In female C57BL/6J mice with a history of more than 30 days of intermittent high-caloric diet exposure, re-exposure to the same diet causes a rapid loss of leptin sensitivity within 3 days, compared to mice without prior dietary exposure, demonstrating that prior dietary history accelerates the development of leptin resistance.

When a mouse eats a high-calorie diet, its fat tissue grows and releases more leptin. Over time, the brain stops responding to leptin because the receptors in key appetite-control neurons become less sensitive. Once this happens, the brain no longer gets the signal to stop eating, so the mouse keeps eating and gains weight. If the mouse has eaten this way before, the brain's leptin receptors stay less sensitive even after the diet stops, so when the high-calorie diet returns, the brain stops responding to leptin almost immediately.