High-fat diet restriction to adult male mice maintains normal body weight but leads to liver impairment by disrupting mitochondrial oxidative phosphorylation

Dietary restriction (DR) delays aging and supports health primarily through its effects on mitochondrial function. Conversely, a high-fat diet (HFD) with excess calories promotes obesity and health risks via mitochondrial dysfunction. However, the role of dietary composition in the benefits of DR remains unclear. This study investigated whether sustainable and intermittent DR with an HFD positively affects liver and heart health. Mice were assigned to four groups: chow diet ad libitum (CTR), HFD ad libitum (H), 60% HFD intake (HDR), and intermittent HFD restriction with weight cycling (WC). The results showed that the mice in the HDR and WC groups had reduced body weight, while animals in neither group had lower blood glucose levels compared to the H group. Hepatic fibrosis and NAFLD activity scores were similar in H, HDR, and WC mice but were higher than in CTR mice. The livers of mice in the HDR and WC groups also showed reduced ATP content and altered protein expressions related to mitochondrial dynamics. Liver in animals from the H group exhibited reduced LC3I expression and an increased LC3II to LC3I ratio compared with liver CTR. In contrast, livers of animals in the HDR and WC groups showed lower levels of p62, LC3I, and LC3II expression. Fibrosis was observed in the hearts of mice in the CTR and H groups, and DR did not reverse this damage. In conclusion, although HFD restriction maintained body weight, it adversely affected liver health by disrupting mitochondrial function. These findings emphasize the critical role of dietary composition in liver health when adopting calorie restriction therapy.

饮食限制（Dietary restriction, DR）主要通过影响线粒体功能延缓衰老并维持机体健康。与之相反，热量过剩的高脂饮食（High-fat diet, HFD）可通过诱发线粒体功能障碍，促进肥胖并增加健康风险。然而，饮食组成在饮食限制的健康获益中所发挥的作用仍不明确。本研究探讨了伴随高脂饮食的持续性与间歇性饮食限制是否对肝脏与心脏健康产生积极影响。实验将小鼠分为四组：自由进食普通饲料组（CTR）、自由进食高脂饮食组（H）、高脂饮食摄入限制为60%组（HDR），以及伴随体重循环的间歇性高脂饮食限制组（WC）。结果显示，HDR与WC组小鼠的体重有所降低，但两组小鼠的血糖水平均未低于H组。H、HDR与WC组小鼠的肝纤维化程度与非酒精性脂肪性肝病活动度评分（NAFLD activity scores）均相近，且均高于CTR组。HDR与WC组小鼠的肝脏三磷酸腺苷（ATP）含量降低，且与线粒体动力学相关的蛋白质表达发生改变。与CTR组相比，H组小鼠肝脏的LC3I表达水平降低，LC3II与LC3I的比值升高；而HDR与WC组小鼠肝脏的p62、LC3I及LC3II的表达水平均更低。CTR组与H组小鼠的心脏均出现纤维化病变，且饮食限制未能逆转该心脏损伤。综上，尽管高脂饮食限制可维持小鼠体重，但该干预方式通过破坏线粒体功能，对肝脏健康产生不利影响。本研究结果强调，在实施热量限制疗法时，饮食组成对于肝脏健康具有关键作用。