In obese male and female C57BL/6 mice, a 70% reduction in calorie intake for 1 to 3 days rapidly restores whole-body insulin sensitivity, as measured by normalized fasting glucose, insulin, HOMA-IR, and insulin tolerance test results, despite minimal weight loss (2–6%), indicating that calorie restriction alone—without substantial fat loss—can reverse insulin resistance.

When food intake drops sharply, the liver stops making new fat, burns more fat for energy, and produces ketones; at the same time, fat tissue releases less fat into the blood. This lowers fat levels in the liver and muscle, which removes a block on insulin's ability to signal cells to take up sugar. As a result, blood sugar and insulin levels return to normal quickly, even before much weight is lost.