Fenofibrate decreases insulin clearance and insulin secretion to maintain insulin sensitivity

Sadeesh K. Ramakrishnan, Lucia Russo, Simona Ghanem, Payal R. Patel, Ana Maria Oyarce, Garrett Heinrich, Sonia M. Najjar

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

High fat diet reduces the expression of CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1), a transmembrane glycoprotein that promotes insulin clearance and down-regulates fatty acid synthase activity in the liver upon its phosphorylation by the insulin receptor. Because peroxisome proliferator-activated receptor α (PPARα) transcriptionally suppresses CEACAM1 expression, we herein examined whether high fat down-regulates CEACAM1 expression in a PPARα-dependent mechanism. By activating PPARα, the lipid-lowering drug fenofibrate reverses dyslipidemia and improves insulin sensitivity in type 2 diabetes in part by promoting fatty acid oxidation. Despite reducing glucose-stimulated insulin secretion, fenofibrate treatment does not result in insulin insufficiency. To examine whether this is mediated by a parallel decrease in CEACAM1-dependent hepatic insulin clearance pathways, we fed wild-type and Pparα-/- null mice a high fat diet supplemented with either fenofibrate or Wy14643, a selective PPARα agonist, and examined their effect on insulin metabolism and action. We demonstrated that the decrease in insulin secretion by fenofibrate and Wy14643 is accompanied by reduction in insulin clearance in wild-type but not Pparα-/- mice, thereby maintaining normoinsulinemia and insulin sensitivity despite continuous high fat intake. Intact insulin secretion in L-CC1 mice with protected hepatic insulin clearance and CEACAM1 levels provides in vivo evidence that insulin secretion responds to changes in insulin clearance to maintain physiologic insulin and glucose homeostasis. These results also emphasize the relevant role of hepatic insulin extraction in regulating insulin sensitivity.

Original languageEnglish
Pages (from-to)23915-23924
Number of pages10
JournalJournal of Biological Chemistry
Volume291
Issue number46
DOIs
Publication statusPublished - 11 Nov 2016
Externally publishedYes

Fingerprint

Fenofibrate
Insulin Resistance
Insulin
Carcinoembryonic Antigen
Cell Adhesion Molecules
Peroxisome Proliferator-Activated Receptors
Fats
Liver
High Fat Diet
Nutrition
Down-Regulation
Glucose
Fatty Acid Synthases
Insulin Receptor
Dyslipidemias
Phosphorylation
Type 2 Diabetes Mellitus

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Ramakrishnan, S. K., Russo, L., Ghanem, S., Patel, P. R., Oyarce, A. M., Heinrich, G., & Najjar, S. M. (2016). Fenofibrate decreases insulin clearance and insulin secretion to maintain insulin sensitivity. Journal of Biological Chemistry, 291(46), 23915-23924. https://doi.org/10.1074/jbc.M116.745778

Fenofibrate decreases insulin clearance and insulin secretion to maintain insulin sensitivity. / Ramakrishnan, Sadeesh K.; Russo, Lucia; Ghanem, Simona; Patel, Payal R.; Oyarce, Ana Maria; Heinrich, Garrett; Najjar, Sonia M.

In: Journal of Biological Chemistry, Vol. 291, No. 46, 11.11.2016, p. 23915-23924.

Research output: Contribution to journalArticle

Ramakrishnan, SK, Russo, L, Ghanem, S, Patel, PR, Oyarce, AM, Heinrich, G & Najjar, SM 2016, 'Fenofibrate decreases insulin clearance and insulin secretion to maintain insulin sensitivity', Journal of Biological Chemistry, vol. 291, no. 46, pp. 23915-23924. https://doi.org/10.1074/jbc.M116.745778
Ramakrishnan, Sadeesh K. ; Russo, Lucia ; Ghanem, Simona ; Patel, Payal R. ; Oyarce, Ana Maria ; Heinrich, Garrett ; Najjar, Sonia M. / Fenofibrate decreases insulin clearance and insulin secretion to maintain insulin sensitivity. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 46. pp. 23915-23924.
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