Abstract Body (Do not enter title and authors here): Background: Obesity-which develops from environmental and biological factors-is disproportionately more prevalent among individuals of African ancestry. Part of this difference may be due to DNA variants specific to African ancestry. Recent observational studies have reported an association between obesity and the common APOL1 G1 and G2 DNA variants, specific to individuals of sub-Saharan African ancestry. Compared to the G0 major allele, the G1 and G2 risk variants (RV) are known to increase the risk of kidney disease in African-ancestry patients and have been extensively studied in the renal context. However, no functional validation has established whether the APOL1 RV are also causal in obesity. The aim of this study is to address the hypothesis that APOL1 RV are causal in the pathogenesis of obesity independent of kidney disease.

Methods: Because APOL1 expression is primate-specific, we leveraged transgenic G0 and APOL1-RV mice (n = 58), which were fed standard chow or high-fat diet (HFD) for 16 weeks. The mice underwent measurements of body mass, body composition by Echo-MRI, and tail cuff BP. Blood, urine, kidneys, perigonadal adipose tissue (AT), and bone-marrow derived macrophages (BMDMs) were examined for cardiometabolic traits.

Results: Concordant with single-cell RNA-seq data of human AT (GSE176067) revealing APOL1 expression in multiple cell types, robust APOL1 protein expression was detected in AT of the APOL1 transgenic mice. Although no differences in body mass were seen among males, female APOL1-RV mice had higher body mass than G0 females in both the standard chow (p = 0.01) and HFD groups (p = 0.04). Both male and female mice on standard chow did not exhibit genotype-specific differences in body composition, but G0 female mice on HFD had significantly higher lean:fat mass ratio than female APOL1-RV mice (7.7 vs. 3.8, p = 0.04). In addition, female APOL1-RV mice on standard chow had significantly higher systolic BP than G0 females (129.5 vs. 107.6 mmHg, p = 0.04), while female APOL1-RV mice on HFD had more albuminuria than G0 females (43.4 vs. 22.7 mg/g, p = 0.01). Although qPCR assays of kidney and AT were unrevealing, APOL1-RV BMDMs modeling inflamed AT macrophages of obesity expressed significantly higher levels of Tnf than G0 when stimulated with interferon-γ.

Conclusion: This is the first study to report a causal link between APOL1 kidney disease variants and obesity, seen more prominently in female transgenic mice.