Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance

Li Kang (Lead / Corresponding author), Louise Lantier, Arion Kennedy, Jeffrey S. Bonner, Wesley H. Mayes, Deanna P. Bracy, Louis H. Bookbinder, Alyssa H. Hasty, Curtis B. Thompson, David H. Wasserman

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)

Abstract

Increased deposition of specific extracellular matrix (ECM) components is a characteristic of insulin-resistant skeletal muscle. Hyaluronan (HA) is a major constituent of the ECM. The hypotheses that 1) HA content is increased in the ECM of insulin-resistant skeletal muscle and 2) reduction of HA in the muscle ECM by long-acting pegylated human recombinant PH20 hyaluronidase (PEGPH20) reverses high-fat (HF) diet-induced muscle insulin resistance were tested. We show that muscle HA was increased in HF diet-induced obese (DIO) mice and that treatment of PEGPH20, which dose-dependently reduced HA in muscle ECM, decreased fat mass, adipocyte size, and hepatic and muscle insulin resistance in DIO mice at 10 mg/kg. Reduced muscle insulin resistance was associated with increased insulin signaling, muscle vascularization, and percent cardiac output to muscle rather than insulin sensitization of muscle per se. Dose-response studies revealed that PEGPH20 dose-dependently increased insulin sensitivity in DIO mice with a minimally effective dose of 0.01 mg/kg. PEGPH20 at doses of 0.1 and 1 mg/kg reduced muscle HA to levels seen in chow-fed mice, decreased fat mass, and increased muscle glucose uptake. These findings suggest that ECM HA is a target for treatment of insulin resistance.

Original languageEnglish
Pages (from-to)1888-1896
Number of pages9
JournalDiabetes
Volume62
Issue number6
DOIs
Publication statusPublished - Jun 2013

Keywords

  • Animals
  • Cell Adhesion Molecules/therapeutic use
  • Diet, High-Fat/adverse effects
  • Hyaluronic Acid/metabolism
  • Hyaluronoglucosaminidase/therapeutic use
  • Immunoblotting
  • Immunohistochemistry
  • Immunoprecipitation
  • Insulin Resistance/physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal/drug effects
  • Obesity/drug therapy

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