• Cardiometabolic Disorder
• Insulin
• Inflammatory Disease
• Obesity

• Cardiometabolic Disorder
• Insulin
• Inflammatory Disease
• Obesity

Jae Bum Kim, PhD, Seoul National University, Seoul, South Korea, presented results of experiments which suggest that invariant natural killer T (iNKT) cells decrease the adipose tissue inflammation. A study using transgenic mice fed a high-fat diet reported that infiltration of human resistin-expressing macrophages into adipose tissue is a key mechanism for development of accelerated adipose tissue inflammation [Qatanani M et al. J Clin Invest 2009]. Resistin interacts with CAP1 on macrophages, stimulating the secretion of inflammatory cytokines that interferes with the normal insulin signaling pathway, demonstrating that adipose tissue inflammation may mediate insulin resistance.

In humans, excess food intake leads to increased lipids in hypertrophic and hyperplastic adipose tissue, stimulation of the inflammatory response in adipose tissue, a state of low-grade, chronic inflammation, and finally to insulin resistance mediated by interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha secreted by macrophages [Wellen KE, Hotamisligil G. J Clin Invest 2003]. Other immune cells associated with adipose tissue inflammation and decreased insulin sensitivity in obesity include T cells, B cells, neutrophils, and mast cells.

Mouse experiments showed that a short-term high-fat diet increases body weight, fat mass, and adipocyte size. In the 3 to 7 days following a short-term high-fat diet, expression of the CD11b and CD11c macrophage markers was increased in adipose tissue, demonstrating increased macrophage recruitment. In vitro experiments demonstrated that hypertrophic adipocytes actively recruit macrophages by secreting monocyte chemoattractant protein-1 (MCP-1).

Mice fed a high-fat diet for 1 week had significantly decreased iNKT cells in adipose tissue compared with mice fed a normal control diet (NCD; p<0.01) [Huh JY et al. Mol Cell Biol 2013]. The reduction in iNKT cells was specific to adipose tissue and did not occur in the spleen and thymus. The activation and memory markers, CD25 and CD44 on iNKT cells, were upregulated in adipose tissue. Annexin V-positive iNKT cell apoptosis increased about 4-fold after 1 week of a high-fat diet. These data demonstrate that adipose iNKT cells are selectively decreased by a short-term high fat diet via activation-induced cell death (AICD).

iNKT cells bridge innate and adaptive immunity. They produce IL-4 and interferon gamma (IFN-γ), and they recognize CD1d, an antigen-presenting molecule that binds lipids. iNKT cell deficient Jα 18 knockout mice are prone to obesity when fed a high-fat diet compared with wild-type mice (p<0.05) [Huh JY et al. Mol Cell Biol 2013]. Macrophage infiltration into adipose tissue was greater after a high-fat diet in the knockout mice than in wild-type mice (p<0.01). The iNKT cell deficient mice also became insulin resistant after a high-fat diet compared with wild-type mice (p<0.05).

Differentiated adipocytes activate iNKT cells via CD1d, which is highly expressed in adipocytes. CD1d expression is decreased in the adipose tissue of obese humans (p=0.005) [Huh JY et al. Mol Cell Biol 2013].

Prof. Kim developed a working model of iNKT interactions in adipose tissue based on these studies. iNKT cells activated by adipocytes presenting CD1d and lipid ligand produce anti-inflammatory cytokines that suppress adipose tissue macrophages. However, iNKT cell death occurs after 1 week of a high-fat diet, resulting in selectively decreased iNKT cells and increased adipose tissue inflammation. These results suggest that iNKT cells can suppress adipose tissue inflammation and insulin resistance in obesity.

• © 2013 MD Conference Express®