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)

Serum pseudocholinesterase (PChE) was discovered in 1932. Since this protein mimics many of the catalytic properties of acetylcholinesterase, it has traditionally been referred to as PChE, even though its true biological function is unknown. Serum PChE is synthesized in the liver and secreted into the circulation as a sialated glycoprotein. Although no convincing evidence of biological function exists, a significant number of obese and diabetic patients have elevated levels of PChE. The same phenomenon is found in experimental animal models of obesity, diabetes and hyperlipoproteinemia. Streptozotocin-induced diabetic mice showed increased serum PChE activity concomitant with increased serum triacylglycerol and PChE activity declined with treatment. Iso-OMPA, a nontoxic inhibitor of serum PChE, reduced serum and liver triacylglycerols and serum VLDL in streptozotocin-induced rodent diabetes. These findings suggest that PChE may have a role in VLDL metabolism.
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PMID:Serum pseudocholinesterase and very-low-density lipoprotein metabolism. 793 19

Lipoprotein lipase (LPL), a 55 kDa secretory glycoprotein produced in numerous tissues, is a hydrolytic enzyme, rate-limiting for the removal of lipoprotein TG from the circulation. It is activated by apoprotein CII present on TG-rich lipoproteins. It is involved in lipid transfer between lipoproteins, and plays an important role in the formation of HDL. The fate of LPL-derived lypolysis products differs between tissues: for instance, in adipose tissue, LPL-mediated delivery of free fatty acids is rate-limiting for TG storage, whereas in muscle it provides an alternate source of lipid fuel. LPL is regulated by hormones like insulin and nutrients; its activity depends on the metabolic state of the tissue. It has distinct roles in many normal tissues, such as adipocytes or muscles, as well as an important role in atherogenic dyslipidemia and in metabolic diseases including obesity and hypertriglyceridemia.
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PMID:[Lipoprotein lipase: a key enzyme of lipid metabolism]. 793 19

Apolipoprotein E (apo E) is a polymorphic glycoprotein that plays an essential part in the binding to receptors for the uptake of chylomicrons and VLDL remnants and of LDL. The three major isoforms are E3 (Cys112/Arg158), E4 (Arg112/Arg158) and E2 (Cys112/Cys158). The apo E genetic variation has a great impact. In most of type III familial hyperlipoproteinemias (HLP), E2 is implicated at the homozygote status. In other cases, rare alleles are directly responsible for dominant type III HLP. Apo E polymorphism is an essential determinant in the interindividual variations of lipids in healthy subjects in various populations. Its influence can be significant on the efficacy of nutritional or therapeutic interventions. The allele epsilon 4 appears to be associated with an increased risk of premature atherosclerosis. Recently, epsilon 4 was demonstrated to be associated with an early Alzheimer's disease onset. Apo E polymorphism contributes to the lipid disorders in diabetes and obesity. The analysis of apo E polymorphism can be carried out with two conceptually different approaches. The first one is based on the separation of plasma isoforms of the protein by isoelectric focusing or bidimensional electrophoresis. The other one consists in the application of molecular biology techniques (PCR and endonuclease restriction profiles) for a detection of the common alleles and of several rare alleles, avoiding the possible errors of the phenotyping technique of the apo E protein. The application of genetic engineering allows a better understanding of the role played by apo E towards its receptors and in other molecular interactions which are not well known up to now.
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PMID:[Pathology of the human apolipoprotein E gene]. 807 81

The obesity-induced kinetic changes have been studied only from twenty years, despite the frequency of such a pathological state; thus many work need to be done in this area. The tissular distribution of drugs may depend on the obesity-induced changes in the body composition taking into account the degree of drug liposolubility. Some other factors such as protein binding and regional blood flow may also be involved in tissular diffusion of drugs in obesity. Drug binding to albumin does not seem to be modified in obesity. On the contrary, the protein binding of some basic drugs is increased because of the rise of the plasma alpha 1 glycoprotein acid levels in obesity. Although the cardiac output and the total blood volume are increased in obese patients, the blood flow recalculated according to the adipose tissue weight, is less than in non obese subjects: this point could reduce the diffusion of some lipophilic drugs. More complex are the obesity induced changes in the hepatic clearance of drugs: some reactions such as oxydo-reduction and acetylation do not vary, some others such as sulfoconjugation or glucuronoconjugation are increased. The renal clearance is increased for drugs totally eliminated by glomerular filtration and for drugs which are both filtrated and secreted. According to the liposolubility characteristic of a drug and its clearance, one can calculate the loading dose and the maintenance dose.
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PMID:[Pharmacokinetic changes in obesity]. 812 23

