Diabetologia

pp 1–12 | Cite as

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

  • Lucia Russo
  • Harrison T. Muturi
  • Hilda E. Ghadieh
  • Simona S. Ghanem
  • Thomas A. Bowman
  • Hye Lim Noh
  • Sezin Dagdeviren
  • Godwin Y. Dogbey
  • Jason K. Kim
  • Garrett Heinrich
  • Sonia M. Najjar
Article

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.

Keywords

CEACAM1 Energy balance Fatty acid synthase Hyperinsulinaemia Insulin clearance Insulin resistance Lipolysis Normoinsulinaemia Steatohepatitis 

Abbreviations

ApoA-1

Apolipoprotein A-1

BAT

Brown adipose tissue

CEACAM1

Carcinoembryonic antigen-related cell adhesion molecule 1

ECL

Enhanced chemiluminescence

FAO

Fatty acid β-oxidation

FASN

Fatty acid synthase

L-CC1

Transgenic mice with liver-specific overexpression of wild-type rat Cc1 driven by ApoA-1 promoter

L-SACC1

Transgenic mice with liver-specific overexpression of the dominant-negative serine to alanine phosphorylation-defective mutant of rat CEACAM1

IRα

α subunit of the insulin receptor

IRβ

β subunit of the insulin receptor

mCc1

Mouse Cc1

PPARα

Peroxisome proliferator-activated receptor-α

rCc1

Rat Cc1

SREBP-1c

Sterol regulatory element binding protein-1c

WAT

White adipose tissue

Supplementary material

125_2017_4432_MOESM1_ESM.pdf (1.2 mb)
ESM(PDF 1265 kb)

