Research conducted at the Methodist DeBakey Heart Center in Houston identifies a molecular link between obesity and inflammation that could lead to new therapies to prevent diabetes and heart disease.
Research presented in November 2006 at the American Heart Association Scientific Sessions shows that a high fat diet draws inflammatory cells into fat tissue, which prevents the tissue from storing the fats we eat. When the tissue can not store these fats, they end up in the liver and muscle, which in turn causes diabetes and heart disease.
“Understanding this link between obesity, diet and inflammation, may help us prevent diabetes and heart disease by tailoring new therapies to block the inflammation that initiates the destructive process,” said Dr. Christie Ballantyne, cardiologist at the Methodist DeBakey Heart Center and principal investigator for the research.
Research presented today shows that a high fat diet leads fat cells to produce molecules called chemokines, which attract inflammatory white blood cells into fat tissue. Both macrophages and T cells, which play a critical role in the immune system, accumulate in fat tissue, beginning the process that leads to disease.
“The results of these studies provide additional evidence that new therapies which block the initial inflammation in fat tissue may help prevent or treat disorders related to obesity such as diabetes and heart disease,” Ballantyne said.
This research was funded jointly by the American Diabetes Association and a grant from the Methodist DeBakey Heart Center.
For more information on the Methodist DeBakey Heart Center, see http://www.debakeyheartcenter.com.
Obesity is associated with chronic inflammation, evidenced by elevated cytokine and chemokine expression and increased macrophage accumulation in adipose (fat) tissue (AT). T cells also play an important role in chronic inflammatory diseases such as atherosclerosis but have not been well studied in obesity. The study hypothesized that elevated chemokine levels in AT in obesity are also associated with increased T cell accumulation.
Using flow cytometry, the study examined T cells in stromal/vascular cells from AT of diet-induced obese mice, which were C57BL/6 fed western high-fat diet 24 wk.
Compared to lean controls on standard chow diet, obese male mice but not obese females had significantly increased T cell number in AT (CD3+ cells: 3.5±0.4 x105/g tissue in obese males vs 1.5 ± 0.2 x105/g tissue in leans, P<0.01, n=5/group). mRNA levels of MCP-1, RANTES, and their receptors, CCR2 and CCR5, were upregulated in AT of obese males as examined by RNase protection assay (relative intensity to GAPDH and L32: MCP-1, 689±63 vs 188±6 in lean, P<0.01; RANTES, 558±84 vs 171±18, P<0.05; CCR2, 137±8 vs 63±4, P<0.01; CCR5, 135±13 vs 34±1, P<0.01; n=4/group).
AT from obese males also secreted higher levels of MCP-1 and RANTES than AT from lean controls when cultured ex vivo for 8 hr (MCP-1, 247±28 vs 133±14 ng/g tissue in lean, P<0.05; RANTES, 1716±133 vs 537±101 pg/g tissue in lean, P<0.01; n=4/group).
In vitro chemotaxis study showed that conditioned culture medium from AT of obese males induced significantly more T cell transmigration than AT of lean controls (448±90 vs 104±22 in lean, P<0.05, n=3/group).
Antibody neutralization of RANTES or MCP-1 markedly inhibited T cell transmigration induced by conditioned medium from AT of obese males (RANTES, inhibition 51±8%, P<0.05; MCP-1, inhibition 74±4%, P<0.05; n=3). In addition, mRNA levels of MCP-1, RANTES, CCR2 and CCR5 were increased in visceral AT compared to subcutaneous AT from morbidly obese humans.
Press release: Methodist DeBakey Heart Center, Houston TX; November 2006.