Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obese KKAy insulin-resistant mice represent a model for the human syndrome of noninsulin-dependent diabetes mellitus. As such, the animals are hyperglycemic and hyperinsulinenic. Treatment of KKAy mice with pioglitazone, a new antihyperglycemic agent, lowered elevated blood glucose and insulin levels to near normal. Since hepatic glucose overproduction is a key abnormality in noninsulin-dependent diabetes mellitus, the aim of the present study was to define the specific effects of pioglitazone on hepatic glucose metabolism and release. To do so, we evaluated the expression of the major liver glucose transporter, GLUT2, and examined the activity and expression of the major rate-limiting enzyme for gluconeogenesis, phosphoenolpyruvate carboxykinase. Our results showed that GLUT2 mRNA abundance was unchanged in diabetic KKAy mice compared to nondiabetic animals, and that no changes were elicited by pioglitazone treatment. Such unaltered GLUT2 levels were consistent with a role for liver GLUT2 in bidirectional transport of glucose during physiological states of uptake or release. In contrast, phosphoenolpyruvate carboxykinase activity and mRNA abundance were concordantly elevated 2-fold in diabetic animals and were returned to normal levels after treatment with pioglitazone. Given that pioglitazone therapy led to decreased hepatic gluconeogenesis while insulin levels were concomitantly lowered, it appeared that pioglitazone acted to restore sensitivity to insulin's normal inhibitory actions.
 ...
PMID:Treatment of insulin-resistant mice with the oral antidiabetic agent pioglitazone: evaluation of liver GLUT2 and phosphoenolpyruvate carboxykinase expression. 173 21

Twenty obese and 20 lean LA/N-cp male rats and 20 male Sprague-Dawley rats were fed a diet containing either 54 percent sucrose or starch for six weeks. After a 14-16 hour fast, rats were killed. Liver and kidney enzyme activities were determined in the LA/N-cp rats while plasma urea and selected amino acids were determined in all rats. Liver glucose-6-phosphatase (G6PASE), fructose-1,6-bisphosphatase (FBPASE), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), malic enzyme (ME), glucokinase (GK), pyruvate kinase (PK), phosphofructokinase (PFK), glutamic-oxaloacetic-transaminase (GOT), glutamic-pyruvic transaminase (GPT), arginase (ARGASE), arginine-synthase (ARG-SYN) and ornithine transcarbamylase (OTC) levels were significantly affected by phenotype (obese greater than lean). All the above changes in enzyme levels were exaggerated by sucrose-feeding with the exception of PK, PFK, GOT, GPT, ARGASE and ARG-SYN. Kidney cortex G6PASE, PEPCK and ARGASE activities were higher in the obese rats as compared to the lean littermates. Sucrose feeding resulted in higher cortex G6PASE, FBPASE and PEPCK as compared to starch-fed rats. A phenotype effect was noted with plasma glutamate, urea, leucine, isoleucine and valine (obese greater than lean) and a diet effect was seen with aspartate, phenylalanine, leucine and valine (sucrose greater than starch) concentration. Sprague-Dawley rats had higher plasma urea and lower alanine than lean LA/N-cp males. Metabolic obesity in the LA/N-cp rat appears to involve an elevated capacity for pathways of glycolysis, gluconeogensis, lipogenesis and amino acid catabolism in the liver.
 ...
PMID:Effect of dietary carbohydrate on liver and kidney enzyme activities and plasma amino acids in the LA/N-cp rat. 204 12

Metabolic alterations in ventromedial hypothalamus (VMH)-lesioned rats were investigated by examining daily changes of enzyme activities and urea concentrations three weeks after the operation. VMH-lesions in female adult rats caused a significant elevation in the activity of acetyl-CoA carboxylase in the liver and parametrial adipose tissue. These changes suggest an increased lipogenesis. VMH-lesions also elicited an increase in activities of glucokinase (GK), pyruvate kinase (PK) and fructose 1,6-bisphosphatase (FBPase), and a decrease in activities of phosphofructokinase (PFK), glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver. The apparently inconsistent changes in activities of key glycolytic enzymes, GK, PK and PFK, and key gluconeogenic enzymes, G6Pase, PEPCK and FBPase in the liver may be explained by the fact that they were favorable for glucose oxidation through pentose phosphate cycle and provide NADPH for lipogenesis in the liver. Furthermore, VMH-lesions induced an increase in urea contents of the liver and serum, and elicited an increase in activity of liver tyrosine aminotransferase (TAT) and a decrease in activity of liver histidase. These changes suggest an accelerated amino acid and protein catabolism, and favor an increment in the supply of the substrate for lipogenesis. Daily rhythms of TAT, histidase activities and serum urea concentration observed in the control rats were abolished by VMH-lesions. These findings suggest that VMH-lesions elicit the loss of these daily rhythms, probably through the disturbance of the circadian rhythm of feeding behavior at this dynamic phase (three weeks after operation) of obesity.
 ...
PMID:Shift of metabolism in rats with ventromedial hypothalamic lesions with respect to changes in daily rhythms of enzyme activity. 614 67

