ABSTRACT

This PhD dissertation is based on investigations performed during my employment as a research fellow at the Department of Endocrinology and Metabolism, Aarhus Amtssygehus, Aarhus University Hospital from April 2001 to December 2003. The dissertation covers a description of the adipocyte-specific protein adiponectin primarily with regard to its regulation and association to insulin sensitivity. The investigations performed include clinical studies as well as in vitro studies on human adipose tissue. The dissertation consists of a review based on four original publications.

Investigations on fat depot differences in human adiponectin mRNA showed that visceral adipose tissue displayed reduced adiponectin gene expression compared to subcutaneous abdominal adipose tissue. This fat depot difference in adiponectin expression might play a role for the increased morbidity associated with the accumulation of especially visceral adipose tissue.

We found that the insulin sensitizer, AICAR, is stimulating adiponectin gene expression in vitro. This indicates that as for glitazones, the molecular mechanism of improved insulin sensitivity during AICAR treatment might involve adiponectin.

In a group of first-degree relatives (FDR) to type 2 diabetic patients adiponectin mRNA levels were found to be lower than in a group of age- and BMI-matched control subjects. Thus, it appears that the adiponectin level is altered in relation to the development of insulin resistance, and that adiponectin might play a role in the development of type 2 diabetes.

We were also able to demonstrate that plasma adiponectin and adiponectin mRNA levels are substantially reduced in patients with HIV-associated lipodystrophy syndrome (HALS) compared to HIV-positive patients without HALS. This syndrome is characterized by fat redistribution and by insulin resistance. Plasma adiponectin was found to be positively associated with insulin sensitivity and with the per cent of fat on the limbs. These findings support to the hypothesis that reduced levels of adiponectin are involved in the development of insulin resistance.

We found that the cytokine TNF- α strongly suppresses the gene expression of adiponectin in vitro. Moreover, plasma adiponectin levels were negatively associated with the level of TNF- α mRNA in adipose tissue. These findings are in line with the results of other studies, which have pointed to a mutual negative regulation of TNF- α and adiponectin. Furthermore, TNF- α is suggested to be an important adipocytokine involved in suppressing adiponectin levels when fat mass is increased or redistributed.

In conclusion, it is demonstrated that adiponectin is an adipose tissue derived hormone, which might play a key role in relation to the development of insulin resistance.