CD14 Deficiency Impacts Glucose Homeostasis in Mice through Altered Adrenal Tone

James L Young,Anna Cerny,Michael P Czech,Silvia Corvera,Alfonso Mora,Bruce Woda,Robert W Finberg,Evelyn A Kurt-Jones

doi:10.1371/journal.pone.0029688

James L Young, Anna Cerny + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0029688

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Journal: PLoS ONE	Publication Date: Jan 13, 2012
Citations: 79	License type: CC BY 4.0

Affiliation: University of Massachusetts Chan Medical School

Abstract

The toll-like receptors comprise one of the most conserved components of the innate immune system, signaling the presence of molecules of microbial origin. It has been proposed that signaling through TLR4, which requires CD14 to recognize bacterial lipopolysaccharide (LPS), may generate low-grade inflammation and thereby affect insulin sensitivity and glucose metabolism. To examine the long-term influence of partial innate immune signaling disruption on glucose homeostasis, we analyzed knockout mice deficient in CD14 backcrossed into the diabetes-prone C57BL6 background at 6 or 12 months of age. CD14-ko mice, fed either normal or high-fat diets, displayed significant glucose intolerance compared to wild type controls. They also displayed elevated norepinephrine urinary excretion and increased adrenal medullary volume, as well as an enhanced norepinephrine secretory response to insulin-induced hypoglycemia. These results point out a previously unappreciated crosstalk between innate immune- and sympathoadrenal- systems, which exerts a major long-term effect on glucose homeostasis.

Highlights

The toll-like receptors (TLR) constitute the initial defense against invading microorganisms, through the recognition of microbial products and activation of innate immune signaling
The recognition of gram-negative bacteria occurs through the specific interaction bacterial lipopolysaccharide (LPS) with TLR4, and the subsequent initiation of a pro-anti-inflammatory response characterized by cytokine induction and secretion
TLR4 and CD14 are predominantly expressed in immune cells such as macrophages, which initiate the earliest responses to invading microorganisms

Summary

Introduction

The toll-like receptors (TLR) constitute the initial defense against invading microorganisms, through the recognition of microbial products and activation of innate immune signaling. It has been proposed that saturated free fatty acids, which are elevated in obesity, may generate insulin resistance through mechanisms that require activation of TLR4 and downstream pro-inflammatory signaling pathways [28,29].

Results

Conclusion