the homeostasis model assessment (HOMA) method. C-58T genotypes--CC (n = 20), CT (n = 47) and TT (n = 25)--were determined by restriction fragment-length polymorphism PCR. Patients subdivided on the basis of C-58T polymorphism, showed no difference in any of the parameters examined, including HOMA index values, after adjustment for age, sex, BMI and waist circumference. The results indicate that the C-58T B2R gene polymorphism is not associated with different levels of insulin resistance within a population of obese patients.
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PMID:Bradykinin B2 receptor gene C-58T polymorphism and insulin resistance. A study on obese patients. 1511 24

The chromosomal localization of adiponectin has been found to be mapped to human chromosome 1q21.4-1q23, a region that was identified as a susceptibility locus for familial combined hyperlipidemia and polygenic type 2 diabetes. As these 2 disorders are associated with low high-density lipoprotein (HDL)-cholesterol, high triglycerides, and insulin resistance (IR), we examined the relation of serum adiponectin concentrations to serum lipid and lipoprotein profiles as well as IR in young healthy men. Serum adiponectin levels were positively associated with HDL-cholesterol, apolipoprotein (apo) A1, and low-density lipoprotein (LDL) particle size, and negatively associated with triglycerides and apo B. Negative associations were also found between adiponectin and body mass index (BMI), percent body fat, and IR,as determined by homeostasis model assessment (HOMA). However, after adjustment for BMI, no significant associations were found between adiponectin and LDL particle size and apo B. In a multiple regression analysis including all variables that showed significant univariate associations with adiponectin, associations of adiponectin with HDL-cholesterol (beta = 0.079, P =.0009), percent body fat (beta = -0.165, P =.002), and serum leptin (beta = -0.291, P =.01) were statistically significant. HDL-cholesterol (beta = 0.077, P =.001), percent body fat (beta = -0.078, P =.03), and LDL size (beta = 0.092, P =.03) emerged as significant and independent determinants of adiponectin after HOMA IR, fasting glucose, triglycerides, and systolic blood pressure (BP) were taken into account. Together, these variables explained 19% of adiponectin variability in the 2 models. HOMA IR did not emerge as a determinant of adiponectin in both models. These findings suggest that in young healthy men hypoadiponectinemia is more closely related to adiposity and dyslipidemia than IR.
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PMID:Serum adiponectin is associated with high-density lipoprotein cholesterol, triglycerides, and low-density lipoprotein particle size in young healthy men. 1513 62

Congenic BB.SHR (D4Got41-Npy-Tacr1; BB.4S) rats develop an incomplete metabolic syndrome with obesity, hyperleptinemia, and dyslipidemia compared with their progenitor strain, the diabetes-prone BB/OK rat. To narrow down the underlying gene(s), two subcongenic BB.SHR rat lines, briefly termed BB.4Sa and BB.4Sb, were generated. Male BB.4S (n = 20), BB.4Sa (n = 24), and BB.4Sb (n = 26) were longitudinally characterized for facets of the metabolic syndrome and analyzed for expression of genes located in the region of interest in liver and blood. Body weight gain was comparable, serum triglycerides and leptin were significantly increased, and total cholesterol and HDL-cholesterol ratio were decreased in BB.4S compared with both subcongenics. Serum insulin was significantly higher in BB.4S and BB.4Sa than in BB.4Sb. The adiposity index showed a graduated decrease from BB.6S to BB.4Sb. Obvious differences in relative expression were found in 6 of 10 genes in liver and in 2 of 9 genes in blood. Only one gene, the eukaryotic translation initiation factor 2alpha kinase 3 (Eif2ak3 also called Perk or Pek), was significantly less expressed in liver and in blood of both subcongenic BB.4Sa and BB.4Sb compared with their "parental" BB.4S rats. Based on the phenotype and genotype in BB.4S and its subcongenic derivatives, the most important region on chromosome 4 can be said to lie between D4Got72 and Tacr1. Eif2ak3 is mapped in this region. Considering the function of Eif2ak3, it may be a candidate gene for the development of glucose intolerance found in both subcongenics but not in BB.4S. Allelic variants between BB/OK and SHR could influence Eif2ak3 function, possibly leading not only to glucose intolerance but also to the disturbances in hepatic and renal function found in human Wolcott-Rallison syndrome.
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PMID:Phenotypic and genetic analyses of subcongenic BB.SHR rat lines shorten the region on chromosome 4 bearing gene(s) for underlying facets of metabolic syndrome. 1517 49

