Abstract
ALMS1 is a protein initially associated with Alström syndrome. This is a rare human disorder characterized by metabolic dysfunction, hypertension, obesity and hyperinsulinemia. In addition, ALMS1 gene was linked to hypertension status in a multipoint linkage population analysis. However, the mechanisms by which ALMS1 contributes to the development of obesity, insulin resistance and other metabolic disturbances are unknown. To study the role of ALMS1 in blood pressure regulation and renal function we previously generated an ALMS1 knockout rat model, where we found these rats are hypertensive. In this study, we further characterized the ALMS1 knockout rat, and found that they exhibit most characteristics of metabolic syndrome including hypertension and higher body weight by 10-12 weeks of age. In contrast, obesity, hyperinsulinemia and vascular dysfunction manifested at around 14-16 weeks of age. Interestingly, ALMS1 KO rats developed hyperleptinemia prior to the development of obesity rapidly after weaning by 7 weeks of age, suggesting an early role for ALMS1 in the hormonal control of leptin. We also found that female ALMS1 KO rats develop severe metabolic syndrome with hypertension similar to their male counterparts, lacking any protection often associated with better cardiovascular outcomes. Therefore, ALMS1 is an essential gene for sex- and age-dependent metabolic function. The ALMS1 knockout rat provides an invaluable pre-clinical animal model that recapitulates most symptoms present in patients and allows the study of new drugs and mechanisms that cause metabolic syndrome.