Adiponectin, hepatocellular dysfunction and insulin sensitivity

López‐Bermejo, Abel; Botas, Patricia; Funahashi, Tohru; Delgado, Elías; Kihara, Shinji; Ricart, Wifredo; Fernández-Real, José Manuel

doi:10.1046/j.1365-2265.2004.01977.x

Cited by 108 publications

(83 citation statements)

References 53 publications

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“…In contrast to their actions in liver, none of the full-length adiponectins, regardless of the composition of the HMW oligomers, had any obvious effect on AMPK phosphorylation in skeletal muscle. These findings are in agreement with recent clinical reports showing that the plasma levels of adiponectin HMW oligomers are strongly correlated with hepatic insulin sensitivity, but are less relevant to the insulin sensitivity in muscle (44,47,48). In line with previous reports (32,33), our results also demonstrate that globular adiponectin, which forms exclusively as trimers, had potent effects on activation of AMPK and on reduction of lipid accumulation in skeletal muscle, which was associated with a significant alleviation of hypertriglyceridemia and insulin resistance.…”

Section: Discussionsupporting

confidence: 83%

Post-translational Modifications of the Four Conserved Lysine Residues within the Collagenous Domain of Adiponectin Are Required for the Formation of Its High Molecular Weight Oligomeric Complex

Wang

Lam

Chan

et al. 2006

Journal of Biological Chemistry

227

180

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Adiponectin is a multifunctional adipokine that circulates as several oligomeric complexes in the blood stream. However, the molecular basis that regulates the production of the adiponectin oligomers remains largely elusive. We have shown previously that several conserved lysine residues (positions 68 Here, we investigated the potential roles of these post-translational modifications in oligomeric complex formation of adiponectin. Gel filtration chromatography revealed that adiponectin produced from mammalian cells formed trimeric, hexameric, and high molecular weight (HMW) oligomeric complexes. These three oligomeric forms were differentially glycosylated, with the HMW oligomer having the highest carbohydrate content. Disruption of hydroxylation and glycosylation by substitution of the four conserved lysines with arginines selectively abrogated the intracellular assembly of the HMW oligomers in vitro as well as in vivo. In type 2 diabetic patients, both the ratios of HMW to total adiponectin and the degree of adiponectin glycosylation were significantly decreased compared with healthy controls. Functional studies of adiponectin-null mice revealed that abrogation of lysine hydroxylation/glycosylation markedly decreased the ability of adiponectin to stimulate phosphorylation of AMP-activated protein kinase in liver tissue. Chronic treatment of db/db diabetic mice with wild-type adiponectin alleviated hyperglycemia, hypertriglyceridemia, hepatic steatosis, and insulin resistance, whereas full-length adiponectin without proper post-translational modifications and HMW oligomers showed substantially decreased activities. Taken together, these data suggest that hydroxylation and glycosylation of the lysine residues within the collagenous domain of adiponectin are critically involved in regulating the formation of its HMW oligomeric complex and consequently contribute to the insulin-sensitizing activity of adiponectin in hepatocytes.,Adiponectin, a hormone synthesized by adipocytes, is an abundant serum adipokine with potent insulin-sensitizing activity (1-3). Unlike most other adipokines, the plasma levels of adiponectin are significantly decreased in obese individuals and patients with insulin resistance, type 2 diabetes mellitus (T2DM), 2 and cardiovascular diseases (4 -7). Elevation of circulating adiponectin by either transgenic overexpression or direct supplementation with recombinant adiponectin can alleviate many metabolic abnormalities associated with various insulin-resistant and/or diabetic animal models (8 -12). The globular domain of adiponectin decreases postprandial blood glucose, enhances lipid clearance, and increases insulin sensitivity by enhancing fatty acid ␤-oxidation in skeletal muscle (8). On the other hand, full-length adiponectin generated from mammalian cells enhances the sensitivity of insulin to inhibit hepatic glucose production by suppressing the expression of several key enzymes involved in gluconeogenesis, including phosphoenolpyruvate carboxylase and glucose-6-phosphatase (10).In addit...

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Section: Discussionsupporting

confidence: 83%

Post-translational Modifications of the Four Conserved Lysine Residues within the Collagenous Domain of Adiponectin Are Required for the Formation of Its High Molecular Weight Oligomeric Complex

Wang

Lam

Chan

et al. 2006

Journal of Biological Chemistry

227

180

View full text Add to dashboard Cite

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“…These correlations reflect the role of adiponectin in the modulation of insulin sensitivity and cholesterol metabolism. In agreement with the postulated role of adiponectin in modulating liver function (21,22), we also found the correlations of adiponectin and liver enzymes. In our study, a significant difference was noted in adiponectin levels in both the sexes between subjects with MS and those without MS.…”

