APOL1 G1 and G2 risk alleles modulate severity of diet-induced obesity in a transgenic mouse model

<i>APOL1</i> G1 and G2 risk alleles are associated with an increased risk of chronic kidney disease. However, a causal relationship between these alleles and cardiometabolic traits has not been experimentally validated. To address this gap, we placed transgenic <i>APOL1</i> G0, G1, and G2 FVB/NJ mice on a high-fat diet and analyzed them for weight gain as well as obesity-related cardiometabolic phenotypes. To test whether <i>APOL1</i> risk alleles modulate the inflammatory basis of obesity, we also exposed bone marrow derived macrophages from these mice to pro-inflammatory, pro-hypertensive, and dyslipidemic conditions. <i>APOL1</i> high-risk allele female mice gained fat mass more readily than their low-risk female counterparts, while <i>APOL1</i> high-risk male mice gained fat mass less readily than low-risk males. A parallel sex difference was seen in expression of higher levels of <i>Abca1</i>, <i>Hmox1</i>, and <i>Srebf1</i> in lipid-loaded female bone-marrow derived macrophages expressing G1 and G2 APOL1, along with minor differences in cardiac function. However, this finding occurred independently of hypertension and insulin resistance, and with only minor albuminuria. Thus, our results highlight the importance of sex as a biological variable in future <i>APOL1</i> experiments.