Fatty acid synthesis configures the plasma membrane for inflammation in diabetes.
Dietary fat promotes pathological insulin resistance through chronic inflammation. The inactivation of inflammatory proteins produced by macrophages improves diet-induced diabetes, but how nutrient-dense diets induce diabetes is unknown. Membrane lipids affect the innate immune response, which requires domains that influence high-fat-diet-induced chronic inflammation and alter cell function based on phospholipid composition. Endogenous fatty acid synthesis, mediated by fatty acid synthase (FAS), affects membrane composition. Here we show that macrophage FAS is indispensable for diet-induced inflammation. Deleting Fasn in macrophages prevents diet-induced insulin resistance, recruitment of macrophages to adipose tissue and chronic inflammation in mice. We found that FAS deficiency alters membrane order and composition, impairing the retention of plasma membrane cholesterol and disrupting Rho GTPase trafficking-a process required for cell adhesion, migration and activation. Expression of a constitutively active Rho GTPase, however, restored inflammatory signalling. Exogenous palmitate was partitioned to different pools from endogenous lipids and did not rescue inflammatory signalling. However, exogenous cholesterol, as well as other planar sterols, did rescue signalling, with cholesterol restoring FAS-induced perturbations in membrane order. Our results show that the production of endogenous fat in macrophages is necessary for the development of exogenous-fat-induced insulin resistance through the creation of a receptive environment at the plasma membrane for the assembly of cholesterol-dependent signalling networks.
Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Xiaochao
X
Wei
Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Haowei
H
Song
Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Li
L
Yin
Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Michael G
MG
Rizzo
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Rohini
R
Sidhu
Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Douglas F
DF
Covey
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Daniel S
DS
Ory
Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA.|Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Clay F
CF
Semenkovich
D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D002465:Cell Movement; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology*; D059305:Diet, High-Fat / Q000009:adverse effects; D064429:Fatty Acid Synthases / Q000172:deficiency / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D007249:Inflammation / Q000201:enzymology / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D019308:Palmitic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D005227:Fatty Acids; D019308:Palmitic Acid; D002784:Cholesterol; D064429:Fatty Acid Synthases; D048031:JNK Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins