Blockade of alpha4 integrin signaling ameliorates the metabolic consequences of high-fat diet-induced obesity.
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 alpha4 integrin signaling can inhibit inflammation while limiting mechanism-based toxicities of loss of alpha4 function. Thus, we hypothesized that mice bearing an alpha4(Y991A) mutation, which blocks signaling, would be protected from development of high-fat diet-induced insulin resistance.


METHODS
Six- to eight-week-old wild-type and alpha4(Y991A) C57Bl/6 male mice were placed on either a high-fat diet that derived 60% calories from lipids or a chow diet. Metabolic testing was performed after 16-22 weeks of diet.


RESULTS
Alpha4(Y991A) mice were protected from development of high-fat diet-induced insulin resistance. This protection was conferred on wild-type mice by alpha4(Y991A) bone marrow transplantation. In the reverse experiment, wild-type bone marrow renders high-fat diet-fed alpha4(Y991A) acceptor animals insulin resistant. Furthermore, fat-fed alpha4(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 production.


CONCLUSIONS
Alpha4 integrins contribute to the development of HFD-induced insulin resistance by mediating the trafficking of monocytes into adipose tissue; hence, blockade of alpha4 integrin signaling can prevent the development of obesity-induced insulin resistance.
Féral
Chloé C
CC
Department of Medicine, University of California, San Diego, La Jolla, California, USA. cferal@unice.fr
Neels
Jaap G
JG
Kummer
Christiane
C
Slepak
Marina
M
Olefsky
Jerrold M
JM
Ginsberg
Mark H
MH
D000273:Adipose Tissue / Q000502:physiology / Q000503:physiopathology; D019943:Amino Acid Substitution; D000818:Animals; D002465:Cell Movement; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D039441:Integrin alpha4 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020738:Leptin / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology; D009765:Obesity / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D020738:Leptin; D008055:Lipids; D039441:Integrin alpha4