scholarly journals Differential hepatic gene expression in a polygenic mouse model with insulin resistance and hyperglycemia: evidence for a combined transcriptional dysregulation of gluconeogenesis and fatty acid synthesis

2004 ◽  
Vol 32 (1) ◽  
pp. 195-208 ◽  
Author(s):  
W Becker ◽  
R Kluge ◽  
T Kantner ◽  
K Linnartz ◽  
M Korn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Glucose Metabolism ◽  
Mrna Levels ◽  
Insulin Resistant ◽  
Glucose And Lipid Metabolism ◽  
Nzo Mice ◽  
Hepatic Glucose

New Zealand obese (NZO) mice exhibit severe insulin resistance of hepatic glucose metabolism. In order to define its biochemical basis, we studied the differential expression of genes involved in hepatic glucose and lipid metabolism by microarray analysis. NZOxF1 (SJLxNZO) backcross mice were generated in order to obtain populations with heterogeneous metabolism but comparable genetic background. In these backcross mice, groups of controls (normoglycemic/normoinsulinemic), insulin-resistant (normoglycemic/hyperinsulinemic) and diabetic (hyperglycemic/hypoinsulinemic) mice were identified. At 22 weeks, mRNA was isolated from liver, converted to cDNA, and used for screening of two types of cDNA arrays (high-density filter arrays and Affymetrix oligonucleotide microarrays). Differential gene expression was ascertained and assessed by Northern blotting. The data indicate that hyperinsulinemia in the NZO mouse is associated with: (i) increased mRNA levels of enzymes involved in lipid synthesis (fatty acid synthase, malic enzyme, stearoyl-CoA desaturase) or fatty acid oxidation (cytochrome P450 4A14, ketoacyl-CoA thiolase, acyl-CoA oxidase), (ii) induction of the key glycolytic enzyme pyruvate kinase, and (iii) increased mRNA levels of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase. These effects were enhanced by a high-fat diet. In conclusion, the pattern of gene expression in insulin-resistant NZO mice appears to reflect a dissociation of the effects of insulin on genes involved in glucose and lipid metabolism. The data are consistent with a hypothetical scenario in which an insulin-resistant hepatic glucose production produces hyperinsulinemia, and an enhanced insulin- and substrate-driven lipogenesis further aggravates the deleterious insulin resistance of glucose metabolism.

scholarly journals Liraglutide Prevents Hypoadiponectinemia-Induced Insulin Resistance and Alterations of Gene Expression Involved in Glucose and Lipid Metabolism

2011 ◽  
Vol 17 (11-12) ◽  
pp. 1168-1178 ◽  
Author(s):  
Ling Li ◽  
Zongyu Miao ◽  
Rui Liu ◽  
Mengliu Yang ◽  
Hua Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Glucose And Lipid Metabolism

scholarly journals Lipid-Lowering Effects of Lotus Leaf Alcoholic Extract on Serum, Hepatopancreas, and Muscle of Juvenile Grass Carp via Gene Expression

2020 ◽  
Vol 11 ◽  
Author(s):  
Junpeng Yao ◽  
Pengcheng Hu ◽  
Yanhong Zhu ◽  
Yingyan Xu ◽  
Qingsong Tan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Lipid Droplet ◽  
Grass Carp ◽  
Lipid Lowering ◽  
Lipid Deposition ◽  
Alcoholic Extract ◽  
Mrna Levels ◽  
Lotus Leaf

Compared with wild grass carp (Ctenopharyngodon idellus), intensively cultured fish displayed disordered lipid metabolism, showing excess lipid deposition in the hepatopancreas and muscle. Lotus leaf prevents fat accumulation in humans and may have similar effects on fish. This study explored the regulatory mechanisms by which the dietary addition of an alcoholic extract of lotus leaf (AELL) reduced lipid deposition in the hepatopancreas and muscle of juvenile grass carp. The fish (average initial weight: 34.00 ± 0.40 g) were fed four experimental diets containing different AELL levels (0, 0.07, 0.14, and 0.21%) for 8 weeks. Serum components, lipid droplet size, triacylglycerol (TAG) content, enzymatic activities, and mRNA levels of genes related to lipid metabolism in the hepatopancreas and muscle were analyzed. The results show that dietary AELL supplementation significantly reduced the TAG content and lipid droplet area in the histological sections as well as the fatty acid synthase (FAS) activity in both the hepatopancreas and muscle but enhanced the activities of lipoprotein lipase (LPL) and carnitine palmitoyltransferase I (CPT1) in both tissues. In addition, dietary AELL supplementation decreased the mRNA expression of genes involved in fatty acid uptake (cd36, fatp1/fatp4/fatp6, fabp10/fabp11, acsl1/acsl4) and de novo lipid synthesis (pgd, g6pd, and fasn) as well as the transcription factors pparg and srebf1 in the hepatopancreas and muscle but increased the mRNA levels of genes relating to lipid catabolism (cpt1a, lipe, pnpla2, lpl), lipid transportation (apob), and the transcription factor ppara in both tissues. In conclusion, dietary AELL supplementation reduced lipid accumulation in the hepatopancreas and muscle by affecting the gene expression of proteins with known effects on lipid metabolism in juvenile grass carp.

