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)

(1) Treatments for obesity are disappointing. None has yet shown an effect on morbidity and mortality. Non drug treatments are poorly assessed. Stable long-term weight loss necessitates long-term management. (2) Orlistat, a gastrointestinal lipase inhibitor, is indicated, in combination with a low-calorie diet, for the management of obesity. (3) The assessment file is rather bulky and methodologically sound, at least in terms of the "weight loss" end point. (4) During medium-term trials (12-24 months), orlistat administered at a dose of 120 mg three times a day and combined with dietary intervention had a moderate positive impact on body weight (-3.5 kg on average). (5) No longer-term trials have been done. (6) It is not known whether this drug affects morbidity and mortality linked to obesity. (7) In clinical trials there was an increase in the frequency of breast cancer among patients treated with orlistat. This potential risk is currently being assessed in a specific trial. (8) Gastrointestinal adverse effects are frequent. (9) Treatment is costly.
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PMID:Orlistat: new preparation. No hurry . . . 1150 34

A novel lipase-catalyzed protocol has been formulated for the simultaneous enantiocontrol of three stereogenic centers in a flexible acyclic system. This involved a porcine pancreatic lipase (PPL)-catalyzed delta-lactonization of a racemic 3,5-dihydroxy-2-alkyl ester to produce the lactone with high enantioselectivity (92.8%). The product lactone and its analogues are useful synthons for the asymmetric synthesis of various bioactive compounds, which include the potential anti-obesity compound, tetrahydrolipstatin.
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PMID:Enzymatic Lactonization Stategy for Enantioselective Synthesis of a Tetrahydrolipstatin Synthon. 1167 16

Our aim was to investigate the effects of one year recombinant human growth hormone (rhGH) therapy on the regulation by insulin of gene expression in muscle and adipose tissue in adults with secondary GH deficiency (GHD). Six GHD subjects without upper-body obesity were submitted to a 3-h euglycemic hyperinsulinemic clamp before and after one year of rhGH therapy. Muscle and abdominal subcutaneous adipose tissue biopsies were taken before and at the end of each clamp. The mRNA levels of insulin receptor, p85 alpha-phosphatidylinositol-3 kinase (p85 alpha PI-3K), insulin dependent glucose transporter (Glut4), hexokinase II, glycogen synthase, lipoprotein lipase (LPL) in muscle and in adipose tissue, hormone sensitive lipase and peroxisome proliferator-activated receptor gamma (PPAR gamma) in adipose tissue were quantified by RT-competitive PCR. One year treatment with rhGH (1.25 IU/day) increased plasma IGF-I concentrations (54+/-7 vs 154+/-11 ng/ml, P<0.01) but did not affect insulin-stimulated glucose disposal rate measured during the hyperinsulinemic clamp (74+/-9 vs 85+/-5 micromol/kg free fat mass/min). Insulin significantly increased p85 alpha PI-3K, hexokinase II and Glut4 mRNA levels in muscle both before and after rhGH treatment. One year of GH therapy increased LPL mRNA levels in muscle (38+/-2 vs 70+/-7 amol/microg total RNA, P<0.05) and in adipose tissue (2490+/-260 vs 4860+/-880 amol/microg total RNA, P<0.05), but did not change the expression of the other mRNAs. We conclude from this study that GH therapy did not alter whole body insulin sensitivity and the response of gene expression to insulin in skeletal muscle of adult GHD patients, but it did increase LPL expression in muscle and adipose tissue. This result could be related to the documented beneficial effect of GH therapy on lipid metabolism.
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PMID:Expression of insulin target genes in skeletal muscle and adipose tissue in adult patients with growth hormone deficiency: effect of one year recombinant human growth hormone therapy. 1169 48

At present only two drugs are approved for long-term treatment of obesity. Sibutramine inhibits the reuptake of serotonin and norepinephrine. In clinical trials it produces a dose-dependent 5-10% decrease in body weight. Its side effects include dry mouth, insomnia, asthenia, and constipation. In addition, sibutramine produces a small increase in blood pressure and pulse that is a contraindication to the use of this drug in some individuals with heart disease. Xenical is the other drug approved for long-term use in the treatment of obesity. It works by blocking lipase and thus increasing the fecal loss of triglyceride. One valuable consequence of this mechanism of action is the reduction of serum cholesterol that averages about 5% more than can be accounted for by weight loss alone. In clinical trials it produces a 5-10% loss of weight. Its side effects are entirely due to undigested fat in the intestine that can lead to increased frequency and change in the character of stools. It can also lower fat-soluble vitamins. The ingestion of a vitamin supplement before bedtime is a reasonable treatment strategy. The effect on weight loss during long-term trials with these two drugs is shown in Figs 7 and 8 above. Also in this figure is data on phentermine used in trials of six months or more. Although there were differences in mean weight losses with these drugs, when the placebo effect was taken into account they all had a surprisingly similar magnitude of weight loss.
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PMID:Drug treatment of obesity. 1172 27

