Adiponectin Improves Insulin Sensitivity Research Articles

Adiponectin stimulates Sca1+CD34−-adipocyte precursor cells associated with hyperplastic expansion and beiging of brown and white adipose tissue

BackgroundThe adipocyte hormone adiponectin improves insulin sensitivity and there is an inverse correlation between adiponectin levels and type-2 diabetes risk. Previous research shows that adiponectin remodels the adipose tissue into a more efficient metabolic sink. For instance, mice that overexpress adiponectin show increased capacity for hyperplastic adipose tissue expansion as evident from smaller and metabolically more active white adipocytes. In contrast, the brown adipose tissue (BAT) of these mice looks “whiter” possibly indicating reduced metabolic activity. Here, we aimed to further establish the effect of adiponectin on adipose tissue expansion and adipocyte mitochondrial function as well as to unravel mechanistic aspects in this area. MethodsBrown and white adipose tissues from adiponectin overexpressing (APN tg) mice and littermate wildtype controls, housed at room and cold temperature, were studied by histological, gene/protein expression and flow cytometry analyses. Metabolic and mitochondrial functions were studied by radiotracers and Seahorse-based technology. In addition, mitochondrial function was assessed in cultured adiponectin deficient adipocytes from APN knockout and heterozygote mice. ResultsAPN tg BAT displayed increased proliferation prenatally leading to enlarged BAT. Postnatally, APN tg BAT turned whiter than control BAT, confirming previous reports. Furthermore, elevated adiponectin augmented the sympathetic innervation/activation within adipose tissue. APN tg BAT displayed reduced metabolic activity and reduced mitochondrial oxygen consumption rate (OCR). In contrast, APN tg inguinal white adipose tissue (IWAT) displayed enhanced metabolic activity. These metabolic differences between genotypes were apparent also in cultured adipocytes differentiated from BAT and IWAT stroma vascular fraction, and the OCR was reduced in both brown and white APN heterozygote adipocytes. In both APN tg BAT and IWAT, the mesenchymal stem cell-related genes were upregulated along with an increased abundance of Lineage−Sca1+CD34− “beige-like” adipocyte precursor cells. In vitro, the adiponectin receptor agonist Adiporon increased the expression of the proliferation marker Pcna and decreased the expression of Cd34 in Sca1+ mesenchymal stem cells. ConclusionsWe propose that the seemingly opposite effect of adiponectin on BAT and IWAT is mediated by a common mechanism; while reduced adiponectin levels are linked to lower adipocyte OCR, elevated adiponectin levels stimulate expansion of adipocyte precursor cells that produce adipocytes with intrinsically higher metabolic rate than classical white but lower metabolic rate than classical brown adipocytes. Moreover, adiponectin can modify the adipocytes' metabolic activity directly and by enhancing the sympathetic innervation within a fat depot.

An Explanation for the Adiponectin Paradox

The adipokine adiponectin improves insulin sensitivity. Functional signal transduction of adiponectin requires at least one of the receptors AdipoR1 or AdipoR2, but additionally the glycosyl phosphatidylinositol-anchored molecule, T-cadherin. Overnutrition causes a reduction in adiponectin synthesis and an increase in the circulating levels of the enzyme glycosyl phosphatidylinositol-phospholipase D (GPI-PLD). GPI-PLD promotes the hydrolysis of T-cadherin. The functional consequence of T-cadherin hydrolysis is a reduction in adiponectin sequestration by responsive tissues, an augmentation of adiponectin levels in circulation and a (further) reduction in signal transduction. This process creates the paradoxical situation that adiponectin levels are augmented, whereas the adiponectin signal transduction and insulin sensitivity remain strongly impaired. Although both hypoadiponectinemia and hyperadiponectinemia reflect a situation of insulin resistance, the treatments are likely to be different.

Effect of Strength Training on Glycemic Control and Adiponectin in Diabetic Children.

