Obesity is defined as abnormal or excessive fat accumulation that may impair health, and increased knowledge about the enzymes controlling lipid metabolism is of great importance in order to combat this disease. Hormone-sensitive lipase (HSL) is a key enzyme in the mobilization of fatty acids from acylglycerols in adipocytes, but also plays important roles in other cell types.
The aim of this thesis has been to study the consequences of a targeted disruption of the HSL gene in mice, with a focus on the white adipose tissue (WAT).
The initial study demonstrated a mild insulin resistance in multiple tissues of the HSL null mice, which was almost fully compensated for by increased insulin secretion by the pancreatic beta-cells.
The HSL null mice were resistant to high-fat diet (HFD)-induced obesity, with severely reduced WAT. A proteomic analysis suggested a local inflammatory response in WAT of HSL null mice, supported by the findings of increased macrophage infiltration in this tissue. Increased energy expenditure and perturbed adipogenesis are possible explanations to the lean phenotype of HSL null mice. Acquirement of brown adipocyte features in white adipocytes was shown in HFD-fed HSL null mice demonstrated by increased UCP-1 expression and oxygen consumption in these cells. A high retinyl ester hydrolase activity of HSL was demonstrated which was almost absent in HSL null mice, suggested that retinoic acid could be a potential ligand normally supplied by HSL. Administration of retinoic acid to the diet partly restored the WAT mass and normalized the levels of several cofactors involved in the differentiation towards the white adipocyte lineage.
The collected data suggests a working model where HSL is responsible for the generation of a retinoid ligand that is crucial for adipocyte determination and differentiation and/or survival of mature adipocytes. Failure to supply this ligand, seen in the HSL null model, results in impaired adipogenesis, attainment of brown adipocyte characteristics in classical WAT depots and a local inflammation in WAT. Increased infiltration of macrophages triggers the release of proinflammatory mediators from WAT e.g. tumor necrosis factor alpha, causing systemic inflammation precipitating in insulin resistance.
Thus, in addition to its key role in energy homeostasis, HSL appears to play an important role by providing signals for transcriptional regulation.
- Holm Wallenberg, Cecilia, handledare
- Degerman, Eva, handledare
|Tilldelningsdatum||2008 maj 23|
|Status||Published - 2008|
Place: Segerfalksalen, BMC, Sölvegatan 17, Lund
Name: Kristiansen, Karsten
Affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
- Endokrinologi och diabetes
- Medicin och hälsovetenskap