Autophagy Activity Is Up-Regulated in Adipose Tissue of Obese Individuals and Modulates Proinflammatory Cytokine Expression

• DOI: 10.1210/en.2012-1625
• Publication Date: 2012-11-02T07:08:39Z
• Authors: H. J. Jansen; P. van Essen; T. Koenen; L. A. B. Joosten; M. G. Netea; C. J. Tack; R. Stienstra
• Keywords: 0301 basic medicine; mice; adipocytes; Interleukin-1beta; adipogenesis; insulin-resistance; Mice; 03 medical and health sciences; interleukin-1-beta; Autophagy; Animals; Humans; Obesity; RNA, Small Interfering; Inflammation; 2. Zero hunger; Interleukin-6; Interleukin-8; differentiation; biogenesis; immunity; Up-Regulation; Adipose Tissue; inflammation; Leukocytes, Mononuclear; cells; Cytokines; IGMD 5: Health aging / healthy living; N4i 1: Pathogenesis and modulation of inflammation NCMLS 1: Infection and autoimmunity; Microtubule-Associated Proteins

Abstract Autophagy, an evolutionary conserved process aimed at recycling damaged organelles and protein aggregates in the cell, also modulates proinflammatory cytokine production in peripheral blood mononuclear cells. Because adipose tissue inflammation accompanied by elevated levels of proinflammatory cytokines is characteristic for the development of obesity, we hypothesized that modulation of autophagy alters adipose tissue inflammatory gene expression and secretion. We tested our hypothesis using ex vivo and in vivo studies of human and mouse adipose tissue. Levels of the autophagy marker LC3 were elevated in sc adipose tissue of obese vs. lean human subjects and positively correlated to both systemic insulin resistance and morphological characteristics of adipose tissue inflammation. Similarly, autophagic activity levels were increased in adipose tissue of obese and insulin resistant animals as compared with lean mice. Inhibition of autophagy by 3-methylalanine in human and mouse adipose tissue explants led to a significant increase in IL-1β, IL-6, and IL-8 mRNA expression and protein secretion. Noticeably, the enhancement in IL-1β, IL-6, and keratinocyte-derived chemoattractant (KC) by inhibition of autophagy was more robust in the presence of obesity. Similar results were obtained by blocking autophagy using small interfering RNA targeted to ATG7 in human Simpson-Golabi-Behmel syndrome adipocytes. Our results demonstrate that autophagy activity is up-regulated in the adipose tissue of obese individuals and inhibition of autophagy enhances proinflammatory gene expression both in adipocytes and adipose tissue explants. Autophagy may function to dampen inflammatory gene expression and thereby limit excessive inflammation in adipose tissue during obesity.