Prevention of obesity-linked renal disease: age-dependent effects of dietary food restriction

BACKGROUND: Hyperphagic obese Zucker rats develop glomerular injury and die of renal disease, an outcome prevented by food restriction at an early age. We examined the effects of food restriction imposed at different ages on systemic, renal hemodynamic, and hormonal changes to gain insight into the mechanisms of obesity-linked glomerular injury. METHODS: At 6 weeks of age obese Zucker rats were either fed ad libitum or were restricted in food intake at various ages (6, 12, 26, or 50 weeks) to that consumed by lean Zucker rats (14 g/day). Every four weeks 24-hour urine collections, blood pressure, and venous blood samples were obtained until the end of study (60 weeks). RESULTS: Food restriction at 6 or 12 weeks of age prevented glomerular injury and hypertrophy and delayed the development of hypertension, hypercholesterolemia, and hyperinsulinemia. Food restriction at 26 weeks of age reduced proteinuria, while restriction at 50 weeks prevented further increases in proteinuria without altering pre-existing hypercholesterolemia, hypertension, or hyperinsulinemia. Hypertriglyceridemia and glomerular hyperfiltration in the obese animals were reversed at any age by food restriction. Plasma leptin levels were elevated in all obese groups. CONCLUSIONS: (1) Early food restriction provided the greatest metabolic and renal benefits; (2) glomerular injury correlated with hyperphagia-induced hyperfiltration and hypertriglyceridemia and both were prevented by food restriction; (3) hypercholesterolemia was due to an increase in LDL and/or VLDL cholesterol; and (4) leptin does not directly contribute to glomerular injury in the obese Zucker rat.