Induction of Cytosolic Phospholipase A2α Is Required for Adipose Neutrophil Infiltration and Hepatic Insulin Resistance Early in the Course of High-Fat Feeding

  1. Rachel Levy1,2
  1. 1Infectious Diseases and Immunology Laboratory, Ben-Gurion University of the Negev, Beer Sheva, Israel
  2. 2Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Soroka Medical University Center, Ben-Gurion University of the Negev, Beer Sheva, Israel
  3. 3Division of Pediatric Endocrinology and Diabetology and Children Research’s Centre, University Children's Hospital, Zurich, Switzerland
  4. 4Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
  5. 5The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel
  1. Corresponding author: Rachel Levy, ral{at}bgu.ac.il.
  1. O.B. and V.E.-C. contributed equally to this work

Abstract

In established obesity, inflammation and macrophage recruitment likely contribute to the development of insulin resistance. In the current study, we set out to explore whether adipose tissue infiltration by neutrophils that occurs early (3 days) after initiating a high-fat diet (HFD) could contribute to the early occurrence of hepatic insulin resistance and to determine the role of cytosolic phospholipase A2α (cPLA2α) in this process. The 3-day HFD caused a significant upregulation of cPLA2α in periepididymal fat and in the liver. A specific antisense oligonucleotide (AS) effectively prevented cPLA2α induction, neutrophil infiltration into adipose tissue (likely involving MIP-2), and protected against 3-day HFD–induced impairment in hepatic insulin signaling and glucose over-production from pyruvate. To sort out the role of adipose neutrophil infiltration independent of cPLA2α induction in the liver, mice were injected intraperitoneally with anti–intracellular adhesion molecule-1 (ICAM-1) antibodies. This effectively prevented neutrophil infiltration without affecting cPLA2α or MIP-2, but like AS, prevented impairment in hepatic insulin signaling, the enhanced pyruvate-to-glucose flux, and the impaired insulin-mediated suppression of hepatic glucose production (assessed by clamp), which were induced by the 3-day HFD. Adipose tissue secretion of tumor necrosis factor-α (TNF-α) was increased by the 3-day HFD, but not if mice were treated with AS or ICAM-1 antibodies. Moreover, systemic TNF-α neutralization prevented 3-day HFD–induced hepatic insulin resistance, suggesting its mediatory role. We propose that an acute, cPLA2α-dependent, neutrophil-dominated inflammatory response of adipose tissue contributes to hepatic insulin resistance and glucose overproduction in the early adaptation to high-fat feeding.

Footnotes

  • Received September 21, 2012.
  • Accepted May 5, 2013.

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  1. Diabetes vol. 62 no. 9 3053-3063
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