Research Article: Toll-like receptor 4 (TLR4) deficient mice are protected from adipose tissue inflammation in aging

Date Published: September 7, 2017

Publisher: Impact Journals LLC

Author(s): Amiya K. Ghosh, Martin O’Brien, Theresa Mau, Raymond Yung.


Adipose tissue (AT) inflammation is a central mechanism for metabolic dysfunction in both diet-induced obesity and age-associated obesity. Studies in diet-induced obesity have characterized the role of Fetuin A (Fet A) in Free Fatty Acids (FFA)-mediated TLR4 activation and adipose tissue inflammation. However, the role of Fet A & TLR4 in aging-related adipose tissue inflammation is unknown. In the current study, analysis of epidymymal fat pads of C57/Bl6 male mice, 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 AT inflammation in old TLR4-deficient mice is linked to impaired ER stress, augmented autophagy activity, and diminished senescence phenomenon. Importantly, old TLR4-deficient mice have improved glucose tolerance compared to age-matched wild type mice, suggesting that the observed reduced AT inflammation in aged TLR4-deficient mice has important physiological consequences. Taken together, our present study establishes novel aspect of aging-associated AT inflammation that is distinct from diet-induced AT inflammation. Our results also provide strong evidence that TLR4 plays a significant role in promoting aging adipose tissue inflammation.

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Adipose tissue inflammation has become widely accepted as a major contributor to metabolic dysfunction and disorders [1, 2]. Previous studies on diet induced obesity (DIO) mice have shown that adipose tissue is primed for inflammatory changes prior to other metabolic organs [3]. 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 under-stood about aging 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.

Chronic low-grade inflammation in adipose tissue contributes to the development of metabolic diseases, including insulin resistance in aging [6, 24]. To understand the mechanism of adipose tissue inflammation, many research groups reported activation of TLR4 receptors by lipids in the context of obesity [1, 15, 25, 26]. Data from obese animals on adipose tissue inflammation have demonstrated that Fet A serves as an adapter for FFA in the activation of the TLR4 pathway [15]. Intriguingly, both Fet A and TLR4 expressions are elevated in the adipose tissue of DIO mouse models, and adipose tissue Fet A serves as a chemoattractant for macrophage migration and polarization [15, 21]. Contrary to the DIO models, we demonstrate here that Fet A level is diminished not only in adipose tissue but also in the serum and liver of old mice (Fig. 2). On the other hand, adipose tissue TLR4 expression remains unchanged between young and old mice. These data indicate that, unlike DIO, the mechanism of aging-associated adipose tissue inflammation is independent of the expression of Fet A or TLR4. To understand TLR4-mediated adipose tissue inflammation in the context of aging, we analyzed the adipose tissue of young and old TLR4 deficient mice, and observed that TLR4 deficiency protects adipose tissue inflammation in old mice (Fig. 3B), as indicated by reduced protein expressions of IL-6 and MCP-1 in the adipose tissue lysates (Fig. 3C).




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