Abstract 004: Caloric Restriction Prevents the Increase in Body Weight but not Hypertension in ALMS1 (Alström syndrome 1) Knockout Rat

Abstract

In humans, mutations in the ALMS1 gene cause obesity, diabetes and kidney disease. The mechanisms causing these alterations are unclear. We generated ALMS1 knockout (KO) rats in the Dahl salt-sensitive (SS) genetic background and found that ALMS1 KO are hypertensive (telemetry or tail-cuff) and develop obesity and insulin resistance. We found that ALMS1 is expressed in the kidney where it regulates thick ascending limb NaCl reabsorption. However, it is unclear whether the hypertension in the ALMS1KO occurs prior to or after the development of obesity and insulin resistance. W e hypothesize that hypertension in the ALMS1 KO rats is primarily caused by a renal defect and not secondary to obesity . We studied the effect of control feeding or caloric restriction (CR) in body weight (BW), blood glucose, glucose tolerance test (GTT) and systolic blood pressure (SBP) by tail-cuff in ALMS1 KO and wild-type Dahl SS (WT) littermate rats. A control group of ALMS1 KO and WT rats received 30 g/day regular chow (0.4% Na). A caloric restricted (CR) group received 20% less food (24 g/day) of a custom diet with 20% higher Na, vitamins and minerals, thereby matching Na intake. At 7 weeks of age, ALMS1 KO rats had similar BW (KO: 209±13 g vs. WT: 182±15 g), baseline glucose (KO: 88±3 vs. WT: 75±7 mg/dL, N.S.) and GTT. Importantly, SBP was higher in ALMS1 KO rats (KO: 156±5 vs. WT: 143+3 mmHg, p<0.05). By 11 weeks of age, KO rats had a greater BW (KO: 393±9 vs. WT:344±5 g, p<0.05) and higher SBP (KO:186±7 vs. WT:162±7 mmHg, p<0.05). Baseline glucose was higher (KO:101±5 vs. WT:65±4 mg/dL, p<.001) and peak levels of glucose during GTT were higher (KO:464±21 vs. WT:341±33, mg/dL, p<.0.05) in KO rats. Caloric restriction for 4 weeks prevented the difference in BW between KO and WT (KO:359±8 vs. WT:340±3 g, N.S.) and lowered BW compared to control feeding (KO control: 393±9 vs. KO- CR: 359±8 g, p<0.05). However SBP remained higher than in WT (KO:178±9 vs. WT:151±3 mmHg, p<0.05) and was not different from KO fed control diet. GTT was also not different between KO control and KO-CR. We conclude that the hypertension in rats with ALMS1 deficiency occurs prior to obesity and metabolic syndrome, and that CR prevents the increase in BW but does not prevent hypertension or improve insulin resistance in this rat model.