To endure prolonged fasting, animals undergo important acute physiological adjustments. However, whether severe fasting also leads to long-term metabolic adaptations is largely unknown. Forty-eight-hour fasting caused a pronounced weight loss in adult C57BL/6 male mice. Seven days of refeeding increased body adiposity to levels above baseline, whereas fasting-induced reductions in lean body mass and energy expenditure were not fully recovered. Respiratory exchange ratio and locomotor activity also remained altered. A fasting/refeeding cycle led to persistent suppression of Pomc mRNA levels and significant changes in the expression of histone deacetylases and DNA methyltransferases in the hypothalamus. Additionally, histone acetylation in the ventromedial nucleus of the hypothalamus was reduced by prolonged fasting and remained suppressed after refeeding. Mice subjected to 48-h fasting 30 days earlier exhibited higher body weight and fat mass compared to aged-matched animals that were never food-deprived. Furthermore, a previous fasting experience altered the changes in body weight, lean mass, energy expenditure and locomotor activity induced by a second cycle of fasting and refeeding. Notably, when acutely exposed to high-palatable/high-fat diet, mice that went through cumulative fasting episodes presented higher calorie intake and reduced energy expenditure and fat oxidation, compared to mice that had never been subjected to fasting. When chronically exposed to high-fat diet, mice that experienced cumulative fasting episodes showed higher gain of body and fat mass and reduced energy expenditure and calorie intake. In summary, cumulative episodes of prolonged fasting lead to hypothalamic epigenetic changes and long-lasting metabolic adaptations in mice.

为了忍受长时间的禁食，动物需要进行重要的急性生理调节。然而，严重的禁食是否还会导致长期的代谢适应尚不清楚。空腹四十八小时使成年C57BL / 6雄性小鼠体重明显减轻。喂食7天后，人体脂肪增加到基线以上的水平，而空腹引起的瘦体重和能量消耗减少并未完全恢复。呼吸交换率和运动能力也保持改变。空腹/进食周期导致Pomc的持续抑制下丘脑中的mRNA水平和组蛋白脱乙酰基酶和DNA甲基转移酶表达的显着变化。此外，长期禁食可降低下丘脑腹膜内侧核中的组蛋白乙酰化，并在再次喂食后仍然受到抑制。30天禁食48小时的小鼠与从未缺食的老年匹配动物相比，体重和脂肪量更高。此外，先前的禁食经历改变了第二次禁食和再喂食所引起的体重，瘦体重，能量消耗和运动能力的变化。值得注意的是，当急性暴露于高口味/高脂肪的饮食中时，经历禁食累积的小鼠表现出更高的卡路里摄入量，减少了能量消耗和脂肪氧化，与从未禁食的老鼠相比。当长期接触高脂饮食时，经历空腹累积发作的小鼠表现出更高的身体和脂肪量增加，并且能量消耗和卡路里摄入减少。总之，长时间禁食的累积发作会导致小鼠下丘脑表观遗传变化和持久的代谢适应。