Membrane glycoprotein PC-1, an inhibitor of insulin signaling, produces insulin resistance when overexpressed in cells transfected with PC-1 cDNA. In the present study, we determined whether PC-1 plays a role in the insulin resistance of skeletal muscle in obesity. Rectus abdominus muscle biopsies were taken from patients undergoing elective surgery. Subjects included both NIDDM patients (n = 14) and nondiabetic patients (n = 34) across a wide range of BMI values (19.5-90.1). Insulin-stimulated glucose transport was measured in incubated muscle strips, and PC-1 content, enzymatic activity, and insulin receptor content were measured in solubilized muscle extracts. Increasing BMI correlated with both an increase in the content of PC-1 in muscle (r = 0.55, P < 0.001) and a decrease in insulin stimulation of muscle glucose transport (r = -0.58, P = 0.008). NIDDM had no effect on either PC-1 content or glucose transport for any given level of obesity. Insulin stimulation of muscle glucose transport was negatively related to muscle PC-1 content (r = -0.68, P = 0.001) and positively related to insulin receptor content (r = 0.60, P = 0.005). Multivariate analysis indicated that both skeletal muscle PC-1 content and insulin receptor content, but not BMI, were independent predictors of insulin-stimulated glucose transport. Muscle PC-1 content accounted for 42% and insulin receptor content for 17% of the variance in glucose transport values. These studies raise the possibility that increased expression of PC-1 and a decreased insulin receptor content in skeletal muscle may be involved in the insulin resistance of obesity.
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PMID:Skeletal muscle content of membrane glycoprotein PC-1 in obesity. Relationship to muscle glucose transport. 882 66

Leptin, a circulating 16-kDa protein secreted by adipocytes, decreases body weight by reducing food intake and enhancing energy utilization. Leptin receptors that share homology to the glycoprotein gp130 have been recently cloned. In addition, differentially spliced leptin receptor messenger RNAs have been identified. Functional mutations in either the leptin or leptin receptor gene cause obesity. In the present study, expression of the full length human leptin receptor complementary DNA encoding the long cytoplasmic domain of leptin receptor in COS7 cells resulted in high affinity membrane binding of 125I-leptin (Ki approximately 200 pM); no detectable binding was present in the medium. In addition, we expressed the extracellular domain of human leptin receptor in COS7 cells and identified a soluble leptin receptor in the conditioned medium that binds human and mouse leptin with high affinity comparable with the full length membrane receptor. Transfected COS7 cells expressing the soluble leptin receptor also demonstrated modest specific 125I-leptin binding in whole cells, presumably due to association of the soluble leptin receptor to cell membrane proteins. Data from cross-linking studies identified two specific bands in the 125I-leptin/soluble leptin receptor complex with molecular masses of approximately 130-150 kDa and 300 kDa. The 130-150 kDa molecular mass was confirmed in Western blot analysis and Coomassie staining of the purified soluble receptor and probably represents the glycosylated form of the receptor. The 300-kDa band most likely represents a homodimer of the soluble leptin receptor complex because HPLC gel filtration analysis of the 125I-leptin/soluble leptin receptor complex identified a single peak corresponding to a molecular mass of approximately 340 kDa. The soluble leptin receptor antagonized 125I-leptin binding to the membrane receptor, suggesting its potential utility as a functional tool for determining the role of endogenous leptin.
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PMID:Expression and characterization of a putative high affinity human soluble leptin receptor. 923 10

Non-insulin-dependent diabetes mellitus (NIDDM) is commonly associated with hypertriglyceridaemia, low serum HDL-cholesterol concentrations, hypertension, obesity and accelerated atherosclerosis (metabolic syndrome X). Since a similar dyslipidaemia occurs with the acute-phase response, we investigated whether elevated acute-phase/stress reactants (the innate immune system's response to environmental stress) and their major cytokine mediator (interleukin-6, IL-6) are associated with NIDDM and syndrome X, and may thus provide a unifying pathophysiological mechanism for these conditions. Two groups of Caucasian subjects with NIDDM were studied. Those with any 4 or 5 features of syndrome X (n = 19) were compared with a group with 0 or 1 feature of syndrome X (n = 25) but similar age, sex distribution, diabetes duration, glycaemic control and diabetes treatment. Healthy non-diabetic subjects of comparable age and sex acted as controls. Overnight urinary albumin excretion rate, a risk factor for cardiovascular disease, was also assayed in subjects to assess its relationship to the acute-phase response. Serum sialic acid was confirmed as a marker of the acute-phase response since serum concentrations were significantly related to established acute-phase proteins such as alpha-1 acid glycoprotein (r = 0.82, p < 0.0001). There was a significant graded increase of serum sialic acid, alpha-1 acid glycoprotein, IL-6 and urinary albumin excretion rate amongst the three groups, with the lowest levels in non-diabetic subjects, intermediate levels in NIDDM patients without syndrome X and highest levels in NIDDM patients with syndrome X. C-reactive protein and cortisol levels were also higher in syndrome X-positive compared to X-negative patients and serum amyloid A was higher in both diabetic groups than in the control group. We conclude that NIDDM is associated with an elevated acute-phase response, particularly in those with features of syndrome X. Abnormalities of the innate immune system may be a contributor to the hypertriglyceridaemia, low HDL cholesterol, hypertension, glucose intolerance, insulin resistance and accelerated atherosclerosis of NIDDM. Microalbuminuria may be a component of the acute-phase response.
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PMID:NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. 2212 8