Section: Discussionsupporting

confidence: 74%

Low plasma adiponectin concentration is an indicator of the metabolic syndrome

Santaniemi¹,

Kesäniemi²,

Ukkola³

2006

eur j endocrinol

103

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Objective: Adiponectin is an adipocytokine known to be decreased in obesity. It functions in glucose and fatty acid metabolism and also has an anti-inflammatory role in microvasculature. We wanted to investigate the role of adiponectin as a biomarker of metabolic syndrome (MS) and see how the plasma adiponectin levels relate to new criteria of MS proposed by the International Diabetes Federation. Methods: Plasma adiponectin concentrations were measured from total of 1041 Finnish subjects with an ELISA -a novel method planned in our laboratory. Results: In both the sexes, the plasma adiponectin levels were lower in subjects with MS when compared with subjects with no diagnosis of MS (P!0.001). Plasma adiponectin levels did not differ between subjects with National Cholesterol Education Program (ATPIII) and International Diabetes Federation-defined MS. Lower adiponectin levels were associated with different components of the MS and there was a trend towards decreasing adiponectin levels with an increasing number of components of MS in both the sexes. Subjects in the lowest adiponectin quartile had a significantly higher probability of having MS (P!0.001), 4.4-fold in males and 7.5-fold in females, when compared with the corresponding individuals in the highest quartile. The probability increased in every lowering quartile of adiponectin level and was independent of body mass index. Conclusion: We conclude that adiponectin levels correlate with most of the components of the MS and the metabolic cluster per se.European Journal of Endocrinology 155 745-750

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“…These prior observations in turn explain why elevated ALT predicted decreasing hepatic insulin sensitivity independent of total adiposity and an increase in hepatic glucose output in a study of Pima Indians (5). Of more recent interest, an inverse correlation between ALT levels and adiponectin concentrations has been demonstrated (16). This observation is relevant since low adiponectin predicts incident diabetes in prospective studies (17)(18)(19) and may do so in part by enhancing hepatic fatty acid oxidation and thereby lessening fat accumulation and ALT levels.…”

Section: Discussionmentioning

confidence: 70%

Elevated Alanine Aminotransferase Predicts New-Onset Type 2 Diabetes Independently of Classical Risk Factors, Metabolic Syndrome, and C-Reactive Protein in the West of Scotland Coronary Prevention Study

et al. 2004

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T he role of the liver in the pathogenesis of type 2 diabetes is attracting increasing interest. In a recent study (1), directly determined liver fat content was shown to correlate with several features of insulin resistance in normal weight and moderately overweight subjects independent of BMI and intraabdominal or overall obesity. However, direct measurements of liver fat require ultrasound, computed tomography scan, or proton spectroscopy, and such techniques are unlikely to be recommended for this purpose in routine clinical practice. Fortunately, circulating concentrations of a number of variables appear to give insight into the extent of liver fat accumulation. Among these are ␥-glutamyltransferase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Of these three, ALT is the most specific marker of liver pathology and appears to be the best marker for liver fat accumulation (2). In addition, circulating concentrations of plasminogen activator inhibitor-1 may give insight into the extent of liver fat content (3) but, unlike ALT, its measurement is perhaps not as simple, standardized, or routinely available in laboratories.In light of the above observations, it is of interest that ALT has been shown to predict incident type 2 diabetes in two prospective studies (4,5). Ohlson et al. (4) determined risk factors for diabetes in 766 men, 47 of whom developed diabetes over 13.5 years of follow-up. They reported that elevated ALT predicted diabetes independently of classical predictors inclusive of BMI, blood pressure, triglycerides, and family history. However, diabetes ascertainment was not uniform in their study, and the potential utility of ALT to predict diabetes was not examined in any detail. Vozarovoa et al. (5) examined the ALT levels in a cohort of 370 Pima Indians with normal glucose tolerance, 63 of whom developed diabetes over an average follow-up of 6.9 years. In their analyses, individuals in the top decile for ALT (Ն70 units/l) had a relative risk of 2.5 (95% CI 1.7-3.7) for diabetes compared with those in the bottom decile (ALT Յ12 units/l), with adjustment for age, sex, percentage body fat, clamp-derived insulin resistance, and acute insulin response. The only minor weaknesses in that study were the absence of data on alcohol consumption and routine clinical measures known to predict diabetes, namely fasting lipids and blood pressure. Moreover, they

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Adiponectin, hepatocellular dysfunction and insulin sensitivity

Abstract: Adiponectin levels are associated in healthy humans with plasma concentrations of various liver function tests. The contributions of adiponectin to maintaining liver integrity through the regulation of both insulin sensitivity and/or the inflammatory response merit further studies.

Cited by 108 publications

References 53 publications

Post-translational Modifications of the Four Conserved Lysine Residues within the Collagenous Domain of Adiponectin Are Required for the Formation of Its High Molecular Weight Oligomeric Complex

Post-translational Modifications of the Four Conserved Lysine Residues within the Collagenous Domain of Adiponectin Are Required for the Formation of Its High Molecular Weight Oligomeric Complex

Low plasma adiponectin concentration is an indicator of the metabolic syndrome

Elevated Alanine Aminotransferase Predicts New-Onset Type 2 Diabetes Independently of Classical Risk Factors, Metabolic Syndrome, and C-Reactive Protein in the West of Scotland Coronary Prevention Study

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