Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

Chronic treatment with compounds activating peroxisome proliferator-activated receptor (PPAR)gamma and -alpha influences body energy stores, but the underlying mechanisms are only partially known. In a chronic-dosing study, equiefficacious antihyperglycemic doses of the PPAR gamma agonist pioglitazone and PPAR alpha/gamma dual activator ragaglitazar were administered to obesity-prone male rats. The PPAR alpha agonist fenofibrate had no effect on insulin sensitivity. Pioglitazone transiently increased and fenofibrate transiently decreased food intake, whereas ragaglitazar had no impact on feeding. As a result, body adiposity increased in pioglitazone-treated rats and decreased in fenofibrate-treated rats. PPAR gamma compounds markedly increased feed efficiency, whereas PPAR alpha agonist treatment decreased feed efficiency. In fenofibrate-treated rats, plasma acetoacetate was significantly elevated. Plasma levels of this potentially anorectic ketone body were unaffected in pioglitazone- and ragaglitazar-treated rats. High-fat feeding markedly increased visceral fat pads, and this was prevented by pioglitazone and ragaglitazar treatment. Pioglitazone treatment enlarged subcutaneous adiposity in high-fat-fed rats. In conclusion, PPAR gamma activation increases both food intake and feed efficiency, resulting in net accumulation of subcutaneous body fat. The impact of PPAR gamma activation on feeding and feed efficiency appears to be partially independent because the PPAR alpha component of ragaglitazar completely counteracts the orexigenic actions of PPAR gamma activation without marked impact on feed efficiency.
...
PMID:Differential influences of peroxisome proliferator-activated receptors gamma and -alpha on food intake and energy homeostasis. 1294 63

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a critical regulator of adipogenesis. PPAR gamma+/- mice are resistant to high-fat diet-induced obesity and thus PPAR gamma may mediate physiological responses to dietary fat in other mammals. The aim of this study was to determine whether the human PPAR gamma proline to alanine substitution polymorphism (Pro12Ala) modifies the association between dietary fat and adiposity and plasma lipids. Subjects (n=2141) were controls selected for three case-control studies nested within the Nurses' Health Study, a large ongoing prospective cohort study. Associations between intake of total fat, fat subtypes and BMI were different in PPAR gamma 12Ala variant allele-carriers compared with non-carriers. Among homozygous wild-type Pro/Pro individuals, those in the highest quintile of total fat intake, had significantly higher mean body mass index (BMI) compared with those in the lowest quintile (27.3 versus 25.4 kg/m2, respectively; P-trend<0.0001) whereas among 12Ala variant allele-carriers there was no significant trend observed between dietary fat intake and BMI (P-trend=0.99; P-interaction=0.003). In contrast, intake of monounsaturated fat was not associated with BMI among homozygous wild-type women but was inversely associated with BMI among 12Ala variant allele-carriers (mean in lowest quintile=27.6 versus mean in highest quintile=25.5 kg/m2; P-trend=0.006; P-interaction=0.003). The relationship between dietary fat intake and plasma lipid concentrations also differed according to PPAR gamma genotype. These data suggest that PPAR gamma genotype is an important factor in physiological responses to dietary fat in humans.
...
PMID:Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass. 1450 27

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) is an important regulator of lipid and glucose homeostasis and cellular differentiation. Studies of many cell types in vitro and in vivo have demonstrated that activation of PPAR gamma can reduce cellular proliferation. We show here that activation of PPAR gamma is sufficient to reduce the proliferation of cultured insulinoma cell lines. We created a model with mice in which the expression of the PPARG gene in beta cells was eliminated (beta gamma KO mice), and these mice were found to have significant islet hyperplasia on a chow diet. Interestingly, the normal expansion of beta-cell mass that occurs in control mice in response to high-fat feeding is markedly blunted in these animals. Despite this alteration in beta-cell mass, no effect on glucose homeostasis in beta gamma KO mice was noted. Additionally, while thiazolidinediones enhanced insulin secretion from cultured wild-type islets, administration of rosiglitazone to insulin-resistant control and beta gamma KO mice revealed that PPAR gamma in beta cells is not required for the antidiabetic actions of these compounds. These data demonstrate a critical physiological role for PPAR gamma function in beta-cell proliferation and also indicate that the mechanisms controlling beta-cell hyperplasia in obesity are different from those that regulate baseline cell mass in the islet.
...
PMID:Targeted elimination of peroxisome proliferator-activated receptor gamma in beta cells leads to abnormalities in islet mass without compromising glucose homeostasis. 1451 92

