Blockade of α4 integrin Signaling Ameliorates the Metabolic Consequences of High Fat Diet-Induced Obesity

Abstract

Objective: Many prevalent diseases of advanced societies, such as obesity-induced Type 2 diabetes, are linked to indolent mononuclear cell-dependent inflammation. We previously proposed that blockade of α4 integrin signaling can inhibit inflammation, while limiting mechanism-based toxicities of loss of α4 function. Thus, we hypothesized that mice bearing an α4(Y991A) mutation, which blocks signaling, would be protected from development of high fat diet (HFD)-induced insulin resistance.

Research Design and Methods: 6-8 weeks old wild-type (WT) and α4(Y991A) C57Bl/6 male mice were placed on either a HFD that derived 60% calories from lipids, or a chow diet. Metabolic testing was performed after 16 to 22 weeks of diet.

Results: α4(Y991A) mice were protected from development of HFD-induced insulin resistance. This protection was conferred on WT mice by α4(Y991A) bone marrow transplantation. In the reverse experiment, WT bone marrow renders HFD-fed α4(Y991A) acceptor animals insulin-resistant. Furthermore, fat-fed α4(Y991A) mice showed a dramatic reduction of monocyte/macrophages in adipose tissue. This reduction was due to reduced monocyte/macrophage migration rather than reduced monocyte chemoattractant protein-1 (MCP-1) production.

Conclusions: α4 integrins contribute to the development of HFD-induced insulin resistance by mediating the trafficking of monocytes into adipose tissue; hence, blockade of α4 integrin signaling can prevent the development of obesity-induced insulin resistance.