Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
Cell Death Dis. 2017 Oct 26;8(10):e3136. doi: 10.1038/cddis.2017.518.
Caspase-2 has been shown to be involved in metabolic homeostasis. Here, we show that caspase-2 deficiency alters basal energy metabolism by shifting the balance in fuel choice from fatty acid to carbohydrate usage. At 4 weeks of age, whole-body carbohydrate utilisation was increased in Casp2 mice and was maintained into adulthood. By 17 weeks of age, Casp2 mice had reduced white adipose mass, smaller white adipocytes decreased fasting blood glucose and plasma triglycerides but maintained normal insulin levels. When placed on a 12-week high-fat diet (HFD), Casp2 mice resisted the development of obesity, fatty liver, hyperinsulinemia and insulin resistance. In addition, HFD-fed Casp2 mice had reduced white adipocyte hypertrophy, apoptosis and expansion of both subcutaneous and visceral adipose depots. Increased expression of UCP1 and the maintenance of adiponectin levels in white adipose tissue of HFD-fed Casp2 mice indicated increased browning and adipocyte hyperplasia. We found that while the preference for whole-body carbohydrate utilisation was maintained, HFD-fed Casp2 mice were not impaired in their ability to switch to utilising fats as a fuel source. Our findings suggest that caspase-2 impacts basal energy metabolism by regulating adipocyte biology and fat expansion, most likely via a non-apoptotic function. Furthermore, we show that caspase-2 deficiency shifts the balance in fuel choice towards increased carbohydrate utilisation and propose that this is due to mild energy stress. As a consequence, Casp2 mice show an adaptive remodelling of adipose tissue that protects from HFD-induced obesity and improves glucose homeostasis while paradoxically increasing their susceptibility to oxidative stress induced damage and premature ageing.
半胱天冬酶-2（Caspase-2）已被证明参与代谢稳态。在这里，我们表明 Caspase-2 缺乏会通过从脂肪酸向碳水化合物使用的燃料选择平衡来改变基础能量代谢。在 4 周龄时，Casp2 小鼠的全身碳水化合物利用率增加，并维持到成年期。到 17 周龄时，Casp2 小鼠的白色脂肪组织减少，白色脂肪细胞较小，空腹血糖和血浆甘油三酯降低，但胰岛素水平正常。当被置于 12 周高脂饮食（HFD）时，Casp2 小鼠抵抗肥胖、脂肪肝、高胰岛素血症和胰岛素抵抗的发展。此外，HFD 喂养的 Casp2 小鼠的白色脂肪细胞肥大、凋亡减少，以及皮下和内脏脂肪组织的扩张减少。在 HFD 喂养的 Casp2 小鼠的白色脂肪组织中，UCP1 的表达增加和脂联素水平的维持表明棕色化和脂肪细胞增生增加。我们发现，虽然维持了全身碳水化合物利用的偏好，但 HFD 喂养的 Casp2 小鼠在切换为利用脂肪作为燃料源的能力方面没有受损。我们的研究结果表明，Caspase-2 通过调节脂肪细胞生物学和脂肪扩张来影响基础能量代谢，这很可能是通过非凋亡功能。此外，我们表明 Caspase-2 缺乏会使燃料选择的平衡向增加碳水化合物利用的方向倾斜，我们推测这是由于轻微的能量应激。因此，Casp2 小鼠表现出脂肪组织的适应性重塑，可防止 HFD 诱导的肥胖和改善葡萄糖稳态，同时矛盾地增加了对氧化应激诱导损伤和过早衰老的易感性。
