Wilson C H, Nikolic A, Kentish S J, Shalini S, Hatzinikolas G, Page A J, Dorstyn L, Kumar S
Centre for Cancer Biology, University of South Australia , Adelaide, SA, Australia.
Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
Cell Death Discov. 2016 Feb 29;2:16009. doi: 10.1038/cddiscovery.2016.9. eCollection 2016.
Gender-specific differences are commonly found in metabolic pathways and in response to nutritional manipulation. Previously, we identified a role for caspase-2 in age-related glucose homeostasis and lipid metabolism using male caspase-2-deficient (Casp2 (-/-) ) mice. Here we show that the resistance to age-induced glucose tolerance does not occur in female Casp2 (-/-) mice and it appears to be independent of insulin sensitivity in males. Using fasting (18 h) as a means to further investigate the role of caspase-2 in energy and lipid metabolism, we identified sex-specific differences in the fasting response and lipid mobilization. In aged (18-22 months) male Casp2 (-/-) mice, a significant decrease in fasting liver mass, but not total body weight, was observed while in females, total body weight, but not liver mass, was reduced when compared with wild-type (WT) animals. Fasting-induced lipolysis of adipose tissue was enhanced in male Casp2 (-/-) mice as indicated by a significant reduction in white adipocyte cell size, and increased serum-free fatty acids. In females, white adipocyte cell size was significantly smaller in both fed and fasted Casp2 (-/-) mice. No difference in fasting-induced hepatosteatosis was observed in the absence of caspase-2. Further analysis of white adipose tissue (WAT) indicated that female Casp2 (-/-) mice may have enhanced fatty acid recycling and metabolism with expression of genes involved in glyceroneogenesis and fatty acid oxidation increased. Loss of Casp2 also increased fasting-induced autophagy in both male and female liver and in female skeletal muscle. Our observations suggest that caspase-2 can regulate glucose homeostasis and lipid metabolism in a tissue and sex-specific manner.
性别特异性差异常见于代谢途径以及对营养调控的反应中。此前，我们利用雄性半胱天冬酶-2缺陷（Casp2 (-/-) ）小鼠，确定了半胱天冬酶-2在年龄相关的葡萄糖稳态和脂质代谢中的作用。在此我们表明，雌性Casp2 (-/-) 小鼠不存在对年龄诱导的葡萄糖耐量的抗性，并且这似乎与雄性的胰岛素敏感性无关。通过禁食（18小时）作为进一步研究半胱天冬酶-2在能量和脂质代谢中作用的手段，我们确定了禁食反应和脂质动员中的性别特异性差异。在老年（18 - 22个月）雄性Casp2 (-/-) 小鼠中，观察到禁食肝脏质量显著下降，但总体重未下降，而在雌性中，与野生型（WT）动物相比，总体重下降，但肝脏质量未下降。雄性Casp2 (-/-) 小鼠中，禁食诱导的脂肪组织脂解增强，表现为白色脂肪细胞大小显著减小以及血清游离脂肪酸增加。在雌性中，喂食和禁食的Casp2 (-/-) 小鼠白色脂肪细胞大小均显著更小。在缺乏半胱天冬酶-2的情况下，未观察到禁食诱导的肝脂肪变性有差异。对白色脂肪组织（WAT）的进一步分析表明，雌性Casp2 (-/-) 小鼠可能增强了脂肪酸循环和代谢，参与甘油生成和脂肪酸氧化的基因表达增加。Casp2的缺失还增加了雄性和雌性肝脏以及雌性骨骼肌中禁食诱导的自噬。我们的观察结果表明，半胱天冬酶-2可以以组织和性别特异性的方式调节葡萄糖稳态和脂质代谢。
