Abstract
The early events that initiate inflammation in the adipose tissue during obesity are not well defined. It is unclear whether the recruitment of CD8 T cells to the adipose tissue during onset of obesity occurs through antigen-dependent or -independent processes. We have previously shown that interaction between NKG2D (natural-killer group 2, member D) and its ligand Rae-1ε is sufficient to recruit cytotoxic T lymphocytes to the pancreas and induce insulitis. Here, we tested whether NKG2D–NKG2D ligand interaction is also involved in obesity-induced adipose tissue inflammation and insulin resistance. We observed a significant induction of NKG2D ligand expression in the adipose tissue of obese mice, especially during the early stages of obesity. However, mice lacking NKG2D developed similar levels of insulin resistance and adipose tissue inflammation compared to control mice when placed on a high-fat diet. Moreover, overexpression of Rae-1ε in the adipose tissue did not increase immune cell infiltration to the adipose tissue either in the setting of a normal or high-fat diet. These results indicate that, unlike in the pancreas, NKG2D–NKG2D ligand interaction does not play a critical role in obesity-induced inflammation in the adipose tissue.
Highlights
Recent studies have pointed to chronic inflammation in insulin target tissues, such as muscle, liver, and adipose tissue, as one of the causal links between obesity and insulin resistance [1,2,3]
Induction of NKG2D ligands in fat tissue of obese mice NKG2D binds to a number of distinct ligands, which are usually not expressed in normal adult tissues, but are up-regulated in response to various ‘cellular stress conditions’, such as oxidative stress, viral infection, and DNA damage [42]
The mRNA levels of Rae-1 and Mult-1 were highest at the earliest time-point measured (3 weeks post-initiation of diet) and gradually decreased during the progression of obesity. These results suggest that early changes that occur in the adipose tissue of mice on a High-fat diet (HFD) induce the expression of NKG2D ligands
Summary
Recent studies have pointed to chronic inflammation in insulin target tissues, such as muscle, liver, and adipose tissue, as one of the causal links between obesity and insulin resistance [1,2,3]. Multiple inflammatory cytokines (TNF-a, IL-6, etc.) and signaling pathways (JNK, NF-kB) have been implicated in obesity-induced insulin resistance [4,5,6,7,8,9,10]. The secretion profile of the adipose tissue is altered by the pro-inflammatory milieu. Secretion of pro-inflammatory adipocytokines, such as resistin, IL-6, and TNF-a is increased while antiinflammatory and insulin-sensitizing adipocytokines like adiponectin are down-regulated. It is thought that dysregulation of the adipose tissue during obesity induces insulinresistance and inflammation in major metabolic tissues
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