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.
Original language | English |
---|---|
Pages (from-to) | 2463-2474 |
Number of pages | 12 |
Journal | Diabetologia |
Volume | 60 |
Issue number | 12 |
DOIs | |
Publication status | Published - 1 Dec 2017 |
Externally published | Yes |
Fingerprint
Keywords
- CEACAM1
- Energy balance
- Fatty acid synthase
- Hyperinsulinaemia
- Insulin clearance
- Insulin resistance
- Lipolysis
- Normoinsulinaemia
- Steatohepatitis
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
Cite this
Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice. / Russo, Lucia; Muturi, Harrison T.; Ghadieh, Hilda E.; Ghanem, Simona; Bowman, Thomas A.; Noh, Hye Lim; Dagdeviren, Sezin; Dogbey, Godwin Y.; Kim, Jason K.; Heinrich, Garrett; Najjar, Sonia M.
In: Diabetologia, Vol. 60, No. 12, 01.12.2017, p. 2463-2474.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice
AU - Russo, Lucia
AU - Muturi, Harrison T.
AU - Ghadieh, Hilda E.
AU - Ghanem, Simona
AU - Bowman, Thomas A.
AU - Noh, Hye Lim
AU - Dagdeviren, Sezin
AU - Dogbey, Godwin Y.
AU - Kim, Jason K.
AU - Heinrich, Garrett
AU - Najjar, Sonia M.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
KW - CEACAM1
KW - Energy balance
KW - Fatty acid synthase
KW - Hyperinsulinaemia
KW - Insulin clearance
KW - Insulin resistance
KW - Lipolysis
KW - Normoinsulinaemia
KW - Steatohepatitis
UR - http://www.scopus.com/inward/record.url?scp=85029485579&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85029485579&partnerID=8YFLogxK
U2 - 10.1007/s00125-017-4432-y
DO - 10.1007/s00125-017-4432-y
M3 - Article
C2 - 28913658
AN - SCOPUS:85029485579
VL - 60
SP - 2463
EP - 2474
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
IS - 12
ER -