High-calorie diet results in reversible obesity-related glomerulopathy in adult zebrafish regardless of dietary fat

Obesity is a risk factor for the development of kidney disease. The role of diet in this association remains undetermined due to practical limitations in studying human nutrition. In particular, the relative importance of calorie excess versus dietary macronutrient content is poorly understood. For example, it is unknown if calorie restriction modulates obesity-related kidney pathology. To study the effects of diet-induced obesity in a novel animal model, the study treated zebrafish for 8 wk with diets varied in both calorie and fat content. Kidneys were evaluated by light and electron microscopy. The study evaluated the glomerular filtration barrier function using a dextran permeability assay. The study assessed the effect of diet on podocyte sensitivity to injury using an inducible podocyte injury model and then tested the effect of calorie restriction on the defects caused by diet-induced obesity. Fish fed a high-calorie diet developed glomerulomegaly (mean: 1,211 vs. 1,010 µm2 in controls, P = 0.007), lower podocyte density, foot process effacement, glomerular basement membrane thickening, tubular enlargement (mean: 1,038 vs. 717 µm2 in controls, P < 0.0001), and ectopic lipid deposition. Glomerular filtration barrier dysfunction and increased susceptibility to podocyte injury were observed with high-calorie feeding regardless of dietary fat content. These pathological changes resolved with 4 wk of calorie restriction. The study findings suggest that calorie excess rather than dietary fat drives obesity-related kidney dysfunction and that inadequate podocyte proliferation in response to glomerular enlargement may cause podocyte dysfunction. We also demonstrate the value of zebrafish as a novel model for studying diet in obesity-related kidney disease.