Randomized male litter S.D. rats (weight: about 60 g, 1 group: 10 rats) were used. By using Crisco (hydrogenated cotton seed oil) within the limits of 10 approximately 60%, the intake of the 30% group was high and a good incidence rate of obesity (about 100%) was obtained in the 6 month experiment. In the 30% group, increases of wet weight in perirenal retroperitoneal and subcutaneous fat depots, increases of the number and diameter of fat cells (perirenal retroperitoneal fat depot), elevations of liver fat % and serum insulin level, and a fall of liver phosphoenolpyruvate carboxykinase activity were observed in the 3 month experiment.
 ...
PMID:[Formation of experimental obesity by Crisco]. 637 37

Thiazolidinediones are potent antidiabetic compounds, in both animal and human models, which act by enhancing peripheral sensitivity to insulin. Thiazolidinediones are high-affinity ligands for peroxisome proliferator-activated receptor-gamma, a key factor for adipocyte differentiation, and they are efficient promoters of adipocyte differentiation in vitro. Thus, it could be questioned whether a thiazolidinedione therapy aimed at improving insulin sensitivity would promote the recruitment of new adipocytes in vivo. To address this problem, we have studied the in vivo effect of pioglitazone on glucose metabolism and gene expression in the adipose tissue of an animal model of obesity with insulin resistance, the obese Zucker (fa/fa) rat. Pioglitazone markedly improves insulin action in the obese Zucker (fa/fa) rat, but doubles its weight gain after 4 weeks of treatment. The drug induces a large increase of glucose utilization in adipose tissue, where it stimulates the expression of genes involved in lipid metabolism such as the insulin-responsive GLUT, fatty acid synthase, and phosphoenolpyruvate carboxykinase genes, but decreases the expression of the ob gene. These changes are related to both an enhanced adipocyte differentiation, as shown by the large increase in the number of small adipocytes in the retroperitoneal fat pad, and a direct effect of pioglitazone on specific gene expression (phosphoenolpyruvate carboxykinase and ob genes) in mature adipocytes.
 ...
PMID:Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. 928 37

Transgenic mice overexpressing a constitutively active human TGF-beta1 under control of the rat phosphoenolpyruvate carboxykinase regulatory sequences developed fibrosis of the liver, kidney, and adipose tissue, and exhibited a severe reduction in body fat. Expression of the transgene in hepatocytes resulted in increased collagen deposition, altered lobular organization, increased hepatocyte turnover, and in extreme cases, hemorrhage and thrombosis. Renal expression of the transgene was localized to the proximal tubule epithelium, and was associated with tubulointerstitial fibrosis, characterized by excessive collagen deposition and increased fibronectin and plasminogen activator inhibitor-1 immunoreactivity. Pronounced glomerulosclerosis was evident, and hydronephrosis developed with low penetrance. Expression of TGF-beta1 in white and brown adipose tissue resulted in a lipodystrophy-like syndrome. All white fat depots and brown fat pads were severely reduced in size, and exhibited prominent fibroplasia. This reduction in WAT was due to impaired adipose accretion. Introduction of the transgene into the ob/ob background suppressed the obesity characteristic of this mutation; however, transgenic mutant mice developed severe hepato- and splenomegaly. These studies strengthen the link between TGF-beta1 expression and fibrotic disease, and demonstrate the potency of TGF-beta1 in modulating mesenchymal cell differentiation in vivo.
 ...
PMID:Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-beta1 transgenic mice. 938 33