This study aimed to examine the effect of isolated supervised progressive resistance training with duration of more than 32 wk on muscle strength, metabolic control and adiponectin. Twenty-one children with type 1 diabetes mellitus were separated into an intervention group (IG) (n = 11 age 11.0 ± 0.8) and a control group (CG) (n = 10 age 11.30 ± 0.7) without training to control for the effect of progressive resistance training on muscle strength, hemoglobin (HbA)1C and adiponectin. All parameters were assessed before and after a period of 32 wk. No attempt was made to change diet and the daily behaviors during the study in both groups. After a period of 32 wk, upper and lower limb strength increased significantly (P < 0.05) in the IG, whereas no changes occurred in the CG. In the IG, HbA1C decreased significantly after 32 wk but not after 17 wk (P < 0.00), whereas HbA1C increased in the CG (P < 0.007). Adiponectin increased significantly (P < 0.000) only in the IG. Self-monitored blood glucose levels, measured before and after each session, showed a significant reduction (P < 0.00) of 26.5% ± 4.4% after each session. Effect size (ES) for the strength training on limb strength was medium (d = 0.464 to d = 0.661), the ES for strength training on HbA1C (d = -1.292) and the ES for strength training on adiponectin (d = 1.34) was large. There was no hypoglycemia as the result of training. An isolated supervised progressive resistance training two times a week in children with type 1 diabetes mellitus must last at least 32 wk to get a significant decrease in blood glucose level HbA1C. In addition, exercise-induced increase in adiponectin improves insulin sensitivity.

165-OR: The Mechanisms by Which Adiponectin Reverses Insulin Resistance in High-Fat Diet Fed Mice

Adiponectin has emerged as an antidiabetic adipokine, and a potential therapy to treat type 2 diabetes. However, the mechanism by which adiponectin improves insulin sensitivity remains unclear. To address this question, we examined the effects of a 2-week continuous infusion of globular adiponectin (gAcrp30) or saline (CON) on glucose and lipid metabolism in a high fat diet fed (HFD) mouse model. Whole-body and tissue-specific insulin action was assessed by a hyperinsulinemic-euglycemic clamp (HEC). gAcrp30-treated mice displayed reduced fasting plasma glucose and insulin concentrations (both P&amp;lt;0.05 vs. CON) and increased glucose infusion rate (14 vs. 22 mg/(kg-min), P&amp;lt;0.001) during the HEC reflecting increased whole-body insulin-sensitivity. Increased insulin sensitivity could be attributed to reduced endogenous glucose production (16.7 vs.14.2 mg/(kg-min), P&amp;lt;0.05), increased glucose uptake in muscle (191 vs. 285 nmol/(kg-min), p=0.006) and adipose tissues (BAT: 112 vs. 217, WAT: 11 vs. 22 nmol/(kg-min), both P&amp;lt;0.05) during the HEC. These improvements in liver and muscle insulin sensitivity were associated with ∼50% reductions in liver and muscle triglyceride (TAG) and ∼40% diacylglycerol (DAG) (both P&amp;lt;0.01 vs. CON) content but no changes in hepatic ceramide content. Reduced tissue TAG/DAG content occurred independent of changes in WAT lipolysis, hepatic AMPK activation, ACC phosphorylation or mitochondrial oxidation. Reduced tissue DAG content was associated with decreased PKCε activation in liver and PKCθ activation in muscle and increased insulin signaling in liver, muscle and white adipose tissue. Conclusion: Taken together these data support the hypothesis that adiponectin improves insulin sensitivity in liver and muscle of HFD fed mice by reducing ectopic lipid (DAG) content in these tissues leading to decreased nPKC activity and increased insulin signaling, and contrary to prior studies, is independent of changes in hepatic ceramide content. Disclosure X. Li: None. D. Zhang: None. R.J. Perry: Research Support; Self; AstraZeneca. D.F. Vatner: None. L. Goedeke: None. Y. Zhang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research &amp; Development, Merck &amp; Co., Inc. Advisory Panel; Spouse/Partner; Merck &amp; Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V. Funding American Heart Association (19PRE34380268); National Institutes of Health (R01DK116774)

2487-PUB: Purinergic Regulation of Adiponectin Exocytosis and the Role of Sympathetic Innervation for Adiponectin Secretion