scholarly journals MON-LB116 FGF-21 Is A Reliable Marker Of Insulin Resistance Before The Occurrence Of Glucose Intolerance

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
ahmed sawah ◽  
Berhane Seyoum ◽  
Zaher Msallaty
Keyword(s):  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Enzyme Linked Immunosorbent Assay ◽  
Insulin Resistant ◽  
Peripheral Insulin Resistance ◽  
Glucose And Lipid Metabolism ◽  
Institutional Review ◽  
Wide Range ◽  
Before And After ◽  
Clamp Study

Abstract Background and aims: Fibroblast growth factor (FGF)-21 is a polypeptide that results in metabolic rearrangement mostly related to glucose and lipid metabolism. Serum FGF-21 level is elevated in obesity and in type 2 diabetes. The goal of this study is to evaluate the relationship between FGF-21 and peripheral insulin resistance in a wide range of baseline BMI and glucose metabolism status. Materials and methods: seventy one participants reported to the clinical research center in a fasting state twice. BMI and fat mass were calculated. Glucose metabolism was determined by fasting glucose, hemoglobin A1c and OGTT. Serum lipids panel was measured. Peripheral insulin resistance was determined using the hyperinsulinemic euglycemic clamp study. FGF-21 level was measured using enzyme-linked immunosorbent assay before and after clamp study. Study was approved by university institutional review board. Results: Of 71 participants, 48 were obese and 23 were lean. Normal glucose metabolism was documented in 43 individuals. Serum FGF-21 was significantly elevated in insulin resistant compared to insulin sensitive subgroups (0.28 ng/ml ± 0.136 vs. 0.14 ng/ml ± 0.112. p < 0.001). Despite the fact that FGF-21 is elevated in all obese population, the level was significantly higher in the insulin resistant obese subgroup compared to the insulin sensitive obese one (0.30 ng/ml ± 0.167 vs. 0.17 ng/ml ± 0.126. P =0.003). Furthermore, significantly higher FGF-21 level was also found in lean insulin resistant compared to lean insulin sensitive subgroups (0.18 ng/ml ± 0.106 vs. 0.09 ng/ml ± 0.061, p = 0.04]. Adjustment to preexisting impaired glucose tolerance did not affect the correlation between FGF-21 level and insulin resistance which remained statically significant in the seemingly healthy obese and lean subgroups. Conclusion: Serum FGF-21 level strongly correlates to peripheral insulin resistance in both obese and lean population. Nonetheless, FGF-21 level rises way before glucose metabolism abnormality can be detected. Our study suggests a cutoff level for each subgroup which may enable clinicians to risk-stratify patients and allow for early intervention.

scholarly journals Roles of Vitamin A Metabolism in the Development of Hepatic Insulin Resistance

2013 ◽  
Vol 2013 ◽  
pp. 1-21 ◽  
Author(s):  
Guoxun Chen
Keyword(s):  
Insulin Resistance ◽  
Transcription Factors ◽  
Retinoic Acid ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Hepatic Insulin Resistance ◽  
Glucose And Lipid Metabolism ◽  
Hepatic Genes

The increase in the number of people with obesity- and noninsulin-dependent diabetes mellitus has become a major public health concern. Insulin resistance is a common feature closely associated with human obesity and diabetes. Insulin regulates metabolism, at least in part, via the control of the expression of the hepatic genes involved in glucose and fatty acid metabolism. Insulin resistance is always associated with profound changes of the expression of hepatic genes for glucose and lipid metabolism. As an essential micronutrient, vitamin A (VA) is needed in a variety of physiological functions. The active metablite of VA, retinoic acid (RA), regulates the expression of genes through the activation of transcription factors bound to the RA-responsive elements in the promoters of RA-targeted genes. Recently, retinoids have been proposed to play roles in glucose and lipid metabolism and energy homeostasis. This paper summarizes the recent progresses in our understanding of VA metabolism in the liver and of the potential transcription factors mediating RA responses. These transcription factors are the retinoic acid receptor, the retinoid X receptor, the hepatocyte nuclear factor 4α, the chicken ovalbumin upstream promoter-transcription factor II, and the peroxisome proliferator-activated receptor β/δ. This paper also summarizes the effects of VA status and RA treatments on the glucose and lipid metabolism in vivo and the effects of retinoid treatments on the expression of insulin-regulated genes involved in the glucose and fatty acid metabolism in the primary hepatocytes. I discuss the roles of RA production in the development of insulin resistance in hepatocytes and proposes a mechanism by which RA production may contribute to hepatic insulin resistance. Given the large amount of information and progresses regarding the physiological functions of VA, this paper mainly focuses on the findings in the liver and hepatocytes and only mentions the relative findings in other tissues and cells.

