Submitted on October 30, 2008
Revised on February 24, 2009
Accepted on March 18, 2009
Muscle inflammatory response and insulin resistance: synergistic interaction between macrophages and fatty acids leads to impaired insulin action
Vijayalakshmi Varma1, Aiwei Yao-Borengasser1, Neda Rasouli1, Greg T Nolen1, Bounleut Phanavanh1, Tasha Starks1, Cathy M Gurley1, Pippa M Simpson2, Robert E. McGehee, Jr.3, Philip A. Kern4, and Charlotte A. Peterson5*
1 University of Arkansas for Medical Sciences
2 University of Wisconsin
3 Arkansas Children's Hospital
4 University of Kentucky College of Medicine
5 University of Kentucky
* To whom correspondence should be addressed. E-mail: cpete4{at}uky.edu.
Obesity is characterized by adipose tissue expansion, as well as macrophage infiltration of adipose tissue. This results in an increase in circulating inflammatory cytokines and non-esterified fatty acids, factors that cause skeletal muscle insulin resistance. Whether obesity also results in skeletal muscle inflammation is not known. In this study, we quantified macrophages immunohistochemically in vastus lateralis biopsies from 8 obese and 8 lean subjects. Our study demonstrates that macrophages infiltrate skeletal muscle in obesity and we developed an in vitro system to study this mechanistically. Myoblasts were isolated from vastus lateral biopsies and differentiated in culture. Co-culture of differentiated human myotubes with macrophages in the presence of palmitic acid, to mimic an obese environment, revealed that macrophages in the presence of palmitic acid synergistically augment cytokine and chemokine expression in myotubes, decrease I
B
protein expression, increase phosphorylated JNK, decrease phosphorylated AKT and increase markers of muscle atrophy. These results suggest that macrophages alter the inflammatory state of muscle cells in an obese milieu, inhibiting insulin signaling. Thus, in obesity, both adipose tissue and skeletal muscle inflammation may contribute to insulin resistance.
