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Lipoic Acid Attenuates Innate Immune Infiltration and Activation in the Visceral Adipose Tissue of Obese Insulin Resistant Mice

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Lipids

Abstract

Visceral adipose inflammation mediated by innate and adaptive immune alterations plays a critical role in diet-induced obesity and insulin resistance (IR). The dietary supplement α-lipoic acid (αLA) has been shown to ameliorate inflammatory processes in macrophages, however the relative significance of these effects in the context of visceral adipose inflammation and IR remain unknown. In this study we investigated its effects via both intraperitoneal and oral administration in lean and obese transgenic mice expressing yellow fluorescent protein (YFP) under control of a monocyte specific promoter (c-fmsYFP+). αLA significantly improved indices of insulin-resistance concomitant with a decrease in total (YFP+CD11b+) and activated (YFP+CD11b+CD11c+) visceral adipose tissue macrophages. Histologically, the visceral adipose tissue of obese mice receiving αLA had fewer “crown-like structures,” a hallmark of adipose inflammation in murine obesity. Monocyte adhesion assessed by intravital microscopy of cremasteric venules was attenuated by αLA. In cultured WT and toll-like receptor 4 (TLR4) null primary mouse macrophages, αLA significantly decreased basal CCR-2, MCP-1 and TNF-α expression levels. LPS treatment resulted in increased TNFα, MCP-1, and IL-6 expression while αLA partially abrogated the LPS effect on MCP-1 and TNFα; Interestingly, CCR-2 was not coordinately regulated. AαLA prevented LPS-induced nuclear factor kappa B (NFκB) activation in the same cultured macrophages. These data suggest that αLA may modulate visceral adipose inflammation, a critical determinant of IR via TLR4 and NF-κB pathways.

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Abbreviations

αLA:

α-Lipoic acid

c-fms:

Proto-oncogene c-fms

CCR-2:

C-C chemokine receptor type 2

FBS:

Fetal bovine serum

HFD:

High fat diet

JNK:

c-Jun NH2-terminal kinase

IFNγ:

Interferon gamma

IL-6:

Interleukin 6

IL-10:

Interleukin 10

IL-12:

Interleukin 12

IP:

Intraperitoneal

IR:

Insulin resistance

LPS:

Lipopolysaccharide

MCP-1/CCL-2:

Monocyte chemoattractant protein 1

PBS:

Phosphate buffered saline

NFκB:

Nuclear factor kappa B

TBE:

Tris-buffered Ethylenediaminetetraacetic acid

TLR4:

Toll-like receptor 4

TNFα:

Tumor necrosis factor alpha

VATM:

Visceral adipose tissue macrophages

YFP:

Yellow fluorescent protein

SVF:

Stromal vascular fraction

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Acknowledgments

The primary author was supported by Award Number F32DK083903 from the National Institute of Diabetes and Digestive and Kidney Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health. The research was also supported in part by Grants to Dr Rajagopalan: R01ES015146, R21DK088522, and R21HL106487.

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  1. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, 43210, USA

    J. A. Deiuliis, T. Kampfrath, Z. Ying, A. Maiseyeu & S. Rajagopalan

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  1. J. A. Deiuliis
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  2. T. Kampfrath
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  3. Z. Ying
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Correspondence to J. A. Deiuliis.

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Deiuliis, J.A., Kampfrath, T., Ying, Z. et al. Lipoic Acid Attenuates Innate Immune Infiltration and Activation in the Visceral Adipose Tissue of Obese Insulin Resistant Mice. Lipids 46, 1021–1032 (2011). https://doi.org/10.1007/s11745-011-3603-8

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