Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA.
Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Irvine Hall 229, 1 Ohio University, Athens, OH, 45701-2979, USA.
Diabetologia. 2017 Dec;60(12):2463-2474. doi: 10.1007/s00125-017-4432-y. Epub 2017 Sep 14.
AIMS/HYPOTHESIS: The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes insulin clearance. Mice with global null mutation (Cc1 ) or with liver-specific inactivation (L-SACC1) of Cc1 (also known as Ceacam1) gene display hyperinsulinaemia resulting from impaired insulin clearance, insulin resistance, steatohepatitis and obesity. Because increased lipolysis contributes to the metabolic phenotype caused by transgenic inactivation of CEACAM1 in the liver, we aimed to further investigate the primary role of hepatic CEACAM1-dependent insulin clearance in insulin and lipid homeostasis. To this end, we examined whether transgenic reconstitution of CEACAM1 in the liver of global Cc1 mutant mice reverses their abnormal metabolic phenotype.
Insulin response was assessed by hyperinsulinaemic-euglycaemic clamp analysis and energy balance was analysed by indirect calorimetry. Mice were overnight-fasted and refed for 7 h to assess fatty acid synthase activity in the liver and the hypothalamus in response to insulin release during refeeding.
Liver-based rescuing of CEACAM1 restored insulin clearance, plasma insulin level, insulin sensitivity and steatohepatitis caused by global deletion of Cc1. It also reversed the gain in body weight and total fat mass observed with Cc1 deletion, in parallel to normalising energy balance. Mechanistically, reversal of hyperphagia appeared to result from reducing fatty acid synthase activity and restoring insulin signalling in the hypothalamus.
CONCLUSIONS/INTERPRETATION: Despite the potential confounding effects of deleting Cc1 from extrahepatic tissues, liver-based rescuing of CEACAM1 resulted in full normalisation of the metabolic phenotype, underscoring the key role that CEACAM1-dependent hepatic insulin clearance pathways play in regulating systemic insulin sensitivity, lipid homeostasis and energy balance.
目的/假设：癌胚抗原相关细胞黏附分子 1（CEACAM1）促进胰岛素清除。全身基因敲除（Cc1）或肝特异性失活（L-SACC1）Cc1（也称为 Ceacam1）基因的小鼠表现出高胰岛素血症，这是由于胰岛素清除受损、胰岛素抵抗、脂肪性肝炎和肥胖引起的。由于肝内 CEACAM1 基因的转基因失活增加脂肪分解，因此我们旨在进一步研究肝 CEACAM1 依赖性胰岛素清除在胰岛素和脂质稳态中的主要作用。为此，我们研究了在全身 Cc1 突变小鼠的肝中转基因再构成 CEACAM1 是否能逆转其异常的代谢表型。
通过高胰岛素-正常血糖钳夹分析评估胰岛素反应，通过间接测热法分析能量平衡。小鼠禁食过夜，然后再喂食 7 小时，以评估胰岛素再释放期间肝和下丘脑中脂肪酸合酶活性对胰岛素的反应。
肝来源的 CEACAM1 挽救恢复了由 Cc1 缺失引起的胰岛素清除、血浆胰岛素水平、胰岛素敏感性和脂肪性肝炎。它还逆转了 Cc1 缺失导致的体重和总脂肪量增加，同时使能量平衡正常化。从机制上讲，食欲亢进的逆转似乎是由于降低了脂肪酸合酶活性和恢复了下丘脑的胰岛素信号。
结论/解释：尽管从肝外组织中删除 Cc1 可能会产生潜在的混杂影响，但肝来源的 CEACAM1 挽救导致代谢表型完全正常化，这突显了 CEACAM1 依赖性肝胰岛素清除途径在调节全身胰岛素敏感性、脂质稳态和能量平衡中的关键作用。