Increasing fructose 2,6-bisphosphate overcomes hepatic insulin resistance of type 2 diabetes

2002 ◽  
Vol 282 (1) ◽  
pp. E38-E45 ◽  
Author(s):  
Chaodong Wu ◽  
David A. Okar ◽  
Christopher B. Newgard ◽  
Alex J. Lange
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Kk Mice ◽  
Hepatic Glucose

Hepatic glucose production is increased as a metabolic consequence of insulin resistance in type 2 diabetes. Because fructose 2,6-bisphosphate is an important regulator of hepatic glucose production, we used adenovirus-mediated enzyme overexpression to increase hepatic fructose 2,6-bisphosphate to determine if the hyperglycemia in KK mice, polygenic models of type 2 diabetes, could be ameliorated by reduction of hepatic glucose production. Seven days after treatment with virus encoding a mutant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase designed to increase fructose 2,6-bisphosphate levels, plasma glucose, lipids, and insulin were significantly reduced in KK/H1J and KK.Cg-Ay/J mice. Moreover, high fructose 2,6-bisphosphate levels downregulated glucose-6-phosphatase and upregulated glucokinase gene expression, thereby reversing the insulin-resistant pattern of hepatic gene expression of these two key glucose-metabolic enzymes. The increased hepatic fructose 2,6-bisphosphate also reduced adiposity in both KK mice. These results clearly indicate that increasing hepatic fructose 2,6-bisphosphate overcomes the impairment of insulin in suppressing hepatic glucose production, and it provides a potential therapy for type 2 diabetes.

scholarly journals Hepatic insulin resistance and increased hepatic glucose production in mice lacking Fgf21

2015 ◽  
Vol 226 (3) ◽  
pp. 207-217 ◽  
Author(s):  
João Paulo G Camporez ◽  
Mohamed Asrih ◽  
Dongyan Zhang ◽  
Mario Kahn ◽  
Varman T Samuel ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Fibroblast Growth Factor 21 ◽  
Glucose And Lipid Metabolism ◽  
Hepatic Glucose

Fibroblast growth factor 21 (FGF21) is an important regulator of hepatic glucose and lipid metabolism and represents a potential pharmacological agent for the treatment of type 2 diabetes and obesity. Mice fed a ketogenic diet (KD) develop hepatic insulin resistance in association with high levels of FGF21, suggesting a state of FGF21 resistance. To address the role of FGF21 in hepatic insulin resistance, we assessed insulin action in FGF21 whole-body knock-out (FGF21 KO) male mice and their littermate WT controls fed a KD. Here, we report that FGF21 KO mice have hepatic insulin resistance and increased hepatic glucose production associated with an increase in plasma glucagon levels. FGF21 KO mice are also hypometabolic and display increased fat mass compared with their WT littermates. Taken together, these findings support a major role of FGF21 in regulating energy expenditure and hepatic glucose and lipid metabolism, and its potential role as a candidate in the treatment of diseases associated with insulin resistance.

Regulation of liver glucokinase activity in rats with fructose-induced insulin resistance and impaired glucose and lipid metabolism

2009 ◽  
Vol 87 (9) ◽  
pp. 702-710 ◽  
Author(s):  
Flavio Francini ◽  
María C. Castro ◽  
Juan J. Gagliardino ◽  
María L. Massa
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Protein Concentration ◽  
Cytosolic Fraction ◽  
Liver Triglyceride ◽  
Glucose And Lipid Metabolism ◽  
Triglyceride Content

