The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent
The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent
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DOI：
10.1101/2022.02.20.481222
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发表时间：
2022-02
期刊：
影响因子：
7.7
通讯作者：
K. Suchacki;Benjamin J. Thomas;Y. Ikushima;Kuang-Chan Chen;C. Fyfe;A. Tavares;Richard J. Sulston;Andrea Lovdel;Holly J. Woodward;Xuan Han;Domenico Mattiucci;E. Brain;Carlos J. Alcaide-Corral;Hiroshi Kobayashi;Gillian Gray;P. Whitfield;R. Stimson;N. Morton;A. Johnstone;W. Cawthorn
中科院分区：
文献类型：
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作者：
K. Suchacki;Benjamin J. Thomas;Y. Ikushima;Kuang-Chan Chen;C. Fyfe;A. Tavares;Richard J. Sulston;Andrea Lovdel;Holly J. Woodward;Xuan Han;Domenico Mattiucci;E. Brain;Carlos J. Alcaide-Corral;Hiroshi Kobayashi;Gillian Gray;P. Whitfield;R. Stimson;N. Morton;A. Johnstone;W. Cawthorn
热量限制（CR）是一种营养干预措施，可降低包括人类在内的许多物种患年龄相关疾病的风险。CR的代谢效应，包括减少脂肪量和改善胰岛素敏感性，在其更广泛的健康益处中发挥着重要作用。然而，CR的健康益处的性别差异的程度和基础尚不清楚。我们发现，30%的CR在年轻（3个月大）的雄性小鼠减少脂肪量和改善葡萄糖耐量和胰岛素敏感性，而这些影响是钝化或年轻的雌性小鼠不存在。与男性相比，女性对脂肪和体重减轻的抵抗力与脂解减少、全身能量消耗和脂肪酸氧化降低以及餐后脂肪生成增加有关。使用18 F-氟脱氧葡萄糖（18 F-FDG）进行的正电子发射断层扫描-计算机断层扫描（PET/CT）显示，两种性别之间的外周葡萄糖摄取相当。相反，葡萄糖稳态的性别差异与肝脏神经酰胺含量和底物代谢的改变有关：与CR男性相比，CR女性的TCA循环活性较低，但血酮浓度较高，这是肝脏乙酰辅酶A含量的标志物。这表明，男性使用肝乙酰辅酶A进行TCA循环，而在女性中，它会蓄积，从而在CR期间刺激肝异生并限制低血糖。在老年小鼠（18个月大）中，当雌性动物处于非发情期时，CR降低脂肪量并改善葡萄糖稳态，在两种性别中的程度相似。最后，在超重和肥胖人群中，CR诱导的脂肪减少也是性别和年龄依赖性的：年轻女性（45岁）不存在这种性别差异。总的来说，这些研究确定了CR代谢效应的年龄依赖性性别差异，并强调脂肪组织、肝脏和雌激素是CR代谢益处的关键决定因素。这些发现对于理解饮食与健康之间的相互作用以及最大限度地发挥CR在人类中的益处具有重要意义。热量限制（CR）减少年轻雄性小鼠的脂肪量并改善葡萄糖稳态，但年轻雌性小鼠抵抗这些作用。CR女性抵抗脂解，减少能量消耗和增加餐后脂肪生成比CR男性，解释女性如何抵抗脂肪损失。葡萄糖稳态的性别差异与肝脏代谢和肝脏异生的改变有关，外周葡萄糖摄取无显著差异。CR对脂肪减少和葡萄糖稳态的影响在老年雄性和雌性小鼠中是相当的，暗示雌激素是年轻小鼠性二态效应的驱动因素。在人类中，女性以年龄依赖性方式抵抗CR诱导的脂肪减少，进一步支持雌激素在CR的性二态效应中的作用。
Caloric restriction (CR) is a nutritional intervention that reduces the risk of age-related diseases in numerous species, including humans. CR’s metabolic effects, including decreased fat mass and improved insulin sensitivity, play an important role in its broader health benefits. However, the extent and basis of sex differences in CR’s health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young female mice. Females’ resistance to fat and weight loss was associated with decreased lipolysis, lower systemic energy expenditure and fatty acid oxidation, and increased postprandial lipogenesis compared to males. Positron emission tomography-computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) showed that peripheral glucose uptake was comparable between sexes. Instead, the sex differences in glucose homeostasis were associated with altered hepatic ceramide content and substrate metabolism: compared to CR males, CR females had lower TCA cycle activity but higher blood ketone concentrations, a marker of hepatic acetyl-CoA content. This suggests that males use hepatic acetyl-CoA for the TCA cycle whereas in females it accumulates, thereby stimulating gluconeogenesis and limiting hypoglycaemia during CR. In aged mice (18-months old), when females are anoestrus, CR decreased fat mass and improved glucose homeostasis to a similar extent in both sexes. Finally, in a cohort of overweight and obese humans CR-induced fat loss was also sex- and age-dependent: younger females (45 years) this sex difference was absent. Collectively, these studies identify age-dependent sex differences in the metabolic effects of CR and highlight adipose tissue, the liver and oestrogen as key determinants of CR’s metabolic benefits. These findings have important implications for understanding the interplay between diet and health and for maximising the benefits of CR in humans. HIGHLIGHTS Caloric restriction (CR) decreases fat mass and improves glucose homeostasis in young male mice, but young females resist these effects. CR females resist lipolysis, decrease energy expenditure and increase postprandial lipogenesis more than CR males, explaining how females resist fat loss. Sex differences in glucose homeostasis are associated with altered hepatic metabolism and gluconeogenesis, without marked differences in peripheral glucose uptake. CR’s effects on fat loss and glucose homeostasis are comparable in aged male and female mice, implicating oestrogen as the driver of the sexually dimorphic effects in young mice. In humans, females resist CR-induced fat loss in an age-dependent manner, further supporting the role of oestrogen in the sexually dimorphic effects of CR.