Adiponectin Multimeric Complexes and the Metabolic Syndrome Trait Cluster

Abstract

Adiponectin circulates in human plasma mainly as a 180-kDa low molecular weight (LMW) hexamer and a high molecular weight (HMW) multimer of approximately 360 kDa. We comprehensively examined the relationships between circulating levels of total adiponectin, adiponectin multimers, and the relative distribution (i.e., ratio) of multimeric forms with key features of the metabolic syndrome. Total adiponectin (r = 0.45), HMW (r = 0.47), LMW (r = 0.31), and HMW-to-total adiponectin ratio (r = 0.29) were significantly correlated with insulin-stimulated glucose disposal rate. Similarly, total (r = -0.30), HMW (r = -0.38), and HMW-to-total adiponectin ratio (r = -0.34) were correlated with central fat distribution but not with total fat mass or BMI. Regarding energy metabolism, although there were no effects on resting metabolic rate, total (r = 0.41) and HMW (r = 0.44) were associated with increasing rates of fat oxidation. HMW-to-total adiponectin ratio increased as a function of total adiponectin, and it was HMW quantity (not total or HMW-to-total adiponectin ratio or LMW) that was primarily responsible for all of these relationships. Impact on nuclear magnetic resonance lipoprotein subclasses was assessed. HMW and total adiponectin were correlated with decreases in large VLDL (r = -0.44 and -0.41); decreases in small LDL (r = -0.41 and -0.36) and increases in large LDL (r = 0.36 and 0.30) particle concentrations accompanied by increased LDL particle size (r = 0.47 and 0.39); and increases in large HDL (r = 0.45 and 0.37) and HDL particle size (r = 0.53 and 0.47). Most of these correlations persisted after adjustment for metabolic covariables. In conclusion, first, serum adiponectin is associated with increased insulin sensitivity, reduced abdominal fat, and high basal lipid oxidation; however, it is HMW quantity, not total or HMW-to-total adiponectin ratio, that is primarily responsible for these relationships. Second, reduced quantities of HMW independently recapitulate the lipoprotein subclass profile associated with insulin resistance after correcting for glucose disposal rate and BMI. Finally, HMW adiponectin is an important factor in explaining the metabolic syndrome.

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

“…Currently available clinical data support the hypothesis that HMW adiponectin is the most physiologically relevant form [39,40]. Only HMW adiponectin shows the same strong associations with parameters of insulin sensitivity as total adiponectin [39]. This is thought to indicate that most of the reported relationships are explained largely by HMW adiponectin.…”

Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum

“…A number of recent papers highlight the relevance of the HMW form for the peripheral functions of adiponectin [19,[25][26][27][28][29][30]. In light of the very large size of this complex (>500 kDa), it is not surprising that the HMW form is very inefficiently translocated across the BBB and not found in any measurable quantities in CSF.…”

Adiponectin in human pregnancy: implications for regulation of glucose and lipid metabolism

“…In obesity and diabetes, low plasma adiponectin concentrations are related to the degree of hyperinsulinaemia and the severity of insulin resistance [11][12][13]. Adiponectin and HMW adiponectin levels are negatively correlated with serum triglycerides and positively with HDL particles [14,15]. The mechanisms mediating adiponectin-lipid interactions remain unknown but it is suggested that HMW adiponectin plays a prominent role in the metabolic changes [15,16].…”