There are two types of anti-obesity agents which are classified as inhibitors of absorption: inhibitors of lipid and carbohydrate absorption. Inhibitors of lipid absorption consist of lipase inhibitor (orlistat, Nomma Herb's extract (CT-II) and fat substitute (olestra, sucrose polyester). Orlistat is now available as an anti-obesity drug in the USA and Europe. CT-II may be useful as a functional diet. Application of fat substitute is still limited in snack food. As for inhibitors of carbohydrate absorption, alpha-glucosidase inhibitors are now available as anti-diabetic drugs. To develop these agents for anti-obesity drug, solution of adverse effects on the gastrointestinal tract are necessary.
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PMID:[Inhibitors of absorption as anti-obesity drugs]. 1172 38

Catecholamines are the major lipolytic hormones in human fat cells, and lipolytic catecholamine resistance is described in obesity. Studies on twins and in rare genetic disorders suggest a strong heredity component of catecholamine-induced lipolysis. Polymorphisms in catecholamine receptor signalling pathways have been described, several of which associate with obesity. Many polymorphisms in adrenoceptor genes are functional in transfected cell lines. The importance of polymorphisms in catecholamine signalling pathways for lipolysis regulation is discussed. A Trp64Arg polymorphism in the beta3-receptor, which associates with obesity, is accompanied by changes in lipolytic sensitivity of the receptor in human fat cells. Similarly, a Gln16Glu and an Arg164Ile variation in the beta2-adrenoceptor cause marked variations in the lipolytic sensitivity of this receptor in human adipocytes. Furthermore, beta2-adrenoceptor gene polymorphisms associate with obesity. A dinucleotide (CA) intron repeat in hormone-sensitive lipase gene is linked to obesity and markedly decreases the ability of catecholamines to activate the lipase and thereby lipolysis in human fat cells. However, an Arg389Gly polymorphism in the beta1-adrenoceptor, which alters receptor function in transfected cell lines, has no effect on lipolysis in human fat cells and is not associated with obesity. Thus, polymorphism in human genes that are involved in catecholamine signal transduction have effects on fat cell lipolysis and also relate to obesity. The lipolysis effects of these polymorphisms cannot always be predicted from gene transfer experiments on artificial cell lines. It is possible that genetic variance in catecholamine signalling pathways, through alterations in adipocyte lipolysis, may promote obesity.
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PMID:Genetic variance and lipolysis regulation: implications for obesity. 1173 Jan 61

Type 2 diabetes is characterised by both impaired insulin secretion and insulin resistance but their relative contribution to the development of hyperglycaemia may differ due to heterogeneity of the disease. Under most circumstances, insulin resistance is the earliest detectable defect in pre-diabetic individuals but it is not known whether this is the primary defect or secondary to other abnormalities such as abdominal obesity with excessive free fatty acid turnover and increased lipid deposits in muscle. Initially, enhanced insulin secretion can compensate for the insulin resistance but early phase insulin secretion is impaired. In the transition from normal to impaired and diabetic glucose tolerance, insulin sensitivity deteriorates about 40% whereas insulin secretion deteriorates 3-4 fold. In addition to insulin resistance, the metabolic syndrome includes hypertension, dyslipidaemia, obesity and microalbuminuria. In patients with manifest diabetes, chronic hyperglycaemia can result in further deterioration of insulin sensitivity and secretion (glucotoxicity), which is aggravated by elevated free fatty acids (lipotoxicity). Abdominal obesity and insulin resistance are strongly correlated and studies have aimed at understanding the genetic basis. Candidate genes for the metabolic syndrome include those for the beta 3-adrenergic receptor, lipoprotein lipase, hormone sensitive lipase, peroxisome proliferator-activated receptor-gamma, insulin receptor substrate-1 and glycogen synthase. Therefore, type 2 diabetes is multigenic and appears to represent a collision between thrifty genes and an affluent society. Successful management will require treatments targeted at defects of both insulin secretion and insulin resistance.
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PMID:Pathogenesis of type 2 diabetes: the relative contribution of insulin resistance and impaired insulin secretion. 1196 29