Type II (non-insulin-dependent) diabetes mellitus is associated with increased blood concentrations of markers of the acute-phase response, including sialic acid, alpha-1 acid glycoprotein, serum amyloid A, C-reactive protein and cortisol, and the main cytokine mediator of the response, interleukin-6. The dyslipidaemia common in Type II diabetes (hypertriglyceridaemia and low serum levels of HDL cholesterol) is also a feature of natural and experimental acute-phase reactions. We review evidence that a long-term cytokine-mediated acute-phase reaction occurs in Type II diabetes and is part of a wide-ranging innate immune response. Through the action of cytokines on the brain, liver, endothelium, adipose tissue and elsewhere, this process could be a major contributor to the biochemical and clinical features of metabolic syndrome X (glucose intolerance, dyslipidaemia, insulin resistance, hypertension, central obesity, accelerated atherosclerosis) but also provides a mechanism for many other abnormalities seen in Type II diabetes, including those in blood clotting, the reproductive system, metal ion metabolism, psychological behaviour and capillary permeability. In the short-term, the innate immune system restores homeostasis after environmental threats; we suggest that in Type II diabetes and impaired glucose tolerance long-term lifestyle and environmental stimulants, probably in those with an innately hypersensitive acute-phase response, produce disease instead of repair.
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PMID:Is type II diabetes mellitus a disease of the innate immune system? 1023 Jun 57

Leukemia inhibitory factor (LIF) regulates the mature hypothalamic-pituitary-adrenal axis in vivo. In vitro, LIF determines corticotroph cell proliferation and induces POMC transcription. To explore LIF action on pituitary development, transgenic mice expressing LIF driven by the pituitary glycoprotein hormone alpha-subunit (alphaGSU) promoter were generated. Transgenic mice exhibited dwarfism with low IGF-I (29 +/- 9 ng/ml vs. wild type (WT) 137 +/- 16 ng/ml; P < 0.001), hypogonadism with low FSH (0.04 +/- 0.023 ng/ml vs. WT 0.63 +/- 0.18 ng/ml; P < 0.001), and Cushingoid features of thin skin and truncal obesity with elevated cortisol levels (86 +/- 22 ng/ml vs. WT 50 +/- 14 ng/ml; P = 0.002). Their pituitary glands showed corticotroph hyperplasia, striking somatotroph and gonadotroph hypoplasia, and multiple Rathke-like cysts lined by ciliated cells. LIF, overexpressed in Rathke's pouch at embryonal day 10, diverts the differentiation stream of hormone-secreting cells toward the corticotroph lineage and ciliated nasopharyngeal-like epithelium. Thus, inappropriate expression of LIF, a neuro-immune interfacing cytokine, plays a key role in the terminal differentiation events of pituitary development and mature pituitary function.
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PMID:Pituitary-directed leukemia inhibitory factor transgene causes Cushing's syndrome: neuro-immune-endocrine modulation of pituitary development. 981 97

Apolipoprotein (apo) A-IV is a glycoprotein synthesized by the human intestine. In rodents, both the small intestine and the liver secrete apo A-IV; the small intestine, however, is by far the major organ responsible for the circulating apo A-IV. Intestinal apo A-IV synthesis is markedly stimulated by fat absorption and appears not to be mediated by the uptake or reesterification of fatty acids to form triglycerides. Rather, it is the formation of chylomicrons that acts as a signal for the induction of intestinal apo A-IV synthesis. Intestinal apo A-IV synthesis is also enhanced by a factor from the ileum and that factor is probably peptide tyrosine-tyrosine (PYY). The inhibition of food intake by apo A-IV is probably mediated centrally. The stimulation of intestinal synthesis and secretion of apo A-IV by lipid absorption are rapid; thus, apo A-IV likely plays a role in the short-term regulation of food intake. Other evidence suggests that apo A-IV may also be involved in the long-term regulation of food intake and body weight. Chronic ingestion of a high fat diet blunts the intestinal apo A-IV response to lipid feeding and may explain why the chronic ingestion of a high fat diet predisposes both animals and humans to obesity.
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PMID:The role of apolipoprotein A-IV in food intake regulation. 1041 81


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