Obesity and lipotoxicity

Portrait of Cecilia Holm
Cecilia Holm

Principal Investigator

Cecilia Holm, Lund University

Research area description

Free fatty acids, derived mainly from the large triglyceride stores in adipose tissue, are the quantitatively most important fuel in mammals. Fatty acids also constitute signaling molecules in a variety of cell types, e.g. a lipid−derived signal appears to be necessary for stimulus−secretion coupling in pancreatic beta−cells and fatty acid derivatives are ligands for a group of nuclear receptors, i.e. the peroxisome−proliferator activated receptors (PPARs). In agreement with this dual role of fatty acids, most cell types contain small triglyceride stores, from which fatty acids can be mobilized through the action hormone−sensitive lipase (HSL) and possibly other lipases. Lipid abnormalities may be the primary pathogenetic factor in the development of insulin resistance and insulin secretion defects, the two hallmarks of type 2 diabetes, with excessive storage of triglycerides in non−adipose cells as the common precipitating event.

The project can be divided into four major parts. The first part involves studies into the structure−function relationships and 3D structure of HSL, the rate−limiting enzyme in triglyceride hydrolysis. In the second part mechanisms of catecholamine−induced lipolysis as well as novel signaling pathways involved in lipolysis regulation are studied. The third part involves the generation and characterization of cell− and animal models with over− and underexpression, respectively, of HSL and other key components in lipolysis regulation to address the role of these for insulin secretion/beta−cell function, skeletal muscle and liver function, adipogenesis and spermatogenesis. The fourth part is a recently initiated line of research, which involves exploiting functional foods with beneficial effects in relation to insulin resistance and type 2 diabetes.

The project increases the understanding of the mechanisms underlying development of lipid metabolism disorders, in particular diabetes and obesity, and may provide new concepts for prevention/intervention in these diseases. The studies on spermatogenesis may reveal novel mechanisms behind male sterility.