The white adipocyte hormone adiponectin improves insulin sensitivity and has a protective role in the development of type 2 diabetes. The rapid incidence of obesity-associated disorders emphasizes the importance of understanding the regulation of adiponectin secretion. Hormones are typically secreted via regulated exocytosis but the mechanisms controlling adiponectin release remains inadequately investigated. We have previously demonstrated that catecholamines/cAMP trigger adiponectin exocytosis via activation of adrenergic beta-3-receptors (β3ARs) and Epac1, while elevations of intracellular Ca2+ potentiate the exocytotic process. White adipose tissue is highly innervated by sympathetic nerves, co-releasing norepinephrine (NE) and ATP, thus suggesting a role of the sympathetic nervous system in regulation of adiponectin secretion. Here we have studied the role of sympathetic innervation and purinergic signaling in adiponectin release. Extracellular NE triggered adipocyte exocytosis, whereas extracellular ATP potentiated NE-triggered adipocyte exocytosis. Short-term adiponectin secretion was stimulated by NE while ATP augmented the catecholamine-stimulated release. The effect of ATP was abolished in adipocytes pre-treated with a P2Y2-receptor antagonist. In adipocytes isolated from obese/diabetic mice, ATP-induced adiponectin release was abrogated together with a reduced gene expression of the P2Y2-receptor. Moreover, white adipose tissue content of NE and tyrosine hydroxylase was reduced in obese/diabetic mice. We propose that the physiological stimulatory pathway for adiponectin exocytosis is via sympathetic innervation, co-releasing NE and ATP which activates β3ARs (elevates cAMP) and P2Y2Rs (increases Ca2+). We also suggest that decreased NE and ATP release within the adipose tissue together with disrupted adipocyte purinergic signaling results in disturbed adiponectin release in diabetic/obese conditions. Disclosure S. Musovic: None. A.M. Komai: None. P. Micallef: None. Y. Wu: None. I. Wernstedt Asterholm: None. C.S. Olofsson: None.

Abundance of adiponectin system and G-protein coupled receptor GPR109A mRNA in adipose tissue and liver of F2 offspring cows of Charolais × German Holstein crosses that differ in body fat accumulation

In addition to its role in energy storage, adipose tissue (AT) is an important endocrine organ and it secretes adipokines. The adipokine adiponectin improves insulin sensitivity by activation of its receptors AdipoR1 and AdipoR2. Lipolysis in AT is downregulated by the G-protein coupled receptor (GPR109A), which binds the endogenous ligand β-hydroxybutyrate (BHBA). Insulin sensitivity is reduced during the transition from late pregnancy to early lactation in dairy cattle and BHBA is increased postpartum, implying the involvement of the adiponectin system and GPR109A in this process. The aim of the current investigation was to study the effect of the genetic background of cows on the mRNA abundance of the adiponectin system, as well as GPR109A, in an F2 population of 2 Charolais × German Holstein families. These families were deduced from full- and half-sibs sharing identical but reciprocal paternal and maternal Charolais grandfathers. The animals of the 2 families showed significant differences in fat accretion and milk secretion and were designated fat-type (high fat accretion but low milk production) and lean-type (low fat accretion but high milk production). The mRNA of the adiponectin system and GPR109A were quantified by real-time PCR in different fat depots (subcutaneous from back, mesenteric, kidney) and liver. The mRNA data were correlated with AT masses (intermuscular topside border fat, kidney, mesenteric, omental, total inner fat mass, total subcutaneous fat mass, and total fat mass) and blood parameters (glucose, nonesterified fatty acids, BHBA, urea, insulin, and glucagon). The abundance of adiponectin system mRNA was higher in discrete AT depots of fat-type cows [adiponectin mRNA in mesenteric fat (trend), AdipoR1 in kidney and mesenteric AT, and AdipoR2 in subcutaneous fat (trend)] than in lean-type cows. More GPR109A mRNA was found in kidney fat of the lean-type family than in that of the fat-type family. In liver, the abundance of AdipoR2 and GPR109A (trend) mRNA was higher in lean-type than in fat-type cows. Correlation analyses disclosed clear differences between the groups. In total, the results revealed obvious disparities for the mRNA targets between the 2 families with common but reciprocal paternal and maternal genetic backgrounds. Visceral AT mass of both families showed most correlations with the mRNA abundance of the target genes in different AT depots. The effect of adiponectin secretion, especially by visceral AT depots, on liver metabolism should be clarified in further studies.