Tumor necrosis factor-alpha (TNF-alpha) is a contributing cause of the insulin resistance seen in obesity and obesity-linked type 2 diabetes, but the mechanism(s) by which TNF-alpha induces insulin resistance is not understood. By using 3T3-L1 adipocytes and oligonucleotide microarrays, we identified 142 known genes reproducibly upregulated by at least threefold after 4 h and/or 24 h of TNF-alpha treatment, and 78 known genes downregulated by at least twofold after 24 h of TNF-alpha incubation. TNF-alpha-induced genes include transcription factors implicated in preadipocyte gene expression or NF-kappaB activation, cytokines and cytokine-induced proteins, growth factors, enzymes, and signaling molecules. Importantly, a number of adipocyte-abundant genes, including GLUT4, hormone sensitive lipase, long-chain fatty acyl-CoA synthase, adipocyte complement-related protein of 30 kDa, and transcription factors CCAAT/enhancer binding protein-alpha, receptor retinoid X receptor-alpha, and peroxisome profilerator-activated receptor gamma were significantly downregulated by TNF-alpha treatment. Correspondingly, 24-h exposure of 3T3-L1 adipocytes to TNF-alpha resulted in reduced protein levels of GLUT4 and several insulin signaling proteins, including the insulin receptor, insulin receptor substrate 1 (IRS-1), and protein kinase B (AKT). Nuclear factor-kappaB (NF-kappaB) was activated within 15 min of TNF-alpha addition. 3T3-L1 adipocytes expressing IkappaBalpha-DN, a nondegradable NF-kappaB inhibitor, exhibited normal morphology, global gene expression, and insulin responses. However, absence of NF-kappaB activation abolished suppression of >98% of the genes normally suppressed by TNF-alpha and induction of 60-70% of the genes normally induced by TNF-alpha. Moreover, extensive cell death occurred in IkappaBalpha-DN-expressing adipocytes after 2 h of TNF-alpha treatment. Thus the changes in adipocyte gene expression induced by TNF-alpha could lead to insulin resistance. Further, NF-kappaB is an obligatory mediator of most of these TNF-alpha responses.
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PMID:Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. 1197 27

(1) Treatments for obesity are disappointing, and none has yet shown an effect on morbidity or mortality. Non drug treatments have not been assessed adequately. Long-term maintenance of weight loss requires long-term patient management. (2) Orlistat, a gastrointestinal lipase inhibitor, is licensed in Europe for the treatment of obesity, in combination with a low-calorie diet. (3) The risk-benefit ratio of orlistat could not be estimated from the initial assessment file in 1999. There were fears over a possible increase in the risk of breast cancer. (4) Few new efficacy data have been obtained since. Medium-term trials (12-24 months) show that orlistat (120 mg three times a day), combined with dietary intervention, has a minor supplementary effect on weight loss (-3.5 kg on average). (5) A meta-analysis of three of the four available comparative trials lasting two years failed to conclude that orlistat prevents the onset of type 2 diabetes. Likewise, there is no firm evidence that orlistat lowers cardiovascular morbidity or mortality. (6) Orlistat frequently has gastrointestinal adverse effects, and case reports of hypertension have been published. Orlistat probably interacts with a number of other drugs. (7) Follow-up of nearly 8,000 women for only a few years showed no increase in the incidence of breast cancer on orlistat. (8) In practice, dietary intervention and risk factor management remain the cornerstones in the management of obesity. Orlistat is only a minor, optional and temporary aid, although it appears so far to have no serious adverse effects.
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PMID:Orlistat: a second look. At best, a minor adjunct to dietary measures. 1198 67

Obesity is a chronic disease so that results of obesity treatment should only be evaluated on a long-term basis. The present paper aims at analyzing the long-term (1 year or more) results of three anti-obesity approaches, i.e. lifestyle modifications, pharmacological treatments and surgical procedures. Dietary interventions include diets with moderate calorie restriction and very-low energy diets (VLED). Even if an initial greater weight loss is observed with VLED, no study has conclusively shown that the long-term approaches including VLED are better than non-VLED programmes. Physical activity is not the most efficient method of initial weight loss, but it appears to be more crucial for maintaining weight loss once it has occurred. In general, long-term results of lifestyle modifications are disappointing because of poor compliance. Several 1-2 year large-scale randomized placebo-controlled clinical trials with orlistat, an intestinal lipase inhibitor, and sibutramine, a central appetite regulator, have demonstrated that both drugs significantly, although modestly on average, increase weight reduction, almost double the number of responders (weight loss >=5 or 10% of initial body weight) and improve weight maintenance up to 2 years. Surgical procedures provide a much greater weight reduction than medical interventions in patients with morbid obesity, particularly after a follow-up of several years. Weight loss is greater with gastric bypass, inducing some malbsorption, than with gastroplasty, a pure gastric restriction technique. Associated risk factors such as markers of insulin resistance syndrome and type 2 diabetes are remarkably reduced, but no prospective study of morbidity or mortality is available yet. In all cases, the management of obesity requires a multidisciplinary approach to improve the success rate.
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PMID:Results of obesity treatment. 1199 82


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