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

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.

Network pharmacology-based strategy to investigate pharmacological mechanisms of Ginkgo Biloba Extract for Aging

“…Inactivation of the ErbB signaling pathway leads to a loss of myocardial protective function during cardiac hypertrophy and to the onset of early failure [51].T cell receptor (TCR) signaling pathway, Toll-like receptor (TLR) signaling pathway and NOD-like receptor (NLR) signaling pathway are responsible for generating innate immune responses and playing a critical role in in ammation. Toll-like receptors play a signi cant role in promoting aging adipose tissue in ammation, and the study shows that old TLR4-de cient mice have improved glucose tolerance compared to age-matched wild type mice [54]. A different set of NOD-like receptors induces caspase-1 activation and the activated of caspase-1 regulates maturation of the pro-in ammatory cytokines IL-1B, IL-18 and drives pyroptosis [55].…”

Administration of hydrogen-rich water prevents vascular aging of the aorta in LDL receptor-deficient mice

“…Signaling via TLRs activates macrophages, resulting in increased secretion of inflammatory cytokines 48 , 49 . Recent study showed the reduced expression of p16 INK4a and p21 in the adipose tissue of TLR4-deficient aged mice 50 , indicating that drinking HW may attenuate cellular senescence by downregulation of TLR signaling. We then stained the aorta with anti-TLR4 antibody and found that drinking HW tended to suppress the increase TLR4 in atheroma, however it was not significant (Supplementary Fig.…”

Novel role of autophagy-associated Pik3c3 gene in gonadal white adipose tissue browning in aged C57/Bl6 male mice

“…To understand the molecular basis of adipose tissue inflammation, our work on gWAT across the lifespan have provided strong evidence of autophagy impairment [ 1 ] as a basis of elevated ER stress response which in turn promotes gWAT inflammation in aging mice. Recently, we have demonstrated that proficient autophagy activity and reduced senescence in gWAT were associated with improved glucose tolerance in aging Tlr4 -knockout mice [ 28 ]. Much of the previous conclusions were derived by comparing expressions of ER stress response genes in young or old animals in basal state or under the influence of chemical inducers for ER stress response [ 29 ].…”