Alms1 KO Rat: A New Model of Cardiometabolic Syndrome With Spontaneous Hypertension.

Abstract

UNLABELLED: Alström syndrome 1 (ALMS1) is a protein linked to Alström syndrome, a rare genetic disorder characterized by obesity, insulin resistance, hyperinsulinemia, and hypertension. Genetic studies have further associated Alms1 with hypertension in human populations. However, the precise mechanisms by which ALMS1 regulates metabolic and cardiovascular function remain unclear. AIM: In this study, we investigate metabolic and cardiovascular functions regulated by ALMS1. METHODS: To investigate this, we developed and characterized an Alms1 knockout (KO) rat model, which spontaneously develops metabolic syndrome and hypertension. RESULTS: Our findings reveal that Alms1 KO rats exhibit age-dependent metabolic dysfunction, with hypertension and increased body weight becoming evident by 10-12 weeks of age. Obesity, hyperinsulinemia, and vascular dysfunction emerge later, at 14-16 weeks, suggesting progressive metabolic deterioration. Notably, Alms1 KO rats develop hyperleptinemia as early as 7 weeks, prior to the onset of obesity, implicating ALMS1 in early leptin regulation and metabolic signaling. Moreover, female Alms1 KO rats develop severe metabolic syndrome with hypertension, like males, demonstrating a lack of the typical female cardiovascular protection. Echocardiographic analysis shows progressive cardiac dysfunction, including left ventricular (LV) dilation, increased wall thickness, and impaired contractility. Despite these structural changes, the LV mass/BW ratio remains unchanged, suggesting a shift toward maladaptive eccentric remodeling rather than hypertrophy. CONCLUSION: Collectively, these findings establish the Alms1 KO rat as a robust preclinical model of metabolic syndrome. This model closely mimics human disease and provides a powerful tool for studying the mechanisms of metabolic and cardiovascular dysfunction as well as for testing potential therapeutic interventions.