Article

C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis.

Department of Medicine, Columbia University, New York, New York, USA.
Diabetes (Impact Factor: 7.9). 04/2010; 59(4):916-25. DOI: 10.2337/db09-1403
Source: PubMed

ABSTRACT Obesity induces a program of systemic inflammation that is implicated in the development of many of its clinical sequelae. Hepatic inflammation is a feature of obesity-induced liver disease, and our previous studies demonstrated reduced hepatic steatosis in obese mice deficient in the C-C chemokine receptor 2 (CCR2) that regulates myeloid cell recruitment. This suggests that a myeloid cell population is recruited to the liver in obesity and contributes to nonalcoholic fatty liver disease.
We used fluorescence-activated cell sorting to measure hepatic leukocyte populations in genetic and diet forms of murine obesity. We characterized in vivo models that increase and decrease an obesity-regulated CCR2-expressing population of hepatic leukocytes. Finally, using an in vitro co-culture system, we measured the ability of these cells to modulate a hepatocyte program of lipid metabolism.
We demonstrate that obesity activates hepatocyte expression of C-C chemokine ligand 2 (CCL2/MCP-1) leading to hepatic recruitment of CCR2(+) myeloid cells that promote hepatosteatosis. The quantity of these cells correlates with body mass and in obese mice represents the second largest immune cell population in the liver. Hepatic expression of CCL2 increases their recruitment and in the presence of dietary fat induces hepatosteatosis. These cells activate hepatic transcription of genes responsible for fatty acid esterification and steatosis.
Obesity induces hepatic recruitment of a myeloid cell population that promotes hepatocyte lipid storage. These findings demonstrate that recruitment of myeloid cells to metabolic tissues is a common feature of obesity, not limited to adipose tissue.

0 Bookmarks
 · 
205 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The escalating epidemic of obesity has increased the incidence of obesity-induced complications to historically high levels. Adipose tissue is a dynamic energy depot, which stores energy and mobilizes it during nutrient deficiency. Excess nutrient intake resulting in adipose tissue expansion triggers lipid release and aberrant adipokine, cytokine and chemokine production, and signaling that ultimately lead to adipose tissue inflammation, a hallmark of obesity. This low-grade chronic inflammation is thought to link obesity to insulin resistance and the associated comorbidities of metabolic syndrome such as dyslipidemia and hypertension, which increase risk of type 2 diabetes and cardiovascular disease. In this review, we focus on and discuss members of the chemokine system for which there is clear evidence of participation in the development of obesity and obesity-induced pathologies.
    Journal of immunology research. 01/2014; 2014:181450.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages, found in circulating blood as well as integrated into several tissues and organs throughout the body, represent an important first line of defense against disease and a necessary component of healthy tissue homeostasis. Additionally, macrophages that arise from the differentiation of monocytes recruited from the blood to inflamed tissues play a central role in regulating local inflammation. Studies of macrophage activation in the last decade or so have revealed that these cells adopt a staggering range of phenotypes that are finely tuned responses to a variety of different stimuli, and that the resulting subsets of activated macrophages play critical roles in both progression and resolution of disease. This review summarizes the current understanding of the contributions of differentially polarized macrophages to various infectious and inflammatory diseases and the ongoing effort to develop novel therapies that target this key aspect of macrophage biology.
    Molecules and Cells 03/2014; · 2.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence of diabetes mellitus will likely increase globally from 371 million individuals in 2013 to 552 million individuals in 2030. This epidemic is mainly attributable to type 2 diabetes mellitus (T2DM), which represents about 90-95% of all cases. Cardiovascular disease is the leading cause of mortality among individuals with diabetes mellitus, and >50% of patients will die from a cardiovascular event-especially coronary artery disease, but also stroke and peripheral vascular disease. Classic risk factors such as elevated levels of LDL cholesterol and blood pressure, as well as smoking, are risk factors for adverse cardiovascular events in patients with type 1 diabetes mellitus (T1DM) and T2DM to a similar degree as they are in healthy individuals. Patients with T1DM develop insulin resistance in the months after diabetes mellitus diagnosis, and patients with T2DM typically develop insulin resistance before hyperglycaemia occurs. Insulin resistance and hyperglycaemia, in turn, further increase the risk of adverse cardiovascular events. This Review discusses the mechanisms by which T1DM and T2DM can lead to cardiovascular disease and how these relate to the risk factors for coronary artery disease.
    Nature Reviews Endocrinology 03/2014; · 11.03 Impact Factor

Full-text

View
0 Downloads
Available from