Differential Effect of Saturated and Unsaturated Free Fatty Acids on the Generation of Monocyte Adhesion and Chemotactic Factors by Adipocytes: Dissociation of Adipocyte Hypertrophy From Inflammation

Abstract

OBJECTIVE—Obesity is associated with monocyte-macroph-age accumulation in adipose tissue. Previously, we showed that glucose-stimulated production by adipocytes of serum amyloid A (SAA), monocyte chemoattractant protein (MCP)-1, and hyaluro-nan (HA) facilitated monocyte accumulation. The current objec-tive was to determine how the other major nutrient, free fatty acids (FFAs), affects these molecules and monocyte recruitment by adipocytes. RESEARCH DESIGN AND METHODS—Differentiated 3T3-L1, Simpson-Golabi-Behmel syndrome adipocytes, and mouse embryonic fibroblasts were exposed to various FFAs (250 mol/l) in either 5 or 25 mmol/l (high) glucose for evaluation of SAA, MCP-1, and HA regulation in vitro. RESULTS—Saturated fatty acids (SFAs) such as laurate, myris-tate, and palmitate increased cellular triglyceride accumulation, SAA, and MCP-1 expression; generated reactive oxygen species (ROS); and increased nuclear factor (NF) B translocation in both 5 and 25 mmol/l glucose. Conversely, polyunsaturated fatty acids (PUFAs) such as arachidonate, eicosapentaenate, and docosahexaenate (DHA) decreased these events. Gene expres-sion could be dissociated from triglyceride accumulation. Al-though excess glucose increased HA content, SFAs, oleate, and linoleate did not. Antioxidant treatment repressed glucose- and palmitate-stimulated ROS generation and NFB translocation and decreased SAA and MCP-1 expression and monocyte che-motaxis. Silencing toll-like receptor-4 (TLR4) markedly reduced SAA and MCP-1 expression in response to palmitate but not glucose. DHA suppressed NFB translocation stimulated by both excess glucose and palmitate via a peroxisome prolifterator– activated receptor (PPAR) –dependent pathway. CONCLUSIONS—Excess glucose and SFAs regulate chemotac-tic factor expression by a mechanism that involves ROS genera-tion, NFB, and PPAR, and which is repressed by PUFAs. Certain SFAs, but not excess glucose, trigger chemotactic factor expression via a TLR4-dependent pathway. Diabetes 59:386