An impaired immune function linked to obesity has been shown in both human and animal studies. The purpose of this work was to analyse the hypothesis that PPAR gamma 1 participates in the inhibition of the immune response by affecting the DNA-binding ability of the NF-kappa B complex and whether the SREBP-1 expression can regulate PPAR gamma 1 expression in spleen. Diet-induced overweight rats showed higher PPAR gamma 1 (p<0.05) and lower SREBP-1 (p<0.01) mRNA expression levels with an inhibition of the DNA-binding ability of NF-kappa B compared to control rats as determined by gel-shift analysis. On the other hand, energy restriction decreased SREBP-1 (p<0.01) mRNA expression with no differences in PPAR gamma 1 mRNA expression compared to non-restricted rats, which was accompanied by a restoration in the DNA-binding ability of NF-kappa B as shown by gel-shift analysis. These results suggest that PPAR gamma 1 may be involved in the altered immune response through changes in the activity of NF-kappa B.
...
PMID:NF-kappa B-binding activity in an animal diet-induced overweightness model and the impact of subsequent energy restriction. 1459 49

Previous data suggesting that polymorphisms in the adiponectin gene were associated with insulin resistance or type 2 diabetes have been inconsistent. We assessed the relationship between five common haplotype-tagging single nucleotide polymorphisms (SNPs) in the adiponectin gene (-11365C>G, -4034A>C, -3964A>G, +45T>G, and +276G>T), haplotypes defined by these SNPs, and the risk of type 2 diabetes by conducting a nested case-control study of 642 incident cases of type 2 diabetes and 995 matching control subjects in the Nurses' Health Study. Overall, we did not observe significant differences in genotype or allele frequencies for the five SNPs between the case and control subjects. After adjustment for diabetes risk factors, the -4034 C/C genotype was associated with a reduced risk of diabetes (odds ratio [OR] compared with the A/A genotype = 0.70, 95% CI 0.50-0.99, P = 0.04). In subgroup analyses, the +276 genotype was significantly associated with diabetes risk only among subjects with peroxisome proliferator-activated receptor-gamma (PPAR gamma) variant 12Ala allele (OR comparing +276 T alleles with the G/G genotype = 1.69, 1.04-2.75, P = 0.035) or among obese subjects (1.46, 1.03-2.08, P = 0.03). These data suggest a potential interaction between the adiponectin genotype and PPAR gamma genotype or obesity, but these analyses should be considered exploratory and require further investigation in larger studies.
...
PMID:Genetic variation at the adiponectin locus and risk of type 2 diabetes in women. 1469 17

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor isoforms with key roles in the regulation of lipid and glucose metabolism. Synthetic ligands for PPAR gamma (and PPAR alpha) have effects of promoting insulin sensitization in the context of obesity. Recent evidence suggests that activation of PPAR delta might produce similar effects. Both PPAR gamma and PPAR alpha have also been shown to produce selected anti-inflammatory effects and to reduce the progression of atherosclerosis in animals (alpha and gamma) or in humans (alpha). Mechanisms underlying insulin-sensitizing effects are complex. For PPAR gamma, direct effects on adipose tissue lipid metabolism with secondary benefits in liver and/or muscle (lipid levels and insulin signaling) have been implicated. For PPAR alpha, accelerated lipid catabolism may contribute to reduced muscle or liver 'steatosis'. Anti-inflammatory mechanisms as contributors to the beneficial metabolic effects of PPAR activation are also worth considering for the following reasons: (1) obesity and insulin resistance are associated with a proinflammatory milieu. (2) PPAR gamma has clear effects to oppose the effects of tumor necrosis factor-alpha (TNFalpha) in adipocytes. (3) effects of PPAR ligands on cytokine-mediated signaling (eg via NF-kappa B) may be expected to enhance insulin action. (4) Adipose production of several molecules that are implicated as markers or mediators of inflammation is reduced. (5) In humans, treatment with either PPAR alpha or PPAR gamma agonists has been shown to reduce circulating levels of proteins that serve as markers of inflammation. (6) Adiponectin, a fat-derived circulating factor that has been implicated as having anti-inflammatory activity, is induced by PPAR gamma agonism.
...
PMID:Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation. 1470 38