The Therapeutic Potential of the Adiponectin Pathway

Adiponectin is an adipocyte-derived hormone that has been shown to play an important role in the regulation of metabolic, inflammatory, and apoptotic pathways. Adiponectin improves insulin sensitivity, promotes vascular health, and increases cell survival. These observations suggest a potential therapeutic role for adiponectin in the treatment of diabetes mellitus, cardiovascular diseases, and cancer. However, biologically active recombinant adiponectin proteins are inherently unstable and difficult to produce, thus making it a challenge for both research and clinical development. One main challenge relates to the existence of adiponectin as homo-/hetero-trimers, and complexes containing multiple adiponectin trimer units, in plasma. The underlying mechanism for adiponectin function is also not completely understood. Two receptors for adiponectin (ADIPOR1 and ADIPOR2) have been cloned, and activation of adenosine monophosphate-activated kinase (AMPK) has been reported to be downstream of the receptors. Recent findings suggest that adiponectin potently stimulates ceramidase activity via activation of its two known receptors, therefore connecting sphingolipid metabolism to adiponectin functions and providing a potential mechanism explaining the different actions of adiponectin. Interestingly, a new report also identified a pathway involving adiponectin and insulin receptor substrate 2, which is independent of the ADIPOR1/ADIPOR2 pathway. In this manuscript, we will review previous approaches and challenges in exploring adiponectin-based therapeutics. In particular, we will review some of the recent developments in engineering adiponectin proteins as well as potential therapeutic opportunities offered by recently elucidated adiponectin-mediated signaling pathways.

Hemoglobin is Associated with Serum High Molecular Weight Adiponectin in Japanese Community-Dwelling Persons

Serum high molecular weight (HMW) adiponectin improves insulin sensitivity, and a decreased level of serum HMW adiponectin has been reported as a risk factor for the development of diabetes and coronary heart disease. This association may be further confounded by the hemoglobin status, which is involved in the development of atherosclerosis. A cross-sectional study was carried out in 2002. Study participants, consisting of 897 men aged 61±14 (mean±standard deviation) years and 1,148 women aged 63±12 years, were randomly recruited from a single community at the time of their annual health examination. Serum HMW adiponectin levels were lowered dose-dependently with an increased hemoglobin level. Stepwise multiple linear regression analyses for serum HMW adiponectin revealed that the hemoglobin status was independently and significantly associated with serum HMW adiponectin levels as well as sex, age, body mass index (BMI), alcohol consumption, total cholesterol, triglycerides, high density lipoprotein cholesterol, antilipidemic medication, uric acid, serum gamma glutamyltransferase, and insulin resistance. Inclusion of hemoglobin levels in the model further increased the coefficient of determination. In stratified analysis, mean serum HMW adiponectin levels were significantly and similarly decreased as hemoglobin levels increased in men, ages ≥ 65 years, BMI < 23.0 kg/m(2), alcohol drinkers, and lower insulin resistance, and there were significant interactions between the two groups for BMI, alcohol consumption and insulin resistance. Hemoglobin status is inversely associated with serum HMW adiponectin levels in community-dwelling persons, especially those aged ≥ 65 years, BMI < 23.0 kg/m(2), alcohol drinkers, and lower insulin resistance groups.

Cross-talk between adipose tissue and vasculature: role of adiponectin

Adipose tissue is a highly dynamic endocrine organ, secreting a number of bioactive substances (adipokines) regulating insulin sensitivity, energy metabolism and vascular homeostasis. Dysfunctional adipose tissue is a key mediator that links obesity with insulin resistance, hypertension and cardiovascular disease. Obese adipose tissue is characterized by adipocyte hypertrophy and infiltration of inflammatory macrophages and lymphocytes, leading to the augmented production of pro-inflammatory adipokines and vasoconstrictors that induce endothelial dysfunction and vascular inflammation through their paracrine and endocrine actions. By contrast, the secretion of adiponectin, an adipokine with insulin sensitizing and anti-inflammatory activities, is decreased in obesity and its related pathologies. Emerging evidence suggests that adiponectin is protective against vascular dysfunction induced by obesity and diabetes, through its multiple favourable effects on glucose and lipid metabolism as well as on vascular function. Adiponectin improves insulin sensitivity and metabolic profiles, thus reducing the classical risk factors for cardiovascular disease. Furthermore, adiponectin protects the vasculature through its pleiotropic actions on endothelial cells, endothelial progenitor cells, smooth muscle cells and macrophages. Data from both animal and human investigations demonstrate that adiponectin is an important component of the adipo-vascular axis that mediates the cross-talk between adipose tissue and vasculature. This review highlights recent work on the vascular protective activities of adiponectin and discusses the molecular pathways underlying the vascular actions of this adipokine.

