Bone marrow-specific Cap gene deletion protects against high-fat diet-induced insulin resistance.
Cbl-associated protein (Cap) is a member of a phosphatidylinositol 3-kinase-independent pathway for insulin-stimulated translocation of the glucose transporter GLUT4. Despite this positive role of Cap in glucose uptake, here we show that deletion of the gene encoding Cap (official gene name: Sorbs1) protects against high-fat diet (HFD)-induced insulin resistance in mice while also having an opposite, insulin-sensitizing effect, accompanied by reduced tissue markers of inflammation. Given the emerging role of chronic inflammation in insulin resistance and the macrophage in initiating this inflammatory process, we considered that Sorbs1 deletion from macrophages may have resulted in the observed protection from HFD-induced insulin resistance. Using bone marrow transplantation to generate functional Sorbs1-null macrophages, we show that the insulin-sensitive phenotype can be transferred to wild-type mice by transplantation of Sorbs1-null bone marrow. These studies show that macrophages are an important cell type in the induction of insulin resistance and that Cap has a modulatory role in this function.
Lesniewski
Lisa A
LA
Department of Endocrinology and Metabolism, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
Hosch
Sarah E
SE
Neels
Jaap G
JG
de Luca
Carl
C
Pashmforoush
Mohammad
M
Lumeng
Carey N
CN
Chiang
Shian-Huey
SH
Scadeng
Miriam
M
Saltiel
Alan R
AR
Olefsky
Jerrold M
JM
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D016026:Bone Marrow Transplantation; D004041:Dietary Fats; D017353:Gene Deletion; D006651:Histocytochemistry; D015151:Immunoblotting; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D008264:Macrophages / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism
D004041:Dietary Fats; D008840:Microfilament Proteins; C119201:ponsin