There are more than 430 chromosomic regions with gene variants involved in body weight regulation and obesity development. Polymorphisms in genes related to energy expenditure--uncoupling proteins (UCPs), related to adipogenesis and insulin resistance--hormone-sensitive lipase (HLS), peroxisome proliferator-activated receptor gamma (PPAR gamma), beta adrenergic receptors (ADRB2,3), and alfa tumor necrosis factor (TNF-alpha), and related to food intake--ghrelin (GHRL)--appear to be associated with obesity phenotypes. Obesity risk depends on two factors: a) genetic variants in candidate genes, and b) biographical exposure to environmental risk factors. It is necessary to perform new studies, with appropriate control groups and designs, in order to reach relevant conclusions with regard to gene/environmental (diet, lifestyle) interactions.
...
PMID:[Obesity studies in candidate genes]. 1511 49

Locally-enhanced glucocorticoid action within cells has been implicated in the pathophysiology of the metabolic syndrome, which is characterized by a cluster of visceral fat obesity, insulin resistance, dyslipidemia, hypertension and liver steatosis. Evidence has accumulated that enzyme activity of intracellular glucocorticoid reactivating enzyme, 11 beta-hydroxysteroid dehydrogenase type 1(11 beta-HSD1) is commonly elevated in fat depots in patients with the metabolic syndrome. Fat-specific 11 beta-HSD1 transgenic mice, those have increased enzyme activity to a similar extent seen in obese humans, develop visceral fat obesity with major components of the metabolic syndrome. In adipocytes, antidiabetic PPAR gamma agonists substantially reduce 11 beta-HSD1 mRNA and enzyme activity, suggesting that suppression of 11 beta-HSD1 in fat cells may be one of the pivotal mechanisms whereby these class of drugs exert beneficial metabolic outcome. Taken together, recent data highlight the importance of adiposteroid in the pathophysiology of the metabolic syndrome.
...
PMID:[Novel transgenic mouse model of the metabolic syndrome]. 1520 42