Smoking Status is Associated with Serum High Molecular Adiponectin Levels in Community-Dwelling Japanese Men

Serum high molecular weight (HMW) adiponectin improves insulin sensitivity, and a decreased level has been reported as a risk factor for the development of diabetes and coronary heart disease. This association may be further confounded by smoking, which is involved in the development of insulin resistance. The aim of this study was to determine whether smoking status is associated with serum HMW adiponectin levels in community-dwelling males. The cross-sectional study was carried out in 2002. Study participants without a clinical history of diabetes (724 men aged 60+/-14 (mean+/-standard deviation) (range, 20-89) years) were randomly recruited from a single community at an annual physical examination. They were classified into never-smokers, ex-smokers, light-smokers (<30 pack x year), and heavy-smokers (>or=30 pack x year). Mean serum HMW adiponectin levels were significantly lower in the current smokers than in the never- and ex-smokers but showed no significant difference between the light and heavy-smokers. Multiple linear regression analyses revealed that smoking status was significantly associated with HMW adiponectin levels, as were age, BMI, alcohol consumption, triglycerides, and high-density lipoprotein cholesterol. Multivariate-adjusted mean serum HMW adiponectin levels were lowest in the heavy-smokers, and significantly decreased in heavy-smokers compared with never-smokers and ex-smokers of an age >or=60 years, BMI >or=22 kg/m(2), alcohol consumption >or=22.9 g of ethanol/day, and HOMA-IR >or=1.6. Smoking status is associated with serum HMW adiponectin levels in community-dwelling Japanese men.

Alcohol Drinking Status is Associated with Serum High Molecular Weight Adiponectin in Community-Dwelling Japanese Men

Serum high molecular weight (HMW) adiponectin improves insulin sensitivity, and a decreased level of serum HMW adiponectin has been reported as a risk factor for the development of diabetes and coronary heart disease. This association may be further confounded by the alcohol drinking status, which is involved in the development of liver dysfunction. The aim of this study was to determine whether the alcohol drinking status is associated with serum HMW adiponectin levels in community-dwelling Japanese men. A cross-sectional study was carried out in 2002. Study participants without a clinical history of diabetes (747 men aged 60 ± 14 (mean ± standard deviation) (range, 20-89) years) were randomly recruited from a single community at the time of their annual health examination. They were classified into never drinkers, light drinkers (< 1 unit/day), moderate drinkers (1-1.9 units/day), and heavy drinkers (≥ 2 units/day). We examined the effects of alcohol consumption on serum HMW adiponectin. Overall, mean serum HMW adiponectin levels were significantly lower in the group with higher alcohol consumption, and there were inter-group differences in the alcohol drinking status. Moreover, age-adjusted mean serum HMW adiponectin levels were significantly lower in the group with higher alcohol consumption. Multiple linear regression analysis showed that the alcohol drinking status was significantly and independently associated with serum adiponectin as well as age, smoking status, TG, HDL-C, LDL-C, serum ALT, and HOMA-IR. Multivariate-adjusted mean serum HMW adiponectin levels were also significantly lower in the group with higher alcohol consumption. The alcohol drinking status is negatively associated with serum HMW adiponectin levels in Japanese community-dwelling men.

Impaired adiponectin-AMPK signalling in insulin-sensitive tissues of hypertensive rats

Aims Adiponectin improves insulin sensitivity by decreasing lipid accumulation in insulin-sensitive tissues. The aim of this study was to investigate whether these effects are altered in hypertension. Main methods Adiponectin receptors (AdipoR1 and AdipoR2) and adiponectin-related enzymes were measured by real-time PCR and Western-blot in insulin-sensitive tissues of 10-week-old male spontaneously hypertensive rats (SHR). Intrahepatic and intramyocellular triglycerides were determined by enzymatic methods. Key findings SHR showed overweight, dyslipidemia, glucose intolerance and insulin resistance. Circulating concentrations of adiponectin as well as the mRNA and protein expression of adiponectin in epididymal and subcutaneous fat depots were significantly increased in hypertensive rats. Adiponectin mRNA levels were strongly associated with PPARγ mRNA levels in both epididymal ( r = 0.54, P < 0.05) and subcutaneous ( r = 0.93, P < 0.0001) fat. The expression of AdipoR1 and AdipoR2, acetyl-CoA carboxylase (ACC), as well as carnitine palmitoyl transferase 1 (CPT1), were increased in skeletal muscle of SHR. These changes were not observed in the liver of SHR. In addition, in spite of the hyperadiponectinemia, SHR showed similar activation of AMP-activated protein kinase (AMPK) and a lower phosphorylation degree of its downstream ACC in liver and skeletal muscle. Accordingly, SHR exhibited a significant increase in intrahepatic (~ 40%) and intramyocellular (~ 60%) lipid accumulation. Significance These findings suggest that dysregulation of the adiponectin downstream effectors contributes to increased intrahepatic and intramyocellular triglycerides in SHR. Hyperadiponectinemia together with overexpression of adiponectin receptors in skeletal muscle may reflect a defective compensatory mechanism to overcome adiponectin resistance in hypertensive rats.

