DNA Debris From Dying Fat Cells Causes Chronic Inflammation
In the paper I'll point out today, researchers propose a novel mechanism by which fat tissue produces inflammation, involving the effects of DNA fragments released from the debris of dying cells. The presence of extracellular DNA increases with age, and this phenomenon is attracting more attention in the research community. Is it a fundamental form of age-related damage, or can it be considered secondary to other forms of damage, such as those that tend to produce more dysfunctional, dying cells? That is an open question for now.
It is well known that the presence of excess visceral fat tissue, found packed around the abdominal organs, causes a significant increase in chronic inflammation, over and above the age-related inflammatory state produced by the progressive dysfunction of the immune system. Subcutaneous fat is more benign, but even a small amount of excess fat in exactly the wrong place can cause grave consequences. You might recall the evidence for type 2 diabetes to result from a tiny excess of fat in the pancreas - but in normal circumstances, a large amount of surrounding visceral fat is required to create the metabolic dysfunction that allows that tiny but critical amount of pancreatic fat to come into being.
Chronic inflammation is a serious concern when considering its effects of the span of years. It speeds and worsens the development of near all of the common fatal age-related conditions. The effect is large enough that surgical removal of visceral fat extends healthy life in rats, though not by as much as is seen in the calorie restricted rats who never put on that fat in the first place. This is mirrored in human studies showing statistical effects on life expectancy and disease risk in people who were overweight at any point in their lives. Consequences scale by the degree of excess fat, and the time is is carried. The generation of inflammation by fat tissue appears to be one of the more important drivers of the well-documented association in human populations between fat tissue and mortality.
How does visceral fat tissue generate inflammation? The paper here outlines one mechanism. Other researchers point to the false distress signals released by fat cells in overweight individuals that cause the immune system to constantly overreact. An older view is that fat cells become overburdened and die in an environment of overnutrition, and this is enough to draw in the immune system and make it overactive, spurring inflammation. There are numerous other explorations of the precise details of the links between overnutrition and immune system misbehavior. The bottom line is that there is unlikely to be just one mechanism or group of mechanisms responsible for the chronic inflammation resulting from fat tissue. Few things in biology are simple or run along just one track. Still, however many mechanisms there are, known or unknown, they can't significantly harm you if you don't get fat, and they can't harm you any more than they already have if you lose the excess visceral fat you are presently carrying around. Food for thought.
Adipocyte-Derived DNA Triggers Inflammation
Dying fat cells in obese mice release cell-free DNA, recruiting immune cells that can drive chronic inflammation and insulin resistance within adipose tissue. The observed accumulation of macrophages in murine fat tissue depended on the expression of Toll-like receptor 9 (TLR9). Obese mice missing TLR9 had fewer macrophages and were more insulin sensitive compared to their TLR9-expressing counterparts. The new work may partly explain how obesity can drive chronic inflammation.Because prior observational studies have shown that fat cells degenerate in obese individuals, researchers investigated whether obese mice fed a high-fat diet had higher levels of cell-free DNA - shed from the dying fat cells - compared to non-obese mice fed a standard diet. The researchers found higher levels of both double- and single-stranded DNA (ssDNA) as well as increases in cell-free ssDNA that were proportional to increases in visceral fat and blood glucose levels in the obese mice compared to controls. Notably, the ssDNA accumulated in adipose tissue macrophages in obese mice, but not in lean mice.
The team focused on TLR9 because it is expressed in several types of immune cells, binds to exogenous DNA, and has been implicated in the development of several inflammation-associated diseases. Recent studies also revealed that TLR9 can recognize DNA fragments released from degenerated or damaged cells and organs. Consumption of a high-fat diet increased the expression of Tlr9 in visceral fat of the obese mice, particularly in the macrophages within the adipose tissue. Using cultured wild-type macrophages or those that did not express TLR9, the researchers demonstrated that TLR9 is activated by cell-free DNA from dying adipocytes and stimulates proinflammatory activity of the macrophages. Adding tumor necrosis factor α (TNF- α) - previously shown to stimulate degeneration of adipocytes - boosted the amount of cell-free DNA released from dying adipocytes.
In the obese mice, TLR9-driven inflammation contributed to decreased insulin sensitivity. TLR9 knockout mice fed the same high-fat diet had less adipose tissue inflammation and better insulin sensitivity. Adding back TLR9 specifically to the bone marrow cells of mice missing Tlr9 restored increased levels of inflammation and insulin resistance compared to control mice that received bone marrow cells that did not express TLR9. Obese mice given a TLR9 inhibitor showed fewer macrophages within their visceral fat tissue, reduced inflammation, and increased insulin sensitivity compared to their placebo-administered counterparts. Consistent with their mouse data, the researchers found that people with high levels of visceral fat also had elevated cell-free, ssDNA levels in their plasma compared to their more-lean counterparts. These cell-free, ssDNA levels correlated with markers of insulin resistance.
Cell-free DNA (cfDNA) circulating in the blood has recently received much attention as a potential biomarker for monitoring both physiological and pathological conditions. Apoptosis and/or necrosis are considered to be the main source of cfDNA. Several studies have reported a link between cfDNA and inflammatory diseases. Here, we assessed the hypothesis that cfDNA released by obesity-related adipocyte degeneration causes adipose tissue inflammation through recognition by TLR9, contributing to the development of insulin resistance. We examined the association between obesity and the release of cfDNA, and investigated the role of cfDNA in macrophage activation and in the development of adipose tissue inflammation and insulin resistance by using a diet-induced obesity model, a bone marrow transplantation (BMT) model, and an in vivo TLR9 inhibition study involving wild-type and TLR9-deficient (Tlr9-/-) mice. Furthermore, we examined cfDNA level in human plasma to show clinically translatable evidence. Our study may provide a novel mechanism for the development of adipose tissue inflammation and a potential therapeutic target for insulin resistance.Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9-/-) macrophages. Fat-fed Tlr9-/- mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9-/- mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with visceral obesity and was associated with the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.