Journal Article

Fatty acid synthesis configures the plasma membrane for inflammation in diabetes

Song, Haowei, Yin, Li, Rizzo, Michael G., Sidhu, Rohini, Ory, Daniel S., Covey, Douglas F., Semenkovich, Clay F., Wei, Xiaochao

2016

Overview

Mice with macrophages deficient in fatty acid synthase exhibit lower levels of diabetes-related insulin resistance and inflammation, qualities that are restored on addition of exogenous cholesterol. Cells must make fat to respond to fat Dietary fat promotes chronic inflammation and insulin resistance. This involves the recruitment of macrophages to adipose tissue. This study shows that macrophage fatty acid synthase (FAS) is necessary for diet-induced inflammation. Deleting FAS from macrophages alters membrane order and composition of the macrophage, impairing retention of plasma membrane cholesterol and Rho GTPase trafficking required for cell adhesion, migration and activation. Hence, the absence of FAS prevents adipose macrophage recruitment, chronic inflammation and diet-induced insulin resistance in mice. Dietary fat promotes pathological insulin resistance through chronic inflammation 1 , 2 , 3 . The inactivation of inflammatory proteins produced by macrophages improves diet-induced diabetes 4 , but how nutrient-dense diets induce diabetes is unknown 5 . Membrane lipids affect the innate immune response 6 , which requires domains 7 that influence high-fat-diet-induced chronic inflammation 8 , 9 and alter cell function based on phospholipid composition 10 . Endogenous fatty acid synthesis, mediated by fatty acid synthase (FAS) 11 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/80/304 / 692/699/2743/137/773 / Adipose tissue / Adipose Tissue - cytology / Adipose Tissue - metabolism / Animals / Cell Adhesion / Cell adhesion & migration / Cell Membrane - chemistry / Cell Membrane - drug effects / Cell Membrane - metabolism / Cell Membrane - pathology / Cell membranes / Cell Movement / Cholesterol / Cholesterol - metabolism / Cholesterol - pharmacology / Development and progression / Diabetes / Diabetes Mellitus, Type 2 - metabolism / Diabetes Mellitus, Type 2 - pathology / Diet / Diet, High-Fat - adverse effects / Fatty Acid Synthases - deficiency / Fatty Acid Synthases - metabolism / Fatty acids / Fatty Acids - biosynthesis / Health aspects / Humanities and Social Sciences / Immune response / Inactivation / Inflammation / Inflammation - enzymology / Inflammation - etiology / Inflammation - metabolism / Inflammation - pathology / Insulin Resistance / JNK Mitogen-Activated Protein Kinases - metabolism / Kinases / letter / Lipids / Macrophages - cytology / Macrophages - enzymology / Macrophages - metabolism / Male / Membranes / Mice / multidisciplinary / Palmitic Acid - metabolism / Plasma / rho GTP-Binding Proteins - metabolism / Science / Signal Transduction - drug effects / Synthesis