The phospholipid scramblases (PLSCR1 to PLSCR4) are a structurally and functionally unique class of proteins, which are products of a tetrad of genes conserved from Caenorhabditis elegans to humans. The best characterized member of this family, PLSCR1, is implicated in the remodeling of the transbilayer distribution of plasma membrane phospholipids but is also required for normal signaling through select growth factor receptors. Mice with targeted deletion of PLSCR1 display perinatal granulocytopenia due to defective response of hematopoietic precursors to granulocyte colony-stimulating factor and stem cell factor. To gain insight into the biologic function of another member of the PLSCR family, we investigated mice with targeted deletion of PLSCR3, a protein that like PLSCR1 is expressed in many blood cells but which, by contrast to PLSCR1, is also highly expressed in fat and muscle. PLSCR3(-/-) mice at 2 months of age displayed aberrant accumulation of abdominal fat when maintained on standard rodent chow, which was accompanied by insulin resistance, glucose intolerance, and dyslipidemia. Primary adipocytes and cultured bone-marrow-derived macrophages from PLSCR3(-/-) mice were engorged with neutral lipid, and adipocytes displayed defective responses to exogenous insulin. Plasma of PLSCR3(-/-) mice was elevated in non-high-density lipoproteins, cholesterol, triglycerides, nonesterified fatty acids, and leptin, whereas adiponectin was low. These data suggest that the expression of PLSCR3 may be required for normal adipocyte and/or macrophage maturation or function and raise the possibility that deletions or mutations affecting the PLSCR3(-/-) gene locus may contribute to the risk for lipid-related disorders in humans.
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PMID:Adiposity, dyslipidemia, and insulin resistance in mice with targeted deletion of phospholipid scramblase 3 (PLSCR3). 1532 4

As occurs in people, nonalcoholic fatty liver disease (NAFLD) is associated strongly with obesity, diabetes, and dyslipidemia in experimental animals. There are many animal models that have been used to investigate the pathogenesis of nonalcoholic fatty liver disease. Most of this work has used mice or rats that are fed diets high in fat or carbohydrates, or mice that exhibit a genetic deficiency of a satiety factor such as leptin, 5-adenosylmethionine,or enzyme deficiencies in fatty acid oxidation. The purpose of this article is to update information regarding animal models in the pathogenesis of NAFLD.
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PMID:Animal models of nonalcoholic fatty liver disease and steatohepatitis. 1533 Oct 64

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and until recently prophylactic cranial radiotherapy (CRT) was important for achieving long-term survival. Hypothalamic-pituitary hormone insufficiency is a well-recognized consequence of CRT for childhood cancer. Another problem is increased cardiovascular risk, which has been shown in long-term survivors of other childhood cancers. In the only previously reported study on cardiovascular risk after childhood ALL, obesity and dyslipidemia were recorded in a small subgroup treated with CRT, compared with patients treated with chemotherapy. The mechanisms behind the increase in cardiovascular risk in survivors of childhood cancer are not clarified. The aim of the present study was to elucidate mechanisms of increased cardiovascular risk in former childhood ALL patients. A group of 44 ALL survivors (23 males, median age 25 yr, range 19-32 yr at the time of study) treated with CRT (median 24 Gy, 18-30 Gy) at a median age of 5 yr (1-18 yr) and chemotherapy were investigated for prevalence of GH deficiency and cardiovascular risk factors. Comparison was made with controls randomly selected from the general population and individually matched for sex, age, smoking habits, and residence. All patients and controls underwent a GHRH-arginine test, and patients with a peak GH 3.9 microg/liter or greater were further investigated with an additional insulin tolerance test. Significantly higher plasma levels of insulin (P = 0.002), blood glucose (P = 0.01), and serum levels of low-density lipoprotein cholesterol, apolipoprotein (Apo) B, triglycerides, fibrinogen, and leptin (all P <or= 0.05) were recorded among the ALL patients, compared with controls. Furthermore, the serum levels of high-density lipoprotein cholesterol (P = 0.03) and Apo A1 (P = 0.005) were significantly lower among the patients. Compared with controls, the patients had higher body mass index and waist to hip ratio, and body composition measured with dual-energy x-ray absorptiometry showed significantly higher fat mass and lower lean mass (P < 0.001). Forty of 44 ALL patients (91%) were considered GH deficient according to the insulin tolerance test and/or the GHRH-arginine test, and the rest were considered GH insufficient. In patients, peak GH during GHRH-arginine was significantly negatively correlated to total body fat mass measured with dual-energy x-ray absorptiometry (r = -0.48, P = 0.001), waist to hip ratio (r = -0.32, P = 0.03), plasma insulin (r = -0.49, P = 0.001), and leptin (r = -0.46, P = 0.002). Moreover, a significantly positive correlation was recorded with high-density lipoprotein cholesterol (r = 0.38, P = 0.012). Using Doppler echocardiography, a marked reduction in cardiac dimensions and performance (ejection fraction P < 0.001 and fractional shortening P = 0.01), compared with controls, was recorded. In conclusion, at a median 17 yr after treatment with CRT and chemotherapy in former childhood ALL patients, a significant increase in cardiovascular risk factors was recorded. We suggest that GH deficiency, induced by CRT, is a primary cause for this because strong correlations between the stimulated GH peak and several of the cardiovascular risk factors were observed.
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PMID:Growth hormone deficiency predicts cardiovascular risk in young adults treated for acute lymphoblastic leukemia in childhood. 1547 98


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