Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice

Abstract

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. Methods 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. Results 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.

Hepatic Insulin Clearance in Regulation of Systemic Insulin Concentrations—Role of Carbohydrate and Energy Availability

“…CEACAM1 promotes internalization of the insulin-receptor complex (62) by insulin receptor tyrosine kinase-induced phosphorylation of CEACAM1 (63), which subsequently forms part of a protein complex mediating insulin receptor endocytosis (64). Hence, CEACAM1 knockout markedly reduces insulin clearance in mice (65), while CEACAM1 reconstitution restores insulin clearance and reverses the insulin-resistant phenotype (66). Interestingly, CEACAM1 can also be associated with the enzyme fatty acid synthase (FAS), which is central to de novo lipogenesis; thus, in hyperinsulinemic ob/ob mice that have elevated FAS activity, insulin failed to induce CEACAM1 phosphorylation (67).…”

Exenatide induces carcinoembryonic antigen‐related cell adhesion molecule 1 expression to prevent hepatic steatosis

“…(B) mRNA levels of (i) hGLP‐1R , (ii) hCEACAM1 ( hCC1 ), (iii) hPPAR α, and (iv) hPPAR γ were analyzed in HepG2 as above except for pre‐incubation with exendin 9‐39 (dark gray). * P < 0.05 versus S, † P < 0.05 Ex + exendin 9‐39 (Ex+ ) versus Ex alone. Abbreviations: Ex, exenatide; Ex , exendin fragment 9‐39; h, human; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; /GAPDH, normalized to GAPDH.…”

“…Combined, this leads to increased hepatic lipid production and accumulation in addition to its redistribution to white adipose tissue to cause visceral obesity followed by lipolysis. In contrast, liver‐specific transgenic reconstitution of CEACAM1 reverses the abnormal metabolic phenotype of Cc1 –/– mice . Reduction of hepatic CEACAM1 plays a key role in the pathogenesis of diet‐induced insulin resistance, hepatic steatosis, and visceral adiposity, and adenoviral‐mediated redelivery of wild‐type but not the phosphorylation‐defective CEACAM1 to the liver reverses these metabolic derangements .…”

“…In contrast, liver-specific transgenic reconstitution of CEACAM1 reverses the abnormal metabolic phenotype of Cc1 -/mice. (33) Reduction of hepatic CEACAM1 plays a key role in the pathogenesis of diet-induced insulin resistance, hepatic steatosis, and visceral adiposity, (20) and adenoviral-mediated redelivery of wild-type but not the phosphorylation-defective CEACAM1 to the liver reverses these metabolic derangements. (21) Thus, it is conceivable that restoring hepatic CEACAM1 content (and phosphorylation) by exenatide contributes substantially to its preventive Compromised hepatic insulin extraction in human subjects is associated with obesity, (34,35) diet-induced insulin resistance, (36) type 2 diabetes, (37) metabolic syndrome, (38,39) and fatty liver disease.…”

CEACAM1 in Liver Injury, Metabolic and Immune Regulation

“…Experiments in mouse models targeting CEACAM1 expression globally or in the liver shed more light on how hepatic CEACAM1 exhibits unique regulatory properties connecting insulin clearance and lipid metabolism to the pathogenesis of NAFLD/NASH. Global null deletion of the Ceacam1 gene and liver-specific inactivation of CEACAM1 impairs insulin extraction to cause hyperinsulinemia, followed by insulin resistance and secondary increase in hepatic lipid production and redistribution to the white adipose tissue to yield visceral adiposity and lipolysis [ 31 , 101 , 117 , 124 , 125 , 126 , 127 , 128 , 129 ] ( Figure 4 ).…”