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United States Department of Agriculture

Agricultural Research Service

Research Project: Linking Foods, Behavior and Metabolism to Promote a Healthy Body Weight

Location: Obesity and Metabolism Research Unit

Title: Acylcarnitines activate pro-inflammatory signaling pathways

Authors
item Rutkowsky, Jennifer -
item Knotts, Trina -
item Ono-Moore, Kikumi -
item Mc Coin, Colin -
item HUANG, SHURONG
item Schneider, Dina
item Singh, Shamsher -
item ADAMS, SEAN
item HWANG, DANIEL

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: April 16, 2014
Publication Date: April 22, 2014
Citation: Rutkowsky, J.M., Knotts, T.A., Ono-Moore, K.D., Mc Coin, C.S., Huang, S., Schneider, D.A., Singh, S., Adams, S.H., Hwang, D.H. 2014. Acylcarnitines activate pro-inflammatory signaling pathways. American Journal of Physiology - Endocrinology and Metabolism. DOI:10.1152/ajpendo.00656.2013.

Interpretive Summary: Inefficient fat metabolism in tissues is a feature of insulin resistance and type 2 diabetes mellitus (T2DM) and the resulting metabolite by-products, medium- and long-chain acylcarnitines are shown to be elevated. In preliminary studies, several of these metabolites activated pro-inflammatory pathways in immune cells. Here, we determined whether physiologically relevant L-acylcarnitines activate classical pro-inflammatory signaling pathways and involve pattern recognition receptor (PRR)-associated pathways. PRRs are targets of a variety of immune system triggers including pathogens, but also can be activated by saturated fats and other metabolites. Acylcarnitines induced expression of the inflammation marker COX-2 in a chain length dependent manner. L-C14 carnitine (5-25 micromolar) stimulated the expression and secretion of pro-inflammatory cytokines in a dose-dependent manner. Furthermore, L-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many pro-inflammatory signaling pathways including PRRs. Knockdown of MyD88, a key co-factor in PRR signaling and inflammation, blunted acylcarnitine-mediated pro-inflammatory effects. While these results point to potential involvement of PRRs, the specific targets involved remain to be identified. Interestingly, L-C14-carnitine failed to induce cytokine production or impact insulin sensitivity in differentiated 3T3-L1 adipocytes (fat cells in culture). Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be clarified. The results indicate that strategies to improve fat combustion in tissues (e.g. improving fitness, reducing overnutrition) could benefit health by reducing accumulation of acylcarnitines that could trigger inflammation.

Technical Abstract: Incomplete beta-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM) and the resulting metabolic by-products, medium- and long-chain acylcarnitines are shown to be elevated. In preliminary studies, mixed isomers of C12- or C14-carnitine activated the pro-inflammatory NFkappaB signaling pathway in RAW 264.7 cells. Here, we determined whether physiologically relevant L-acylcarnitines activate classical pro-inflammatory signaling pathways and involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced expression of COX-2 in a chain length dependent manner in RAW 264.7 cells. L-C14 carnitine (5-25 micromolar) stimulated the expression and secretion of pro-inflammatory cytokines in a dose-dependent manner. Furthermore, L-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many pro-inflammatory signaling pathways including PRRs. Knockdown of MyD88, a key co-factor in PRR signaling and inflammation, blunted acylcarnitine-mediated pro-inflammatory effects. While these results point to potential involvement of PRRs, L-C14 carnitine promoted IL-8 secretion from cells lacking TLR2 and TLR4, and did not activate reporter constructs in TLR-overexpression cell models. Interestingly, L-C14-carnitine failed to induce cytokine production or impact insulin sensitivity in differentiated 3T3-L1 adipocytes. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be clarified.

Last Modified: 9/10/2014
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