Adiponectin

Adiponectin (also referred to as Acrp30, apM1) is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid catabolism. Adiponectin is exclusively secreted from adipose tissue into the bloodstream and is very abundant in plasma relative to many hormones. Levels of the hormone are inversely correlated with body mass index (BMI). The hormone plays a role in metabolic disorders such as type 2 diabetes, obesity and atherosclerosis.

Contents

1 History of Adiponectin 2 Adiponectin Structure and Function 3 Metabolic Effects 4 Pharmaceutical Therapy 5 Sources

History of Adiponectin

Adiponectin was first characterised in mice as a transcript overexpressed in preadipocytes (precursors of fat cells) differentiating into adipocytes. The human homologue was identified as the most abundant transcript in adipose tissue. Contrary to expectations, despite being produced in adipose tissue, adiponectin was found to be decreased in obesity. This downregulation has not been fully explained. The gene was localised to chromosome 3p27, a region highlighted as affecting genetic susceptibility to type 2 diabetes and obesity. Supplementation by differing forms of adiponectin were able to improve insulin control, blood glucose and triglyceride levels in mice models.

The gene was investigated for variants that predispose to type 2 diabetes. Several single nucleotide polymorphisms in the coding region and surrounding sequence were identified from several different populations, with varying prevalences, degrees of association and strength of effect on type 2 diabetes.

Adiponectin Structure and Function

Most adipokines are secreted at higher than normal levels in obesity and the metabolic syndrome, but adiponectin is an exception as its secretion is decreased in these states. Adiponectin promotes insulin sensitivity and has anti-inflammatory effects. Of the various circulating isoforms of adiponectin, high molecular weight adiponectin which is active in the liver, is important for insulin sensitivity and is induced by thiazolidinediones.

Adiponectin is a 244 amino acid (aa) long polypeptide. There are four distinct regions of adiponectin. The first is a short signal squence that targets the hormone for secretion outside the cell, next is a short region that varies between species. Thirdly is a 65 aa region with similarity to collagenous proteins and lastly is a globular domain. Overall this gene shows similarity to the complement 1Q factors. However, when the 3-dimensional structure of the globular region was determined a striking similarity to TNFα was observed, despite unrelated protein sequences.

Adiponectin is secreted into the bloodsteam where it accounts for approximately 0.01% of all plasma protein at around 5-10 μg/mL. Plasma concentrations reveal a sexual dimorphism with females having increased levels compared to males. Levels of adiponectin are reduced in diabetics compared to non-diabetics. Weight reduction significantly increases circulating levels.

Adiponectin auomatically self-associates into larger structures. Initially, three adiponectin molecules bind together to form a homotrimer. The trimers continue to self-associate and form hexamers or dodecamers. Like the plasma concentration, the relative levels of the higher-order structures are sexually dimorphic, where females have increased proportions of the high molecular weight forms. Questions remain about what the physiologically active forms of the protein are or how they carry out their action.

Adiponectin binds to a number of receptors. So far, two receptors have been identified, with homology to G protein-coupled receptors. These have distinct tissue specificities within the body and have different affinities to the various forms of adiponectin. The receptors affect the downstream target AMP kinase, an important cellular metabolic rate control point. Expression of the receptors are correlated with insulin levels as well as reduced in mouse models of diabetes, particularly in skeletal muscle and adipose tissue.

Adiponectin exerts some of its weight reduction effects via the brain. This is similar to the action of leptin, but the two hormones perform complementary actions, and can have additive effects.

Metabolic Effects

Adiponectin affects:

• glucose flux
  • gluconeogenesis
  • glucose uptake
• lipid catabolism
  • β-oxidation
  • triglyceride clearance
• endothelial dysfunction (important facet of atherosclerotic formation)
• insulin resistance/sensitivity
• weight gain

Pharmaceutical Therapy

Owing to the fact that adiponectin is a novel hormone, no therapy has yet been developed with adiponectin and it may be some years before clinical trials commence. One obvious pharmaceutical treatment would be the administration of adiponectin as mice models have shown positive effects when treated with adiponectin. Problems to be overcome prior to human administration include establishing what the biologically active molecule is, what role post-translational modifications have upon the function and associated difficulties in generating biologically active molecules on a large scale. However, this remains a promising area of research for clinical therapy in diseases such as obesity and type 2 diabetes.

Sources

• Prof. John Prins Adiponectin CMEonDiabetes (http://www.cmeondiabetes.com/pub/adiponectin.php)

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