Glucagon-like peptide I (GLP-I) stimulates glucose-dependent insulin secretion and inhibits food intake in the central nervous system. Because leptin reduces food intake but inhibits insulin secretion, we examined leptin action in mice with a null mutation in the GLP-I receptor. Intracerebroventricular leptin administration inhibited food intake in both wild-type and GLP-I receptor (GLP-IR) -/- mice, and daily intraperitoneal administration of leptin for 2 weeks produced comparable reductions in food intake and body weight in control and GLP-IR -/- mice. Glucose tolerance was improved in both wild-type and GLP-IR -/- mice, whether pair fed or leptin treated; however, blood sugars were significantly lower in the leptin-treated GLP-IR -/- mice following oral glucose challenge (P < 0.01). Glucose-stimulated insulin was reduced in both pair-fed and leptin-treated mice (P < 0.01-0.001); however, insulin levels were significantly lower in leptin-treated versus pair-fed GLP-IR -/- mice (P < 0.01). A single leptin injection had no effect on glucose tolerance in GLP-IR -/- mice, but decreased hepatic PEPCK mRNA in both wild-type and GLP-IR -/- mice. The improvement in blood glucose excursion, despite lower levels of glucose-stimulated insulin in lean leptin-treated GLP-IR -/- mice, suggests that leptin may have beneficial effects on control of blood glucose in the absence of obesity. Furthermore, the greater effects of leptin on glucose and insulin in leptin-treated versus pair-fed GLP-IR -/- mice raises the possibility that disruption of GLP-I signaling modifies the sensitivity to leptin in vivo.
 ...
PMID:Leptin sensitivity in nonobese glucagon-like peptide I receptor -/- mice. 939 91

In 1988, insulin-like growth factor-binding protein-1 (IGFBP-1) became the first characterized member of a group of structurally related soluble proteins which specifically bind and modulate the actions of the IGFs. Since then, a wealth of information has accumulated regarding the physiology of this dynamic serum protein. In this review, we update our 1993 summary (Lee PDK et al. Proc Soc Exp Biol Med 204:4-29) of the status of IGFBP-1 research. The IGFBP-1 protein sequence contains 12 N-terminal and 6 C-terminal cysteine residues which are conserved in other mammalian IGFBP-1 sequences and amongst other IGFBPs; both of the cysteine-rich regions are required for optimal IGF binding. The nonconserved IGFBP-1 midregion may act as both a hinge which defines ligand binding characteristics and as a specific target for protease activity. Integrin-binding and phosphorylation sites within the IGFBP-1 sequence have functional significance in vitro, but their physiologic relevance in vivo have not been defined. The human IGFBP-1 and IGFBP-3 genes are contiguous and located in close proximity to the homeobox A (HOXA) gene cluster on chromosome 7. The other IGFBP genes, located on chromosomes 2, 12, and 17, are also associated with HOX clusters, suggesting evolutionary linkage of the IGFBP and HOX gene families. Similarities between the hIGFBP-1 and phosphoenolpyruvate kinase (PEPCK) promoters, including regions conferring insulin, glucocorticoid, and cyclic adenosine-monophosphate responses, are consistent with our previous hypothesis that IGFBP-1 is involved in regulation of glucose metabolism. The tissue-specific patterns of IGFBP-1 gene expression in liver, kidney, decidua, and ovary may be due to stimulation of IGFBP-1 transcription by hepatic nuclear factor 1 (HNF1) proteins. Clinical and basic studies of IGFBP-1 physiology have been aided by several recently developed assay methods. Numerous investigations have confirmed that insulin, via inhibition of IGFBP-1 transcription, is the primary determinant of IGFBP-1 expression both in vitro and in vivo. IGF-I and IGF-II also have specific inhibitory effects on IGFBP-1 expression. Glucocorticoids and cAMP stimulate IGFBP-1 transcription, but these effects are observed only in conditions of low or absent insulin effect. Other stimulants of IGFBP-1 expression include thyroid hormones and epidermal growth factor. Phorbol ester stimulation of IGFBP-1 expression can supersede the effects of insulin in vitro;however, the mechanism and in vivo correlates of this effect have not been determined. Cytokines and, perhaps, growth hormones may affect IGFBP-1 expression, perhaps by altering the regulatory actions of insulin; this effect may have important clinical relevance. IGFBP-1 expression is upregulated in liver and (nonhuman) kidney during postinjury regeneration. The IGF-inhibitory actions of IGFBP-1 has been confirmed by numerous in vitro studies and several in vivo animal investigations, including administration of recombinant IGFBP-1 and IGFBP-1 transgenic models. IGFBP-1 has been shown to inhibit somatic linear growth, weight gain, tissue growth, and glucose metabolism. Moreover, IGFBP-1 appears to be a primary determinant of free IGF-I levels in serum. Excess levels of IGFBP-1 may contribute to growth failure in intrauterine growth restriction and in pediatric chronic renal failure, while low IGFBP-1 levels are associated with obesity and with cardiovascular risk factors in insulin resistance syndromes. Serum IGFBP-1 measurements may be useful biochemical marker in these pathologic conditions. IGFBP-1 is expressed in decidualized stromal cells of the uterine endometrium and in ovarian granulosa cells. IGFBP-1, together with IGFs, insulin, ovarian steroids, cytokines, and other factors, is involved in a complex system which regulates menstrual cycles, ovulation, decidualization, blastocyst implantation, and fetal growth. (ABSTRACT TRUNCATED)
 ...
PMID:Insulin-like growth factor binding protein-1: recent findings and new directions. 940 39

