The way to avoid the harms done to long-term health and life expectancy by excess visceral fat tissue is not to gain that fat, or to lose it if you have it. This is not the path pursued by that part of the research community interested following the large-scale funding associated with the metabolic diseases of obesity, of course. There is comparatively little profit to be made in telling people to lose weight, versus selling them compensatory pharmaceuticals for a lifetime. However, even with normal, healthy levels of fat tissue, as aging progresses that tissue starts to cause similar issues to those produced by excess fat in earlier life: chronic inflammation, metabolic disruption leading to type 2 diabetes, and so forth. The changes of aging include processes that introduce dysfunction into the relationship between fat and the immune system, one of which is examined here.
Adipose tissue inflammation has become widely accepted as a major contributor to metabolic dysfunction and disorders. Previous studies on diet induced obesity mice have shown that adipose tissue is primed for inflammatory changes prior to other metabolic organs. There is a plethora of research investigating factors in obese adipose tissue inflammation to identify valuable therapeutic targets for metabolic dysfunction. However, much less is understood about age-related adipose tissue inflammation and dysfunction. A better understanding of the cellular and molecular mechanisms of adipose tissue inflammation in aging will be crucial in the development of therapeutics for metabolic diseases beyond cases of diet-induced adipose tissue inflammation and insulin resistance.
Both age-related adiposity and diet-induced obesity are characterized by immune cell infiltration and a sustained inflammatory cycle. Among these various immune cells, adipose tissue macrophage (ATM) accumulation, proliferation, and polarization are major contributors to adipose tissue inflammation and dysfunction. Interestingly, recent studies suggest that changes in preadipocyte function during aging also lead to dysfunctional adipose tissue, eventually progressing to chronic inflammation. Our group have recently shown that elevated endoplasmic reticulum (ER) stress response in aging contributes to greater inflammatory responses, in part due to compromised autophagy activity in the aging adipose tissue. Recent studies have also indicated that with aging there is increased accumulation of senescent cells in many organs including fat depots, which contributes to aging pathologies. However, the detailed molecular mechanisms that lead to increased inflammation in aging adipose tissue are poorly defined.
During the last decade, major advances were made in identifying the molecular mechanisms by which lipid-derived products promote inflammation in different cell types. One type of lipid-derived product, non-esterified fatty acids (NEFA), elevates tissue inflammation through interaction with the pattern recognition receptor Toll-like receptor 4 (TLR4) via its endogenous ligand Fetuin-A (Fet A), a liver derived glycoprotein. Fet A is considered a biomarker of chronic inflammation due to its ability to stimulate the production of inflammatory mediators from both adipocytes and macrophages. Interestingly, Fet-A null mice were protected against obesity and insulin resistance with aging.
The involvement of Fet A-mediated activation of TLR4 pathway in adipose tissue inflammation in diet-induced obesity is well explored. However, the role of this pathway in age-associated adipose tissue inflammation is unknown. We undertook this study to test the hypothesis that age-related adipose tissue inflammation is dependent on the Fet A-mediated TLR4 signaling pathway. We first evaluated the expression of Tlr4 and Fet A gene products in adipose tissue, liver, and plasma samples derived from young and old mice. We then exploited the TLR4-deficient mice to investigate the role of TLR4 in age-associated adipose tissue inflammation, ER stress response, autophagy activity, cellular senescence, and metabolic status (glucose tolerance).
We found that, in contrast to data from diet-induced obesity models, adipose tissue from aged mice have normal Fet A and TLR4 expression. Interestingly, aged TLR4-deficient mice have diminished adipose tissue inflammation compared to normal controls. We further demonstrated that reduced adipose tissue inflammation in old TLR4-deficient mice is linked to impaired ER stress, augmented autophagy activity, and diminished cellular senescence. Importantly, old TLR4-deficient mice have improved glucose tolerance compared to age-matched wild type mice, suggesting that the observed reduced adipose tissue inflammation in aged TLR4-deficient mice has important physiological consequences. Taken together, our present study establishes novel aspect of aging-associated adipose tissue inflammation that is distinct from diet-induced adipose tissue inflammation. Our results also provide strong evidence that TLR4 plays a significant role in promoting aging adipose tissue inflammation.