4.3 Adiponectin
The Study of Obesity: What to Measure
Our understanding of adipose tissue has matured in recent years as a result of scientific breakthroughs in the obesity research field. What was once considered a passive, lipid storage tissue is now understood to be a very active endocrine tissue.
Adiponectin is an adipocyte-secreted hormone, consisting of 244 amino acids with a molecular weight of approximately 30 kDa. It is one of the most abundant proteins in human blood, with a concentration of 5-30 µg/ml, which accounts for approximately 0.01% of total plasma protein (1). The protein consists of four domains: one globular C-terminus, one collagen-like N-terminus, one signalling peptide domain and one hypervariable domain. The globular domain has significant sequence and structural similarities to the complement factor C1q. The globular domain also has structural similarities to TNF-α.
Adiponectin has been suggested to exist in different forms in circulation: monomers, isolated globular form (the globular domain), trimers, hexamers and larger oligomers. Studies have suggested that adiponectin may not be present in circulation as monomers or globular forms, but rather as multimeric structures. (2,3) Monomers are believed to associate, forming a trimer through the globular domain. Trimers are associated with larger oligomers through the collagen-like domain.
Lara-Castro and colleagues found adiponectin to be present in human serum mainly as hexamers and HMW (high molecular weight) multimers. Furthermore, they demonstrated that total serum adiponectin is significantly decreased in insulin resistant and type 2 diabetic subjects compared to insulin sensitive subjects and that this decrease is attributed to HMW adiponectin rather than LMW (low molecular weight) adiponectin. (4) Blüher et al. showed a correlation between total serum adiponectin and insulin sensitivity and the ability of total serum adiponectin levels to predict insulin resistance and impaired glucose tolerance (5).
Adiponectin concentration is inversely associated with type 2 diabetes, coronary artery disease and obesity, all components of the metabolic syndrome. It has been shown that adiponectin can lower blood glucose and free fatty acids (6), and possesses anti-inflammatory and anti-apoptotic properties (7).
The strong connection between adiponectin and glucose control was highlighted by collaborative work organized by the Metabolic Disorders Steering Committee of the (FNIH) Biomarkers Consortium. Clinical trial data from four large pharmaceutical companies were pooled and examined by independent statisticians. They found a very robust association between adiponectin levels and changes in HbA1c, supporting the use of adiponectin as a predictive biomarker of glycemic efficacy. (8)
While there has been some debate regarding the appropriate form of adiponectin to measure (total vs. HMW), it is interesting to note that the utility of adiponectin in predicting glycemic control was demonstrated using assays that measure “different circulating forms of adiponectin” (i.e., a HMW assay was not needed to establish the relationship between adiponectin levels and blood glucose regulation over time).
References
- Arita et al. (1999) Biochem Biophys Res Commun 257:79-83
- Halperin et al. (2005) Diabetologia 48:2147-2154
- Bodles et al. (2006) J Physiolo Endocrinol Metab 291:1100-1105
- Lara-Castro et al. (2006) Diabetes 55:249-259
- Blüher et al. (2007) Diabetes Care 30:280-285
- Fruebis et al. (2000) PNAS 98:2005-2010
- Kadowaki and Yamauchi (2005) Endocr Rev 26:439-451
- Wagner et al. (2009) Clin Pharmacol Ther 86:619-625
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