Endocrine Abstracts

Inability to store excess lipids in the subcutaneous adipose tissue leads to ectopic lipid deposition in several sites including the liver, skeletal muscles, intra-abdominal and pericardial depots. This, in turn, has negative consequences for degree of insulin sensitivity and the dysmetabolic state associated with insulin resistance and type 2 diabetes.

Storage of fat in the adipose tissue can either lead to inappropriate cellular enlargement (hypertrophic obesity) or the recruitment of new adipose cells (hyperplastic obesity). The latter is more favourable from a metabolic point of view and is associated with the ‘obese but metabolically normal’ phenotype.

The reason for this difference in storing excess lipids is related to an ability or not to recruit and differentiate new adipose cells from precursor cells. We have in a series of papers shown that hypertrophic obesity is associated with insulin resistant adipose tissue with reduced expression of IRS1, GLUT4 and several other PPARγ-regulated genes and occurred around four times more frequently in individuals with a genetic predisposition for type 2 diabetes (first degree relatives, FDR) than in individuals lacking a genetic predisposition. In recent studies, we have found that FDR exhibit an obese metabolic phenotype with inappropriately enlarged adipose cells, reduced insulin sensitivity and a dysregulated adipose tissue even in the absence of obesity while this phenotype is not found in subjects with heredity for obesity/overweight. These findings provide a link between diabetes heredity and increased sensitivity to the environment and caloric excess. Furthermore, we have recently identified a novel mechanism whereby mesenchymal stem cells and other precursor cells become committed to the adipose lineage in response to BMP4 and subsequently can undergo differentiation.