Inflammation Is Necessary for Long-Term but Not Short-Term High-Fat Diet–Induced Insulin Resistance

• DOI: 10.2337/db11-0194
• Publication Date: 2011-09-13T06:46:45Z
• Authors: Yun Sok Lee; Pingping Li; Jin Young Huh; In Jae Hwang; Min Lu; Jong In Kim; Mira Ham; Saswata Talukdar; Ai Chen; Wendell J. Lu; Guatam K. Bandyop...; Reto Schwendener; Jerrold Olefsky; Jae Bum Kim
• Keywords: Blood Glucose; Male; 0301 basic medicine; ADIPOSE-TISSUE; T-CELLS; OBESITY; ACIDS; MACROPHAGES; MUSCLE; CONTRIBUTES; DELETION; GLUCOSE; STRESS; Ceramides; Drug Administration Schedule; Mice; 03 medical and health sciences; Animals; Muscle, Skeletal; Epididymis; Inflammation; 2. Zero hunger; 10061 Institute of Molecular Cancer Research; Glucose Tolerance Test; Dietary Fats; Mice, Inbred C57BL; 2712 Endocrinology, Diabetes and Metabolism; Glucose; Adipose Tissue; Liver; 2724 Internal Medicine; 570 Life sciences; biology; Insulin Resistance; Obesity Studies

OBJECTIVE Tissue inflammation is a key factor underlying insulin resistance in established obesity. Several models of immuno-compromised mice are protected from obesity-induced insulin resistance. However, it is unanswered whether inflammation triggers systemic insulin resistance or vice versa in obesity. The purpose of this study was to assess these questions.

RESEARCH DESIGN AND METHODS We fed a high-fat diet (HFD) to wild-type mice and three different immuno-compromised mouse models (lymphocyte-deficient Rag1 knockout, macrophage-depleted, and hematopoietic cell-specific Jun NH2-terminal kinase–deficient mice) and measured the time course of changes in macrophage content, inflammatory markers, and lipid accumulation in adipose tissue, liver, and skeletal muscle along with systemic insulin sensitivity.

RESULTS In wild-type mice, body weight and adipose tissue mass, as well as insulin resistance, were clearly increased by 3 days of HFD. Concurrently, in the short-term HFD period inflammation was selectively elevated in adipose tissue. Interestingly, however, all three immuno-compromised mouse models were not protected from insulin resistance induced by the short-term HFD. On the other hand, lipid content was markedly increased in liver and skeletal muscle at day 3 of HFD.

CONCLUSIONS These data suggest that the initial stage of HFD-induced insulin resistance is independent of inflammation, whereas the more chronic state of insulin resistance in established obesity is largely mediated by macrophage-induced proinflammatory actions. The early-onset insulin resistance during HFD feeding is more likely related to acute tissue lipid overload.