Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance.
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.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA. li.kang@vanderbilt.edu
Li
L
Kang
Louise
L
Lantier
Arion
A
Kennedy
Jeffrey S
JS
Bonner
Wesley H
WH
Mayes
Deanna P
DP
Bracy
Louis H
LH
Bookbinder
Alyssa H
AH
Hasty
Curtis B
CB
Thompson
David H
DH
Wasserman
D000818:Animals; D015815:Cell Adhesion Molecules / Q000627:therapeutic use*; D059305:Diet, High-Fat / Q000009:adverse effects*; D006820:Hyaluronic Acid / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000627:therapeutic use*; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; C066852:hyaluronidase PH-20