References

  1. 1.
    Petersen KF, Dufour S, Savage DB et al (2007) The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A 104:12587–12594CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Cook JR, Langlet F, Kido Y, Accili D (2015) Pathogenesis of selective insulin resistance in isolated hepatocytes. J Biol Chem 290:13972–13980CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J (2008) Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 31(Suppl 2):S262–S268CrossRefPubMedGoogle Scholar
  4. 4.
    Matveyenko AV, Liuwantara D, Gurlo T et al (2012) Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling. Diabetes 61:2269–2279CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Han E, Phan D, Lo P et al (2001) Differences in tissue-specific and embryonic expression of mouse Ceacam1 and Ceacam2 genes. Biochem J 355:417–423CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Poy MN, Yang Y, Rezaei K et al (2002) CEACAM1 regulates insulin clearance in liver. Nat Genet 30:270–276CrossRefPubMedGoogle Scholar
  7. 7.
    DeAngelis AM, Heinrich G, Dai T et al (2008) Carcinoembryonic antigen-related cell adhesion molecule 1: a link between insulin and lipid metabolism. Diabetes 57:2296–2303CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Heinrich G, Ghadieh HE, Ghanem SS et al (2017) Loss of hepatic CEACAM1: a unifying mechanism linking insulin resistance to obesity and non-alcoholic fatty liver disease. Front Endocrinol (Lausanne) 8:8PubMedCentralGoogle Scholar
  9. 9.
    Najjar SM, Philippe N, Suzuki Y et al (1995) Insulin-stimulated phosphorylation of recombinant pp120/HA4, an endogenous substrate of the insulin receptor tyrosine kinase. Biochemistry 34:9341–9349CrossRefPubMedGoogle Scholar
  10. 10.
    Choice CV, Howard MJ, Poy MN, Hankin MH, Najjar SM (1998) Insulin stimulates pp120 endocytosis in cells co-expressing insulin receptors. J Biol Chem 273:22194–22200CrossRefPubMedGoogle Scholar
  11. 11.
    Ghosh S, Kaw M, Patel PR et al (2010) Mice with null mutation of Ceacam I develop nonalcoholic steatohepatitis. Hepat Med: Res Evidence 2010:69–78Google Scholar
  12. 12.
    Xu E, Dubois MJ, Leung N et al (2009) Targeted disruption of carcinoembryonic antigen-related cell adhesion molecule 1 promotes diet-induced hepatic steatosis and insulin resistance. Endocrinology 150:3503–3512CrossRefPubMedGoogle Scholar
  13. 13.
    Najjar SM, Yang Y, Fernstrom MA et al (2005) Insulin acutely decreases hepatic fatty acid synthase activity. Cell Metab 2:43–53CrossRefPubMedGoogle Scholar
  14. 14.
    Dai T, Abou-Rjaily GA, Al-Share QY et al (2004) Interaction between altered insulin and lipid metabolism in CEACAM1-inactive transgenic mice. J Biol Chem 279:45155–45161CrossRefPubMedGoogle Scholar
  15. 15.
    Al-Share QY, DeAngelis AM, Lester SG et al (2015) Forced hepatic overexpression of CEACAM1 Curtails diet-induced insulin resistance. Diabetes 64:2780–2790CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ramakrishnan SK, Russo L, Ghanem SS et al (2016) Fenofibrate decreases insulin clearance and insulin secretion to maintain insulin sensitivity. J Biol Chem 291:23915–23924CrossRefPubMedGoogle Scholar
  17. 17.
    Russo L, Ghadieh HE, Ghanem SS et al (2016) Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte-hepatocyte axis. J Lipid Res 57:2163–2175CrossRefPubMedGoogle Scholar
  18. 18.
    Huang J, Ledford KJ, Pitkin WB, Russo L, Najjar SM, Siragy HM (2013) Targeted deletion of murine CEACAM 1 activates PI3K-Akt signaling and contributes to the expression of (Pro)renin receptor via CREB family and NF-kappaB transcription factors. Hypertension 62:317–323CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Najjar SM, Ledford KJ, Abdallah SL et al (2013) Ceacam1 deletion causes vascular alterations in large vessels. Am J Physiol Endocrinol Metab 305:E519–E529CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Houde C, Roy S, Leung N, Nicholson DW, Beauchemin N (2003) The cell adhesion molecule CEACAM1-L is a substrate of caspase-3-mediated cleavage in apoptotic mouse intestinal cells. J Biol Chem 278:16929–16935CrossRefPubMedGoogle Scholar
  21. 21.
    Pereira S, Park E, Mori Y et al (2014) FFA-induced hepatic insulin resistance in vivo is mediated by PKCδ, NADPH oxidase, and oxidative stress. Am J Physiol Endocrinol Metab 307:E34–E46CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wong RH, Chang I, Hudak CS, Hyun S, Kwan HY, Sul HS (2009) A role of DNA-PK for the metabolic gene regulation in response to insulin. Cell 136:1056–1072CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Heinrich G, Russo L, Castaneda TR et al (2016) Leptin resistance contributes to obesity in mice with null mutation of carcinoembryonic antigen-related cell adhesion molecule 1. J Biol Chem 291:11124–11132CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Shimokawa T, Kumar MV, Lane MD (2002) Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. Proc Natl Acad Sci U S A 99:66–71CrossRefPubMedGoogle Scholar
