Endocrine Abstracts

Introduction: Metabolic syndrome (MetS), the combination of obesity, glucose metabolism impairment, dyslipidemia and high blood pressure, is becoming a worldwide burden of morbidity and mortality. Both genetic and enviromental factors are involved in its pathogenesis, with heritability of each component of MetS 25–80%.

Aim: We aim to contribute to dissection of the genetic architecture of MetS using PD (polydactylous) rats, which present a unique mix of diet-sensitive MetS with severe hypertriglyceridemia, obesity and insulin resistance but normal blood pressure. In comparison, SHR (spontaneously hypertensive rat) has milder dyslipidemia and insulin resistance combined with hypertension. BN (Brown Norway) represents a strain resistant to MetS development.

Materials and methods: 6 months old male rats of inbred strains PD, SHR and BN were fed high-fat diet (HFD, short to long-chain fatty acids (FAs)) for 4 weeks. Morphometric and metabolic parameters were measured and liver transcriptome was determined.

Results: The development of MetS was most striking in PD. Weight gain and adiposity increase was significantly higher in PD compared to both BN and SHR. PD animals also showed hyperinsulinemia and hypertriglyceridemia and impaired glucose tolerance after HFD. Analysis of liver transcriptome showed 941, 875 and 348 deregulated genes comparing PD vs BN, BN vs SHR and PD vs SHR, respectively. In PD, we found lack of Acsm3 transcript and protein product – mitochondrial enzyme involved in activation of medium chain FAs for beta oxidation. Mitochondrial respiration rate for octanoate in liver homogenates revealed significantly lower oxygen consumption in PD compared to SHR rats. In addition, Acsm3 absence in PD rats was associated with about 100 times increase in hepatic stearoyl-CoA desaturase 1 (Scd1) gene expression.

Conclusion: Most striking finding in liver transcriptome was absence of Acsm3 expression in PD rats. Since the gene is coding for an enzyme activating medium chain FAs, we suppose it could play a role in development of MetS in PD. This hypothesis is supported by the observed reduced mitochondrial octanoate respiration in liver homogenates and increased Scd1 expression. We found no causal mutation in Acsm3coding sequence, introns and core promoter, which could explain the absence of mRNA. To elucidate role of Acsm3in MetS pathogenesis, a transgenic rescue of Acsm3 in PD is underway.