Effects of timing of food intake and fat/carbohydrate ratio on insulin sensitivity and preconditioning against renal ischemia reperfusion injury by calorie restriction

BACKGROUND: Dietary restriction (DR) improves lifespan, metabolic fitness and resilience in many organisms, but the role of dietary macronutrient composition and timing of food intake in specific benefits remains unclear. OBJECTIVE: We sought to compare the effects of two isocaloric DR regimes differing in the timing of food intake - every other day (EOD) fasting/feeding vs. daily calorie restriction (CR) – at two different fat/carbohydrate ratios on two well-established DR benefits, improved glucose homeostasis and protection from renal ischemia reperfusion injury in mice. We hypothesized that both EOD fasting and isocaloric CR would result in similar improvements in glucose homeostasis and stress resistance independent of macronutrient composition. METHODS: Six groups of mice were fed either semi-purified low-fat diet (LFD, 10% calories from fat) or high-fat diet (HFD, 60% calories from fat) and randomized into one of three dietary regimens: 1) ad libitum (AL), 2) EOD feeding/fasting, or 3) pair-fed daily to the average daily EOD intake within LFD or HFD feeding group resulting in daily CR. After 6 weeks, the following assessments were made: fasting blood glucose, glucose and insulin tolerance, and resistance to bilateral renal ischemia reperfusion injury using serum urea as a marker of renal function. Within the EOD group, the effects of prior day feeding (EOD(fed) vs. EOD(fast)) were also assessed. RESULTS: EOD mice ate ∼20–25% less food over time than AL mice on the corresponding LFD or HFD. EOD and CR mice displayed changes in body weight, fasting blood glucose levels and glucose tolerance commensurate with total calorie intake. No significant differences were observed in circulating IGF-1 levels. Insulin sensitivity improved independent of fat/carbohydrate ratio on daily CR and EOD(fast) regimens, but not EOD(fed). HFD increased susceptibility to renal ischemia reperfusion in AL mice, while CR and EOD regimens gave significant protection independent of dietary fat content or fed or fasted day in the EOD group. CONCLUSIONS: Reduced food intake protects mice against renal ischemia reperfusion injury within 6 weeks independent of timing of food intake (CR, EOD(fast), EOD(fed)) or fat content of diet (10% vs. 60%). Neither circulating IGF-1 levels (unchanged) nor whole-body insulin sensitivity (improved upon daily CR and EOD(fast) but not EOD(fed)) correlated with protection, so are unlikely to be involved mechanistically.