ALMS1 deletion in rats causes hyperleptinemia, progressive obesity, and renal damage
Authors: Monu Sumit , King‐Medina Keyona , Jayakumar Ankita , Ortiz Pablo 
Published: June 2021

Genome‐wide association studies identified single nucleotide polymorphisms in the Alström syndrome 1 (ALMS1) gene linked to chronic kidney disease (CKD). ALMS1 has also been associated to obesity and insulin resistance. Inactivating mutations in the ALMS1 gene cause Alström syndrome in humans, characterized by early onset obesity, insulin resistance and renal dysfunction. We recently found that ALMS1 is expressed in renal tubules and its deletion from Dahl salt sensitive rats induced hypertension, in part by enhancing renal NaCl reabsorption. We also observed that ALMS1 KO rats developed progressive obesity as they aged which was evident by 11 weeks of age. In mice, mutations in ALMS1 cause obesity and hyperleptinemia, yet it is not known whether higher leptin levels are secondary to obesity. The effect of deleting ALMS1 in glomerular filtration is not known. We hypothesized that ALMS1 deletion causes hyperleptinemia before an increase in body weight (BW) and also induces decreased renal function in rats. To test this we studied homozygous ALMS1 knockout (KO) and littermates wild‐type Dahl SS (WT) rats at different time points. We found age‐dependent effects. ALMS1 KO rats developed a progressive increase in BW. At 7 weeks BW was not different between strains but was significantly higher by 11 weeks (ALMS1: 377±18 vs. WT: 319±18 g, p<0.05) or 16 weeks (ALMS1: 442±21 vs. WT: 366±22 g, p<0.05). We then measured plasma leptin prior to the development of obesity (7 week old) and at 16 weeks. Interestingly leptin was already higher at 6–7 weeks (ALMS1: 3530±300 vs. WT: 172±16 pg/ml, p<0.05) and was higher at 18 weeks of age (ALMS1: 39517 ± 3843 vs. WT: 1954 ± 171 pg/ml, p<0.05). We also found ALMS1 rats were hyperphagic (ALMS1: 19±1 vs. WT: 27±2 g/day, p<0.05). Since the ALMS1 gene is associated to lower renal function in humans, we measured GFR in conscious rats, calculated from inulin clearance. We found that GFR was not different by 10 weeks of age (ALMS1: 2.8±0.1 vs. WT: 3.1±0.2 ml/min, p=0.28) but was severely reduced by 50% at 18 weeks of age (ALMS1: 2.3±0.4 vs. WT: 5.0±1.1 ml/min, p<0.05). This difference was maximized after correction by BW, thus we elected to show net filtration rates. To further asses renal damage we measured urinary albumin/creatinine ratio. Urinary albumin/creatinine ratio was similar in 7 week‐old rats (ALMS1: 0.85±0.07 vs. WT: 0.98±0.12, p=0.12) but was higher in 15 week‐old ALMS1 KO (ALMS1: 28.74±6.28 vs. WT: 3.20±1.38, p=0.07) indicating progressive renal damage. We concluded that deletion of ALMS1 caused primary hyperleptinemia, progressive obesity and gradual renal dysfunction. This is the first study indicating a role of ALMS1 in leptin metabolism prior to the development of obesity. Our findings establish a link between the ALMS1, obesity and progressive renal dysfunction. Our data point to ALMS1 as a potentially novel gene involved in leptin biology/function and renal disease.

Support or Funding Information

Funding: RO1 DK105818A1, Henry Ford Fund.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.