Insulin resistance is a characteristic feature of obesity and type 2 diabetes mellitus, but it is also present in up to 25% of healthy nonobese individuals. The molecular mechanisms causing insulin resistance are not yet fully understood. Recently, overexpression of several potential inhibitors of the insulin receptor tyrosine-kinase activity, a key step in insulin signaling, has been described in insulin-resistant subjects . PC-1 is expressed in many tissues and inhibits insulin signaling either at the level of the insulin receptor or downstream at a postreceptor site. An elevated PC-1 content in insulin target tissues may play an important role in the development of insulin resistance in obesity and type 2 diabetes mellitus. A polymorphism in PC-1 has been demonstrated to be associated with insulin resistance. This was a DNA polymorphism in exon 4 that causes an amino acid change from lysine to glutamine at codon 121 (K121Q). PC-1 121Q allele might predispose independently of other well established risk factors for early myocardial infarction. Testing for the PC-1 K121Q polymorphism might be valuable in patients with a family history of atherosclerotic vascular disease and myocardial infarction. There is growing evidence that genetic factors play an important role in the development of diabetic nephropathy (DN). Efforts to identify these factors rely primarily on the candidate gene approach; candidate genes for insulin resistance may be considered candidates for DN as well. In a stratified analysis according to duration of diabetes, the risk of early-onset end-stage renal disease (ESRD) for carriers of the Q variant was 2.3 times that for noncarriers. The cellular mechanisms for the insulin resistance of pregnancy and gestational diabetes mellitus (GDM) are unknown. Women with GDM have an increased PC-1 content and excessive phosphorylation of serine/threonine residues in muscle insulin receptors. The postreceptor defects in insulin signaling may contribute to the pathogenesis of GDM and the increased risk for type 2 diabetes later in life. Although widely explored, the true cause of insulin resistance in uremic patients is not entirely elucidated yet. During the last decade it was found that erythropoietin (EPO) therapy, used for correction of anemia in patients with end stage renal failure, ameliorates insulin resistance. An increased lymphocyte PC-1 activity over control was found in hemodialysis patients. A two-month EPO therapy significantly decreased PC-1 activity to the control values, suggesting that an effect on PC-1 expression could be implicated in the amelioration of insulin resistance in uremic patients treated with EPO. Current investigations implicate that therapeutic modification of PC-1 expression would be of great benefit for insulin-resistant type 2 diabetics. Metformin, a biguanide oral antidiabetic agent, was shown to affect insulin resistance by decreasing enzymatic activity of overexpressed PC-1 molecules in obese type 2 diabetics. Thiazolidinedione (TZD) insulin-sensitizing drugs are a class of compounds that improve insulin action in vivo. Treatment of patients with TZDs seems to have a beneficial effect on most, if not all, components of metabolic syndrome. TZDs have also been used in the treatment of nondiabetic human insulin-resistant states, and have demonstrated an improvement in insulin sensitivity. Although much remains to be learned about PPAR gamma receptor and TZD action, the advent of TZD insulin-sensitizing agents has an enormous impact on our understanding of insulin resistance. The great potential of insulin resistance therapy illuminated by the TZDs will continue to catalyze research in this area directed toward the discovery of new insulin-sensitizing agents that work through other mechanisms.
...
PMID:Plasma cell membrane glycoprotein 1 (PC-1): a marker of insulin resistance in obesity, uremia and diabetes mellitus. 1520 35

Adiponectin (also called AdipoQ, gelatin-binding protein 28, Acrp30) is a novel adipocytokine with important metabolic effects. It is physiologically released from adipose tissue and circulates in serum as a hexamer and larger multimeric structure of high molecular weight. Serum level of the protein correlates with systemic insulin sensitivity. Recently adiponectin receptors AdipoR1 and AdipoR2 have been discovered by expression cloning. AdipoR1 is abundantly expressed in skeletal muscles, whereas AdipoR2 is predominantly expressed in the liver. Marked expression of mRNA for AdipoR1 and AdipoR2 has been lately reported in pancreatic beta cells. Both of the receptors activate AMPK and PPAR alpha metabolic pathways leading to an increase in fatty acid oxidation, glucose uptake and a decreased rate of gluconeogenesis, thus enhancing insulin sensitivity. Moreover effects of adiponectin mimic many metabolic actions of insulin such as augmenting blood flow and glucose disposal in NO-dependent manner. The precise mechanism of regulation of plasma adiponectin level is unknown. Recently the mechanism of transcriptional activation of adiponectin gene via PPAR gamma was described. Its level seems to be decreased by TNFalfa and beta-adrenergic agonists. Furthermore there is increasing evidence that some genetic variants in the adiponectin gene may be associated with its ethnical differences in level as well as its likely clinical consequences. Hipoadiponectynemia is associated with obesity, metabolic syndrome, diabetes type 2, cardiovascular disease, lipodystrophy in AIDS. In patients with chronic renal failure, anorexia nervosa plasma adlponectin level is increased. Weight loss and therapy with thlazolidinediones are proved to enhance endogenous adlponectin production in humans. In summary, the ability of adiponectin to increase insulin sensitivity in conjunction with its anti-inflammatory and antiatherogenic properties have made this novel adipocytokine a promising therapeutic tool for the future, especially in individuals with low plasma levels of adiponectin.
...
PMID:[Adiponectin--adipocytokine with a broad clinical spectrum]. 1523 Jan 53


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---