We evaluated the relative role of different regulatory mechanisms, particularly 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFK2/FBPase-2), in liver glucokinase (GK) activity in intact animals with fructose-induced insulin resistance and impaired glucose and lipid metabolism. We measured blood glucose, triglyceride and insulin concentration, glucose tolerance, liver triglyceride content, GK activity, and GK and PFK2 protein and gene expression in fructose-rich diet (FRD) and control rats. After 3 weeks, FRD rats had significantly higher blood glucose, insulin and triglyceride levels, and liver triglyceride content, insulin resistance, and impaired glucose tolerance. FRD rats also had significantly higher GK activity in the cytosolic fraction (18.3 ± 0.35 vs. 11.27 ± 0.34 mU/mg protein). Differences in GK protein concentration (116% and 100%) were not significant, suggesting a potentially impaired GK translocation in FRD rats. Although GK transcription level was similar, PFK2 gene expression and protein concentration were 4- and 5-fold higher in the cytosolic fraction of FRD animals. PFK2 immunological blockage significantly decreased GK activity in control and FRD rats; in the latter, this blockage decreased GK activity to control levels. Results suggest that increased liver GK activity might participate in the adaptative response to fructose overload to maintain glucose/triglyceride homeostasis in intact animals. Under these conditions, PFK2 increase would be the main enhancer of GK activity.

scholarly journals Increased Hepatic Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 Gene Expression in a Rat Model of Intrauterine Growth Retardation and Subsequent Insulin Resistance

Endocrinology ◽  
2002 ◽  
Vol 143 (7) ◽  
pp. 2486-2490 ◽  
Author(s):  
Robert H. Lane ◽  
Nicole K. MacLennan ◽  
Jennifer L. Hsu ◽  
Sara M. Janke ◽  
Tho D. Pham
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Intrauterine Growth ◽  
Hepatic Glucose

Abstract Uteroplacental insufficiency and subsequent intrauterine growth retardation (IUGR) increase the risk of type 2 diabetes in humans and rats. Unsuppressed endogenous hepatic glucose production is a common component of the insulin resistance associated with type 2 diabetes. Peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) mediates hepatic glucose production by controlling mRNA levels of glucose-6-phosphatase (G-6-Pase), phosphoenolpyruvate carboxykinase (PEPCK), and fructose-1,6-bisphosphatase (FBPase). We therefore hypothesized that gene expression of PGC-1 would be increased in juvenile IUGR rat livers, and this increase would directly correlate with hepatic mRNA levels of PEPCK, G-6-Pase, and FBPase, but not glucokinase. We found that IUGR hepatic PGC-1 protein levels were increased to 230 ± 32% and 310 ± 47% of control values at d 0 and d 21 of life, respectively. Similarly, IUGR hepatic PGC-1 mRNA levels were significantly elevated at both ages. Concurrent with the increased PGC-1 gene expression, IUGR hepatic mRNA levels of G-6-Pase, PEPCK, and FBPase were also significantly increased, whereas glucokinase mRNA levels were significantly decreased. These data suggest that increased PGC-1 expression and subsequent hepatic glucose production contribute to the insulin resistance observed in the IUGR juvenile rat.

scholarly journals Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice

2008 ◽  
Vol 41 (2) ◽  
pp. 53-64 ◽  
Author(s):  
Yanjun Liu ◽  
Yuichi Nakagawa ◽  
Ying Wang ◽  
Limei Liu ◽  
Hongwei Du ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Primary Cultures ◽  
Mrna Levels ◽  
Insulin Resistant ◽  
Beneficial Effects ◽  
Tissue Sensitivity

Intracellular glucocorticoid (GC) receptor (GR) function determines tissue sensitivity to GCs and strongly affects the development of type 2 diabetes and obesity. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) mediates intracellular steroid exposure to mouse liver GR by prereceptor reactivation of GCs and is crucially dependent on hexose-6-phosphate dehydrogenase (H6PDH)-generating NADPH system. Pharmacological inhibition of 11β-HSD1 improves insulin intolerance and obesity. Here, we evaluated the potential beneficial effects of 11β-HSD1 inhibitor carbenoxolone (CBX) in diet-induced obese (DIO) and insulin-resistant mice by examining the possible influence of CBX on the expression of GR, 11β-HSD1, and H6PDH in vivo and in vitro in hepatocytes. Treatment of DIO mice with CBX markedly reduced hepatic GR mRNA levels and reduced weight gain, hyperglycemia, and insulin resistance. The reduction of hepatic GR gene expression was accompanied by CBX-induced inhibition of both 11β-HSD1 and H6PDH activity and mRNA in the liver. Moreover, CBX treatment also suppressed the expression of both phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase enzyme (G6Pase) mRNA and improved hepatic [1, 2-3H] deoxy-d-glucose uptake in DIO mice. In addition, the treatment of primary cultures of hepatocytes with increasing concentrations of CBX led to a dose-dependent downregulation of GR mRNA levels, which correlated with the suppression of both 11β-HSD1 and H6PDH activity and their gene expression. Addition of CBX to primary hepatocytes also resulted in suppression of both PEPCK and G6Pase mRNA levels. These findings suggest that CBX exerts some of its beneficial effects, at least in part, by inhibiting hepatic GR and H6PDH expression.

Sign in / Sign up

Export Citation Format

Share Document