Adaptation and Maladaptation of the Heart in Obesity

Obesity affects the cardiovascular system at many different levels, including the heart muscle itself. Clinical and experimental studies have shown an accumulation of triglycerides and other lipid species in cardiomyocytes. Analogous to hepatic steatosis, investigators have introduced the term “cardiac steatosis”. The present review addresses the complex relationships between cardiac fuel homeostasis, insulin resistance, and proposed mechanisms of damage to cardiomyocytes in different models of obesity, insulin resistance, and lipotoxicity. Specifically, the review weighs the evidence whether there is a heart muscle disorder in human obesity. It discusses how adipokines can modulate cardiac metabolism, and it focuses on the metabolic remodeling accompanying increased fatty acid supply in the heart of rodent models of lipotoxicity, with special attention to the role played by mitochondrial uncoupling and futile cycling. We stress the notion that, in spite of the many proposed mechanisms, cardiac lipotoxicity is still a hypothesis rather than an established pathophysiologic principle. Although the concept of a “lipotoxic cardiomyopathy” seems attractive, we propose instead a series of steps on a path from adaptation to maladaptation of the heart in obesity. A case in point is insulin resistance of the heart which may be both adaptive (protecting the heart from excess fuel) or maladaptive (associated with reactive oxygen species formation and activation of signaling pathways of programmed cell death). The present literature reflects an extraordinary complexity of the heart’s metabolic, functional and structural changes in obesity.

Adiponectin: A Promising Marker for Cardiovascular Disease

Obesity is a major risk factor for coronary heart disease (CHD). Obese persons have an ∼1.5- to 2.0-fold increased risk for CHD, and between 15% and 20% of all cases of CHD can be attributed to overweight and obesity (1). Although hypertension, dyslipidemia, insulin resistance, and type 2 diabetes are core components of the metabolic syndrome and are probably key elements in the causal pathway from obesity to CHD, the underlying mechanisms are only poorly understood. It is known that adipose tissue itself is capable of producing a variety of cytokines and hormones (called adipokines or adipocytokines) that may be relevant for CHD development. Among others, these include pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6; hormones involved in blood pressure regulation, such as those of the renin-angiotensin system; factors that affect hemostasis and angiogenesis, such as plasminogen activator inhibitor-1 and vascular endothelial growth factor; and hormones involved in energy metabolism, such as leptin (2). Adiponectin may be the most relevant and promising adipokine with respect to a better understanding of the link between obesity and CHD. Adiponectin (also called ARCP30, AdipoQ, apM1, and GBP28) is a 247–amino acid peptide hormone discovered in 1995 (3). It is induced early in the differentiation of fat cells (adipocytes), consists of an N-terminal collagenous and a C-terminal globular domain, and shares homology with subunits of complement factor C1q. Contrary to other adipose-derived hormones, adiponectin circulates at relatively high concentrations in the blood stream, accounting for 0.05% of total serum proteins, and is inversely associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease (CVD) (3)(4)(5)(6)(7)(8)(9)(10). Data from animal studies suggest that administration of adiponectin improves insulin sensitivity and may …

Reduced plasma adiponectin concentrations may contribute to impaired insulin activation of glycogen synthase in skeletal muscle of patients with type 2 diabetes

Circulating levels of adiponectin are negatively associated with multiple indices of insulin resistance, and the concentration is reduced in humans with insulin resistance and type 2 diabetes. However, the mechanisms by which adiponectin improves insulin sensitivity remain unclear. Combining euglycaemic-hyperinsulinaemic clamp studies with indirect calorimetry and skeletal muscle biopsies, we examined the relationship between plasma adiponectin and parameters of whole-body glucose and lipid metabolism, and muscle glycogen synthase (GS) activity in 51 Caucasians (ten lean, 21 obese and 20 with type 2 diabetes). Plasma adiponectin was significantly reduced in type 2 diabetic compared with obese and lean subjects. In lean and obese subjects, insulin significantly reduced plasma adiponectin, but this response was blunted in patients with type 2 diabetes. Plasma adiponectin was positively associated with insulin-stimulated glucose disposal (r = 0.48), glucose oxidation (r = 0.54), respiratory quotient (r = 0.58) and non-oxidative glucose metabolism (r = 0.38), and negatively associated with lipid oxidation during insulin stimulation (r = -0.60) after adjustment for body fat (all p < 0.01). Most notably, we found a positive association between plasma adiponectin and insulin stimulation of GS activity in skeletal muscle (r = 0.44, p < 0.01). Our results indicate that plasma adiponectin may enhance insulin sensitivity by improving the capacity to switch from lipid to glucose oxidation and to store glucose as glycogen in response to insulin, and that low adiponectin may contribute to impaired insulin activation of GS in skeletal muscle of patients with type 2 diabetes.