  25. 25.
    Mobbs CV, Makimura H (2002) Block the FAS, lose the fat. Nat Med 8:335–336CrossRefPubMedGoogle Scholar
  26. 26.
    Kumar MV, Shimokawa T, Nagy TR, Lane MD (2002) Differential effects of a centrally acting fatty acid synthase inhibitor in lean and obese mice. Proc Natl Acad Sci U S A 99:1921–1925CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Heinrich G, Ghosh S, Deangelis AM et al (2010) Carcinoembryonic antigen-related cell adhesion molecule 2 controls energy balance and peripheral insulin action in mice. Gastroenterology 139:644–652CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Loftus TM, Jaworsky DE, Frehywot GL et al (2000) Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288:2379–2381CrossRefPubMedGoogle Scholar
  29. 29.
    Gonzalez E, Flier E, Molle D, Accili D, McGraw TE (2011) Hyperinsulinemia leads to uncoupled insulin regulation of the GLUT4 glucose transporter and the FoxO1 transcription factor. Proc Natl Acad Sci U S A 108:10162–10167CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yang X, Mei S, Gu H et al (2014) Exposure to excess insulin (glargine) induces type 2 diabetes mellitus in mice fed on a chow diet. J Endocrinol 221:469–480CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Battezzati A, Terruzzi I, Perseghin G et al (1995) Defective insulin action on protein and glucose metabolism during chronic hyperinsulinemia in subjects with benign insulinoma. Diabetes 44:837–844CrossRefPubMedGoogle Scholar
  32. 32.
    Broussard JL, Kolka CM, Castro AV et al (2015) Elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation during diet-induced insulin resistance in dogs. Diabetologia 58:2663–2670CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Najjar SM, Russo L (2014) CEACAM1 loss links inflammation to insulin resistance in obesity and non-alcoholic steatohepatitis (NASH). Semin Immunopathol 36:55–71CrossRefPubMedGoogle Scholar
  34. 34.
    Lester SG, Russo L, Ghanem SS et al (2015) Hepatic CEACAM1 over-expression protects against diet-induced fibrosis and inflammation in white adipose tissue. Front Endocrinol (Lausanne) 6:116–122PubMedCentralGoogle Scholar
  35. 35.
    Obici S, Rossetti L (2003) Minireview: nutrient sensing and the regulation of insulin action and energy balance. Endocrinology 144:5172–5178CrossRefPubMedGoogle Scholar
  36. 36.
    Woods SC, Lotter EC, McKay LD, Porte D Jr (1979) Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282:503–505CrossRefPubMedGoogle Scholar
  37. 37.
    Plum L, Belgardt BF, Bruning JC (2006) Central insulin action in energy and glucose homeostasis. J Clin Invest 116:1761–1766CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Obici S, Zhang BB, Karkanias G, Rossetti L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376–1382CrossRefPubMedGoogle Scholar
  39. 39.
    D'Souza AM, Johnson JD, Clee SM, Kieffer TJ (2016) Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetes in leptin-deficient Lepob/ob mice. Mol Metab 5:1103–1112CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kellerer M, Lammers R, Fritsche A et al (2001) Insulin inhibits leptin receptor signalling in HEK293 cells at the level of janus kinase-2: a potential mechanism for hyperinsulinaemia-associated leptin resistance. Diabetologia 44:1125–1132CrossRefPubMedGoogle Scholar
  41. 41.
    Chakravarthy MV, Zhu Y, Yin L et al (2009) Inactivation of hypothalamic FAS protects mice from diet-induced obesity and inflammation. J Lipid Res 50:630–640CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Lee W (2011) The CEACAM1 expression is decreased in the liver of severely obese patients with or without diabetes. Diagn Pathol 6:40CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Heinrich G, Muturi HT, Rezaei K et al (2017) Reduced hepatic carcinoembryonic antigen-related cell adhesion molecule 1 level in obesity. Front Endocrinol (Lausanne) 8:54PubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Lucia Russo
    • 1
  • Harrison T. Muturi
    • 1
    • 2
  • Hilda E. Ghadieh
    • 1
  • Simona S. Ghanem
    • 1
  • Thomas A. Bowman
    • 1
  • Hye Lim Noh
    • 3
  • Sezin Dagdeviren
    • 3
  • Godwin Y. Dogbey
    • 2
  • Jason K. Kim
    • 3
  • Garrett Heinrich
    • 2
    • 4
  • Sonia M. Najjar
    • 1
    • 2
    • 4
  1. 1.Center for Diabetes and Endocrine Research, College of Medicine and Life SciencesUniversity of ToledoToledoUSA
  2. 2.Department of Biomedical Sciences, Heritage College of Osteopathic MedicineOhio UniversityAthensUSA
  3. 3.Division of Endocrinology, Metabolism and DiabetesUniversity of Massachusetts Medical SchoolWorcesterUSA
  4. 4.Diabetes Institute, Heritage College of Osteopathic MedicineOhio UniversityAthensUSA

Personalised recommendations