Abstract
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.
Highlights
Adipose tissue inflammation has become widely accepted as a major contributor to metabolic dysfunction and disorders [1, 2]
Adipose tissue expression of Toll-like receptor 4 (TLR4) and Fetuin A (Fet A) are elevated in diet induced obesity (DIO) but not in aging
Consistent with previous reports [15, 21], our present analysis indicates that DIO increases the expression of both TLR4 and Fet A, and contributes to adipose tissue inflammation as indicated by higher mRNA expression of Mcp1 (Fig.1)
Summary
Adipose tissue inflammation has become widely accepted as a major contributor to metabolic dysfunction and disorders [1, 2]. 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. Recent studies suggest www.aging‐us.com that changes in preadipocyte function during aging lead to dysfunctional adipose tissue, eventually progressing to chronic inflammation [6]. These changes include reduced preadipocyte replication, decreased adipogenesis, increased lipid toxicity, increased proinflammatory cytokines, chemokines, extracellular matrix (ECM)-modifying proteases, and stress response elements. The detailed molecular mechanisms that lead to increased inflammation in aging adipose tissue are poorly defined
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