Abstract

Objectives: Obesity is associated with monocyte-macrophage accumulation in adipose tissue. Previously, we showed that glucose-stimulated production by adipocytes of serum amyloid A (SAA), monocyte chemoattractant protein-1 (MCP-1) and hyaluronan (HA) facilitated monocyte accumulation. The current objective was to determine how the other major nutrient, free fatty acids (FFA), affects these molecules and monocyte recruitment by adipocytes.

Research design and methods: Differentiated 3T3-L1, SGBS adipocytes and MEFs were exposed to various FFAs (250μM) in either 5mM or 25mM (high) glucose for evaluation of SAA, MCP-1 and HA regulation in vitro.

Results: Saturated fatty acids (SFA) such as laurate, myristate and palmitate increased cellular triglyceride accumulation, SAA and MCP-1 expression, generated reactive oxygen species (ROS) and increased NFκB translocation in both 5 and 25mM glucose. Conversely, polyunsaturated fatty acids (PUFA) such as arachidonate, eicosapentaenate (EPA) and docosahexaenate (DHA) decreased these events. Gene expression could be dissociated from triglyceride accumulation. Although excess glucose increased HA content, SFAs, oleate and linoleate did not. Antioxidant treatment repressed glucose and palmitate-stimulated ROS generation and NFκB translocation and decreased SAA and MCP-1 expression and monocyte chemotaxis. Silencing toll-like receptor-4 (TLR4) markedly reduced SAA and MCP-1 expression in response to palmitate but not glucose. DHA suppressed NFκB translocation stimulated by both excess glucose and palmitate via a PPARγ-dependent pathway.

Conclusions: Excess glucose and SFAs regulate chemotactic factor expression by a mechanism that involves ROS generation, NFκB and PPARγ, and which is repressed by PUFAs. Certain SFAs, but not excess glucose, trigger chemotactic factor expression via a TLR4-dependent pathway.