Regulatory enzymes of mitochondrial B-oxidation as targets for treatment of the metabolic syndrome

The incidence of insulin resistance and obesity is rising to alarming numbers in the developing world. This is mainly attributable to the intake of excessive amounts of calories combined with a lack of exercise. Prevention and/or treatment of obesity and insulin resistance is crucial, not only to reduce the costs of our daily health care but also, even more importantly, to improve the quality of life of these patients and of their children. It is obvious that behavioral aspects should also not be underestimated in this respect but these have not been addressed in this thesis.
Several animal models to evaluate the relationship between obesity, food intake and insulin resistance were developed over the past years, including the ob/ob and the db/db mouse (leptin-defi cient and leptin receptor-defi cient, respectively) but also models of diet-induced insulin resistance such as a high saturated fat diet or a high carbohydrate diet. Th e rationale for using the high fat diet and the consequences for hepatic and peripheral insulin resistance in mice assessed by novel techniques is described in chapter 2.
Targets like acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase (CPT) have been considered to be of interest for treatment of components of the metabolic syndrome for quite some years. However, so far clinical applications have not been developed.
In chapter 3 and 4 we assessed the role of ACC in the development of insulin resistance in an animal model of diet-induced insulin resistance. Both CP-640186 (chapter 3) and Soraphen (chapter 4), general ACC inhibitors of different structure, were found to improve peripheral insulin resistance and metabolic clearance of glucose after 6 weeks of treatment. In view of the presumed role of ACC, in the synthesis of fat, de novo lipogenesis was assessed by stable isotope procedures in mice treated with Soraphen: results showed that de novo lipogenesis in these mice was actually inhibited by Soraphen (via ACC1). Ketone body levels were dramatically increased in Soraphen-treated mice indicating inhibition of β-oxidation and ketogenesis via ACC2 as well. Total body fat content in HF-fed mice treated with Soraphen was reduced to levels of chow-fed controls aft er 6 weeks of treatment. To evaluate the effects of insulin-dependent diabetes (type I) in mice, alloxan (glucose analogues) was applied to induce damage to the pancreatic β-cells via DNA alkylation and ROS production. Alloxan-induced diabetes is accompanied by high plasma levels of ketone bodies. We used the alloxan model in mice whether hyperglycemia and hyperketonemia could be reversed by CPT2 inhibition (chapter 5). CPT2 inhibition by aminocarnitine showed also lowered plasma ketone body levels. However, in the diabetic mice model used, a glucose-lowering effect was not observed. Chapter 6 describes the results of our experiments with the CPT1a+/- heterozygous mice and their wild-type littermates. During these experiments it became clear that the heterozygous mice did not have a clear phenotype as was expected from their CPT1a heterozygosity. Also stressing the system with a high fat diet and fasting periods of various lengths did not reveal a clear phenotype for these animals.
Chapter 7 is a general discussion and describes future perspectives with respect with the utilization of the use of ACC inhibitors and inhibitors of fatty acid oxidation, respectively,
in clinical practice.

	Titel en inhoudsopgave
	Hoofdstuk 1
	Hoofdstuk 2
	Hoofdstuk 3
	Hoofdstuk 4
	Hoofdstuk 5
	Hoofdstuk 6
	Hoofdstuk 7
	Engelse samenvatting
	Samenvatting
	Dankwoord
	Curriculum vitae
	Volledige dissertatie

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