Glucocorticoid hormones, acting via nuclear receptors, regulate many metabolic processes, including hepatic gluconeogenesis. It recently has been recognized that intracellular glucocorticoid concentrations are determined not only by plasma hormone levels, but also by intracellular 11beta-hydroxysteroid dehydrogenases (11beta-HSDs), which interconvert active corticosterone (cortisol in humans) and inert 11-dehydrocorticosterone (cortisone in humans). 11beta-HSD type 2, a dehydrogenase, thus excludes glucocorticoids from otherwise nonselective mineralocorticoid receptors in the kidney. Recent data suggest the type 1 isozyme (11beta-HSD-1) may function as an 11beta-reductase, regenerating active glucocorticoids from circulating inert 11-keto forms in specific tissues, notably the liver. To examine the importance of this enzyme isoform in vivo, mice were produced with targeted disruption of the 11beta-HSD-1 gene. These mice were unable to convert inert 11-dehydrocorticosterone to corticosterone in vivo. Despite compensatory adrenal hyperplasia and increased adrenal secretion of corticosterone, on starvation homozygous mutants had attenuated activation of the key hepatic gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, presumably, because of relative intrahepatic glucocorticoid deficiency. The 11beta-HSD-1 -/- mice were found to resist hyperglycamia provoked by obesity or stress. Attenuation of hepatic 11beta-HSD-1 may provide a novel approach to the regulation of gluconeogenesis.
 ...
PMID:11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. 940 15

Fatty acid transport protein (FATP) was identified by expression cloning strategies (Schaffer, J. E., and Lodish, H. F. (1994) Cell 79, 427-436) and shown by transfection analysis to catalyze the transfer of long-chain fatty acids across the plasma membrane of cells. It is expressed highly in tissues exhibiting rapid fatty acid metabolism such as skeletal muscle, heart, and adipose. FATP mRNA levels are down-regulated by insulin in cultured 3T3-L1 adipocytes and up-regulated by nutrient depletion in murine adipose tissue (Man, M. Z., Hui, T. Y., Schaffer, J. E., Lodish, H. F., and Bernlohr, D. A. (1996) Mol. Endocrinol. 10, 1021-1028). To determine the molecular mechanism of insulin regulation of FATP transcription, we have isolated the murine FATP gene and its 5'-flanking sequences. The FATP gene spans approximately 16 kilobases and contains 13 exons, of which exon 2 is alternatively spliced. S1 nuclease and RNase protection assays revealed the presence of multiple transcription start sites; the DNA sequence upstream of the predominant transcription start sites lacks a typical TATA box. By transient transfection assays in 3T3-L1 adipocytes, the inhibitory action of insulin on FATP transcription was localized to a cis-acting element with the sequence 5'-TGTTTTC-3' from -1347 to -1353. This sequence is very similar to the insulin response sequence found in the regulatory region of other genes negatively regulated by insulin such as those encoding phosphoenolpyruvate carboxykinase, tyrosine aminotransferase, and insulin-like growth factor-binding protein 1. Fluorescence in situ hybridization analysis revealed that the murine FATP gene is localized to chromosome 8, band 8B3.3. Interestingly, this region of chromosome 8 contains a cluster of three other genes important for fatty acid homeostasis, lipoprotein lipase, the mitochondrial uncoupling protein 1 (UCP1) and sterol regulatory element-binding protein 1. These results characterize the murine FATP gene and its insulin responsiveness as well as present a framework for future studies of its role in lipid metabolism, obesity, and type II diabetes mellitus.
 ...
PMID:Characterization of the murine fatty acid transport protein gene and its insulin response sequence. 976 71


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