-SACC1 transgenic mice with liver inactivation of CEACAM1 demonstrated that CEACAM1 promotes insulin action by coordinated regulation of insulin and lipid metabolism (8
). The purpose of this study was to use the null Cc1−/−
mouse to reevaluate the role of CEACAM1 in insulin action in the absence of the potential confounding effect of the dominant-negative transgene. We herein report that homozygosity for a null Cc1 allele phenocopies transgenic inactivation of CEACAM1 in liver and causes visceral obesity together with impairment of insulin clearance and hyperinsulinemia, followed by insulin resistance, with an earlier onset when propagated on a mixed C57BL/6x129sv relative to pure C57BL/6 background (as with null mutation of the insulin receptor substrate 2 gene [25
]). Despite abundant expression in β-cells, null mutation of Ceacam1 does not reduce β-cell secretory function or β-cell area in response to glucose. This supports a key role for CEACAM1 in promoting hepatic insulin clearance.
Like its liver-specific inactivation, null mutation of Ceacam1 impairs insulin clearance and causes hyperinsulinemia and hepatic insulin resistance in association with increased steatosis. These findings are consistent with the high expression of CEACAM1 in liver (27
), a major site for insulin clearance. We have shown that CEACAM1-dependent pathways mediate a decrease in FAS activity to protect the liver from the lipogenic effect of high insulin levels in portal vein and that this effect is abolished in the hyperinsulinemic Ceacam1 mutant mice (24
). Together with increased Srebp-1c
mRNA and FAS protein levels, this leads to increased de novo lipogenesis and contributes to increase in hepatic triglyceride content in Cc1−/−
mice. Moreover, these mice exhibit a reduction in the suppressive effect of insulin on lipid oxidation and gluconeogenesis, which is manifested by increased G6P content, which, in association with reduced G6Pase
mRNA level (and presumably activity), is partitioned to the triglyceride synthetic pathways. The data suggest that null mutation of Ceacam1 chronically gears the liver toward steatosis by increasing hepatic FFA supply and de novo lipogenesis in addition to increasing G6P production and its partitioning toward triglyceride synthesis.
Consistent with a positive correlation between liver steatosis, hyperinsulinemia, and high serum ApoB levels in humans and rodents (23
), serum ApoB100/48 levels are elevated in Cc1−/−
mice, suggesting increased triglyceride output. Normal circulating triglyceride levels support redistribution into peripheral tissues in response to compensatory increase in insulin secretion. As in leptin deficiency (32
) and transgenic lipoatrophic AZIP mutation (33
), propagation of Ceacam1 deletion on the C57BL/6 genetic background favors substrate redistribution to the adipose tissue rather than muscle. Although this leads to visceral obesity in Cc1−/−
mice, it does not adversely affect insulin action in the periphery, in particular in muscle, where fatty acid uptake is reduced and triglyceride content is normal. Selective increase in triglyceride accumulation and alteration of insulin action in liver as opposed to muscle appears to be common in the C57BL/6 strain, as has been suggested by the phenotype of Ob/Ob
) and lipoatrophic AZIP mice (33
), which when propagated onto the FVB background exhibit triglyceride partitioning from liver to muscle. Likewise, transgenic inactivation of CEACAM1 in liver causes insulin resistance and fat accumulation in muscle and adipose tissue, in addition to liver, when propagated on a C57BL/6xFVB mixed background (8
). In light of the modulation of the diabetes phenotype by strain-related genetic factors (34
), it is possible that Ceacam1-null mutation would cause insulin resistance in muscle if propagated on the FVB genetic background. Conditional null mutation of the insulin receptor in liver yields hepatic insulin resistance with elevated lipogenesis and serum ApoB100/48 but with reduced serum triglycerides in comparison with wild-type mice (35
). Whereas this mouse emphasizes the impact of interrupted insulin signaling at the receptor level on steatosis in liver, the Cc1−/−
mouse phenotype highlights the critical role of CEACAM1 in regulating insulin action by coordinating insulin and lipid metabolism in liver and subsequently in extrahepatic tissues. This in vivo demonstration of a distinct CEACAM1-dependent postreceptor signaling pathway modulating insulin action by promoting insulin clearance provides proof of principle that hyperinsulinemia and hepatic steatosis can be a primary cause of insulin resistance, rather than a marker thereof.
Null mutation of Ceacam1 alters neither the insulin secretory function of β-cells in response to glucose nor β-cell area. Because β-cell–specific null mutation of insulin receptor (βIRKO) causes reduction in acute-phase insulin secretion in response to glucose (18
), our finding suggests that CEACAM1 does not modulate the insulin signaling pathways mediating insulin secretion. It remains possible that deletion of Ceacam1 is compensated for by Ceacam2, a close relative of Ceacam1 (36
), whose expression, albeit lower than that of Ceacam1 in β-cells, is not significantly altered in the Cc1−/−
mouse (not shown).
Taken together, the data suggest that the primary metabolic effect of Cc1 deficiency is impaired insulin clearance rather than increased insulin secretion. The underlying mechanism of insulin resistance induced by hyperinsulinemia is a manifestation of several metabolic and cellular abnormalities, including increased lipogenesis in liver. This paradigm assigns a primary role for CEACAM1 in regulating insulin action by promoting insulin clearance and regulating lipogenesis in liver.