The metabolic syndrome : Studies on thrifty genes

Abstract: The metabolic syndrome consists of a cluster of atherogenic risk factors that include insulin resistance, glucose intolerance, hyperglycemia, dyslipidemia, obesity and a procoagulant state with impaired fibrinolysis. Genetic factors might predispose to the metabolic syndrome while the increasing prevalence of visceral and abdominal obesity linked to the shift to more sedentary lifestyles exacerbates the manifestation. The aim of this thesis was to explore molecular mechanisms underlying insulin resistance in different insulin-sensitive target tissues. We also studied whether the impact of polymorphisms in one potential candidate gene contributes to variation in cholesterol levels. Further, expression of several candidate genes for the insulin resistance syndrome was investigated during different acquired pathophysiologic conditions such as high-fat feeding, lipodystrophy and obesity. Skeletal muscle is an important insulin target-tissue and the most important site for the insulindependent glucose and lipid oxidation. We found increased expression of anti-diabetic targetgenes, PPARalpha and-delta in rat skeletal muscle, which correlated with early signs of metabolic syndrome such as increasing visceral fat depots and circulating FFA-levels. This effect declined during developing muscle insulin resistance but the induction was reactivated during exercise and simultaneously decreasing muscle lipid-content. Thus, PPARalpha and PPARdelta might mediate metabolic responses to altered energy balance in skeletal muscle and their dysfunction might be associated with increased muscle lipid accumulation and insulin resistance. The relative contribution of the two glucose transport proteins GLUT1 and GLUT4 was studied by using a novel photolabeling technique in primary cultures of human skeletal muscle. Insulin-stimulated glucose transport was mediated by GLUT4, as no effect on GLUT1 appearance at plasma membrane was noted. Insulin also two-fold increased GLUT4 mRNA and protein expression (p < 0.05). Regarding polymorphisms in the PPARdelta gene, of four polymorphisms analysed, only the +294T/C polymorphism showed a significant association with LDL cholesterol. Homozygous carriers of the rare C-allele had a higher plasma LDL-cholesterol concentration than carriers of the common T-allele. Transfection studies showed increased promoter activity associated with the Callele. An interaction with the PPARalpha L162V polymorphism was also detected for several lipid parameters. Fat may accumulate in the liver and skeletal muscle in obesity but also in the absence of subcutaneous fat in lipodystrophic conditions in humans and animals. The subcutaneous adipose tissue expression of multiple genes was studied in HAART-treated HIV-infected patients. The expression of PPARgamma and SREBP-1c, PGC-1, LPL, ACS and GLUT4 were decreased, whereas the expression of CD45 and IL6 were increased in lipodystrophic compared with non-lipodystrophic HIV-infected patients. Decreased adipocyte maturation, mitochondrial pathogenesis and increased inflammation in subcutaneous adipose tissue might contribute to the insulin resistance seen in these patients. The mRNA expression of the oxo-reductase 11 beta-HSD-1, generating active cortisol from its inactive form, was also decreased in subcutaneous adipose tissue in patients with HAART-associated lipodystrophy and correlated with features of insulin resistance. Also in acquired obesity in healthy monozygotic twin pairs with intra-pair differences in BMI, the 11beta-HSD-1 mRNA and protein expression in subcutaneous adipose tissue were increased and associated with accumulation of intra-abdominal fat and features of insulin resistance. This thesis provides further evidence that lipid accumulation may contribute to alterations in adipose tissue and muscle gene expression and thereby to the pathogenesis of insulin resistance. Several of the genes presented in this thesis may become attractive drug-targets against metabolic syndrome and type2 diabetes.