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Hyperinsulinemia drives hepatic insulin resistance in male mice with
liver-specific Ceacam1 deletion independently of lipolysis.
Authors Ghadieh HE, Russo L, Muturi HT, Ghanem SS, Manaserh IH, Noh HL, Suk S, Kim JK,
Hill JW, Najjar SM
Submitted By Submitted Externally on 3/13/2019
Status Published
Journal Metabolism: clinical and experimental
Year 2019
Date Published 4/1/2019
Volume : Pages 93 : 33 - 43
PubMed Reference 30664851
Abstract CEACAM1 regulates insulin sensitivity by promoting insulin clearance.
Accordingly, global C57BL/6J.Cc1-/- null mice display hyperinsulinemia due to
impaired insulin clearance at 2?months of age, followed by insulin resistance,
steatohepatitis, visceral obesity and leptin resistance at 6?months. The study
aimed at investigating the primary role of hepatic CEACAM1 in insulin and lipid
homeostasis independently of its metabolic effect in extra-hepatic tissues.,
Liver-specific C57BL/6J.AlbCre+Cc1fl/fl mice were generated and their metabolic
phenotype was characterized by comparison to that of their littermate controls
at 2-9?months of age, using hyperinsulinemic-euglycemic clamp analysis and
indirect calorimetry. The effect of hyperphagia on insulin resistance was
assessed by pair-feeding experiments., Liver-specific AlbCre+Cc1fl/fl mutants
exhibited impaired insulin clearance and hyperinsulinemia at 2?months, followed
by hepatic insulin resistance (assessed by hyperinsulinemic-euglycemic clamp
analysis) and steatohepatitis at ~ 7?months of age, at which point visceral
obesity and hyperphagia developed, in parallel to hyperleptinemia and blunted
hypothalamic STAT3 phosphorylation in response to an intraperitoneal injection
of leptin. Hyperinsulinemia caused hypothalamic insulin resistance, followed by
increased fatty acid synthase activity, which together with defective
hypothalamic leptin signaling contributed to hyperphagia and reduced physical
activity. Pair-feeding experiment showed that hyperphagia caused systemic
insulin resistance, including blunted insulin signaling in white adipose tissue
and lipolysis, at 8-9?months of age., AlbCre+Cc1fl/fl mutants provide an in vivo
demonstration of the key role of impaired hepatic insulin clearance and
hyperinsulinemia in the pathogenesis of secondary hepatic insulin resistance
independently of lipolysis. They also reveal an important role for the
liver-hypothalamic axis in the regulation of energy balance and subsequently,
systemic insulin sensitivity.


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