Mice Lacking Adiponectin Show Decreased Hepatic Insulin Sensitivity and Reduced Responsiveness to Peroxisome Proliferator-activated Receptor γ Agonists

The adipose tissue-derived hormone adiponectin improves insulin sensitivity and its circulating levels are decreased in obesity-induced insulin resistance. Here, we report the generation of a mouse line with a genomic disruption of the adiponectin locus. We aimed to identify whether these mice develop insulin resistance and which are the primary target tissues affected in this model. Using euglycemic/insulin clamp studies, we demonstrate that these mice display severe hepatic but not peripheral insulin resistance. Furthermore, we wanted to test whether the lack of adiponectin magnifies the impairments of glucose homeostasis in the context of a dietary challenge. When exposed to high fat diet, adiponectin null mice rapidly develop glucose intolerance. Specific PPARgamma agonists such as thiazolidinediones (TZDs) improve insulin sensitivity by mechanisms largely unknown. Circulating adiponectin levels are significantly up-regulated in vivo upon activation of PPARgamma. Both TZDs and adiponectin have been shown to activate AMP-activated protein kinase (AMPK) in the same target tissues. We wanted to address whether the ability of TZDs to improve glucose tolerance is dependent on adiponectin and whether this improvement involved AMPK activation. We demonstrate that the ability of PPARgamma agonists to improve glucose tolerance in ob/ob mice lacking adiponectin is diminished. Adiponectin is required for the activation of AMPK upon TZD administration in both liver and muscle. In summary, adiponectin is an important contributor to PPARgamma-mediated improvements in glucose tolerance through mechanisms that involve the activation of the AMPK pathway.

“HypoAdiponectinemia” – A link between central obesity and liver inflammation

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder, which occurs as a consequence of abnormal insulin action, and is the hepatic manifestation of insulin resistance (IR) and the systemic complex known as the metabolic syndrome (MS). Fat infiltration (NAFLD alone) may lead to inflammation in the liver (NASH or non-alcoholic steatohepatitis). With the rising incidence of obesity and MS, it is highly likely that pediatric practitioners will encounter affected children. In a recent autopsy study of liver biopsies from 278 cases of traumatic death in San Diego county, 17% demonstrated NAFLD (Gastro 2004;126:A753). What is the mechanism of fat infiltration and of inflammation of the liver? When adiposity reaches a certain threshold, factors derived from adipocytes induce macrophage activation and infiltration. Activated macrophages secrete cytokines that can impair adipocyte insulin sensitivity and stimulate further activation and infiltration of peripheral monocytes and macrophages into fat. Adipocytes can also secrete chemokines, which can contribute to macrophage infiltration. These amplifying signals increasingly impair adipocyte insulin signaling and eventually cause systemic IR. (JCI 2003;112:1821) A “protective” factor is apparently involved in this process- adiponectin – a protein secreted only by adipocytes. Serum levels of adiponectin are inversely related to obesity and IR and NASH. Adiponectin improves insulin sensitivity by enhancing hepatic fatty acid oxidation (Gastro 2005;128:511). Adiponectin also has anti-inflammatory actions via suppression of hepatic production of TNFα. Exogenous adiponectin given to mice with NASH promotes weight loss and improves IR, steatosis, and inflammation (Gut 2005;54:117). Hiu et al recently reported low serum adiponectin levels and IR in 77% of patients with NASH vs. none of the BMI matched controls (Hepatology 2004;40:46). Thus serum adiponectin seems to be a marker of NASH and perhaps is involved in protecting the liver from inflammation. Louthan et al report the relative concentration of serum cytokines in 30 children with NAFLD. Serum adiponectin levels were significantly lower and negatively correlated with BMI in those with NAFLD compared to controls. This early decrease supports the concept that reduction in adiponectin may be an early step in the downhill spiral to hepatic inflammation in obesity. In addition, serum levels of adiponectin may be an early sign of NASH in obese children.

