A Role for Recruited Myeloid Cells in Obesity Induced Fatty Liver Disease.

摘要

Obesity is strongly associated with insulin resistance which predisposes individuals to Type 2 Diabetes Mellitus. Despite the fact that this association was first noted decades ago, the molecular link between these entities is not clear. In both humans and rodents obesity provokes a multi-organ chronic inflammatory network in multiple metabolic tissues. Macrophages accumulate in adipose tissue of obese subjects and provoke local and systemic inflammatory changes that are linked to insulin resistance. While this macrophage population has received attention since their initial discovery, few reports have characterized the state of macrophages in other organs critical to glucose and lipid metabolism such as the liver.;To address how obesity affects the immune cell populations of the liver we catalogued all these cells in genetic and dietary forms of murine obesity using lineage markers and fluorescence activated cell sorting. We discovered that Kupffer cells numbers decline in response to obesity, however another population of myeloid cells increases by almost double. We found that these cells, which we call "recruited myeloid cells" (RMC), vary significantly from resident hepatic Kupffer cells. They are smaller, less phagocytic, more inflammatory, and appear to be less reliant on lipids to meet their metabolic needs than Kupffer cells. These traits are consistent with an M1 polarization state. Importantly these cells express high levels of the chemokine receptor CCR2 and the inflammatory cytokine TNFalpha. CCR2 has previously been implicated in regulating the hepatosteatotic response to obesity. We found that chimeric mice with hematopoietic specific Ccr2 deficiency were likewise protected from steatosis. Furthermore both whole body and hematopoietic specific Ccr2 deficiency reduced hepatic RMC numbers suggesting that these cells provoke steatosis in response to high fat feeding.;To test whether this was true, we overexpressed the primary ligand of CCR2, CCL2, in the liver of mice. We found that this treatment rapidly increases RMC numbers and leads to enhanced steatosis when mice are concurrently fed high fat diet. By characterizing the livers of these mice on a molecular level we implicated the transcription factor C/EBP(3 in regulating the triglyceride synthesis gene Dgat2 and provoking RMC induced steatosis.;These studies reveal a new element of the inflammatory milieu incited by the obese state, and demonstrate how it may act as a new link between obesity and its complications.