Mechanisms of Disease: adipocytokines and visceral adipose tissue—emerging role in nonalcoholic fatty liver disease

There is increasing evidence that visceral adipose tissue is a causative risk factor for fatty liver and nonalcoholic steatohepatitis. Adipose tissue-derived secretory proteins are collectively named adipocytokines. Obesity and mainly visceral fat accumulation impair adipocyte function and adipocytokine secretion and the altered release of these proteins contributes to hypertension, impaired fibrinolysis and insulin resistance. This review summarizes recent findings on the role of the adipocytokines adiponectin, leptin and resistin in the context of hepatic insulin resistance, fatty liver and liver fibrosis. Elevated levels of resistin antagonize hepatic insulin action and raise plasma glucose levels. Leptin exerts insulin-sensitizing effects, but obesity has been linked to leptin resistance and low levels of circulating leptin receptor, indicating that high levels of leptin cannot mediate its beneficial effects. Adiponectin improves insulin sensitivity; however, low circulating adiponectin is found in the obese state. Adiponectin is an anti-inflammatory protein, whereas leptin augments inflammation and fibrogenesis. Disturbed adipocytokine secretion might, therefore, promote hepatic steatosis and the development of nonalcoholic steatohepatitis. The beneficial effects of the therapeutic approaches so far tested in the treatment of fatty liver disease and fibrosis might be due to the modulation of these adipocytokines.

Adiponectine : de l’adipocyte au muscle

Insulin resistance is characterized by a peripheral resistance to insulin-mediated glucose uptake, and an hepatic resistance of glucose production to insulin. Insulin resistance in skeletal muscle is of a particular importance, and could be the consequence of an increase in intracellular and circulating fatty acids and triglycerides. Adipose tIssue plays an important role to regulate mobilization and release of fatty acids. Adipose tIssue is an endocrine organ which secretes several factors, including adiponectin. Adiponectin improves insulin sensitivity in skeletal muscle and liver, through a stimulation of fatty acid oxidation and glucose utilization. Thiazolidinediones enhance adiponectin expression and synthesis through PPARgamma, although the precise mechanism remains controversial. AMP-activated protein kinase (AMPK) is the main adiponectin target. Adiponectin, clearly, is a major modulator of glucose and lipid metabolism in insulin-sensitive tIssue and/or regulator of insulin-sensitivity, in obese and/or glucose intolerant subjects, as well as in type 2 diabetes mellitus. Recent works and the links between insulin resistance, adipose tIssue, adiponectin and its PPARgamma-enhanced secretion are reviewed in this paper.

Adiponectin: stability in plasma over 36 hours and within-person variation over 1 year.

Adiponectin (Arcp30, AdipoQ, apM1, or GBP28), a novel 247-amino acid peptide, is secreted predominantly by adipocytes and accounts for ∼0.05% of total serum proteins (1)(2)(3)(4). It is induced early in adipocyte differentiation (1), consists of an N-terminal collagenous and a C-terminal globular domain, and shares homology to subunits of complement factor C1q (1)(3). Adiponectin expression is reduced in obesity and type 2 diabetes, and plasma concentrations of adiponectin are inversely related to body weight and insulin concentrations (5)(6)(7)(8). Treatment with adiponectin improves insulin sensitivity in mouse models of insulin resistance (9)(10), and in adiponectin knockout mice, adiponectin substitution can reverse diet-induced insulin resistance (11). Adiponectin is also inversely associated with other traditional cardiovascular risk factors, such as blood pressure, heart rate, total cholesterol, LDL-cholesterol, and triglycerides (12)(13). In addition, recent studies suggest that it may have antiatherogenic and antiinflammatory properties (14)(15)(16)(17)(18)(19). Adiponectin may therefore be an important blood biomarker to assess in large-scale epidemiologic studies of several chronic diseases. To gain a reliable risk estimate with a single blood measurement, the within-person variability over time should be small compared with the between-person variability (20). In addition, the stability of a valid biological marker should not be substantially affected by length of storage or temperature (21)(22)(23)(24)(25). Ideally, serum or plasma from whole blood should be separated immediately and stored in deep freeze. In large epidemiologic studies, however, blood specimens are often collected at different times and locations and transported on ice over several hours or days to central laboratories for processing and storage. The aims of the present study were to evaluate the stability of …