An Advanced Glycation End Product (AGE)-Receptor for AGEs (RAGE) Axis Restores Adipogenic Potential of Senescent Preadipocytes through Modulation of p53 Protein Function

Abstract

Background:The impaired adipogenic potential is a hallmark of preadipocyte senescence. Results: Senescent preadipocytes treated with advanced glycation end products (AGEs) resumed adipogenesis in vitro and ex vivo. Conclusion: AGE-induced expression of the receptor for AGEs (RAGE) and AGE-RAGE-dependent inhibition of p53 function restore adipogenesis in senescent preadipocytes. Significance: Glycated proteins could participate in aging-impaired adipose development.The impaired adipogenic potential of senescent preadipocytes is a hallmark of adipose aging and aging-related adipose dysfunction. Although advanced glycation end products (AGEs) derived from both foods and endogenous nonenzymatic glycation and AGE-associated signaling pathways are known to play a key role in aging and its related diseases, the role of AGEs in adipose aging remains elusive. We show a novel pro-adipogenic function of AGEs in replicative senescent preadipocytes and mouse embryonic fibroblasts, as well as primary preadipocytes isolated from aged mice. Using glycated bovine serum albumin (BSA) as a model protein of AGEs, we found that glycated BSA restores the impaired adipogenic potential of senescent preadipocytes in vitro and ex vivo. However, glycated BSA showed no effect on adipogenesis in nonsenescent preadipocytes. The AGE-induced receptor for AGE (RAGE) expression is required for the pro-adipogenic function of AGEs in senescent preadipocytes. RAGE is required for impairment of p53 expression and p53 function in regulating p21 expression in senescent preadipocytes. We also observed a direct binding between RAGE and p53 in senescent preadipocytes. Taken together, our findings reveal a novel pro-adipogenic function of the AGE-RAGE axis in p53-regulated adipogenesis of senescent preadipocytes, providing new insights into aging-dependent adiposity by diet-driven and/or endogenous glycated proteins.Preadipocytes from aged adipose tissue display impaired adipogenic potential and increased pro-inflammatory cytokine secretion (1,2). This is accompanied by cellular senescence of preadipocytes as evidenced by increased levels of senescenceassociated ␤-galactosidase (SA-␤-gal) 2 activity, reactive oxygen species (ROS), and p53, a tumor suppressor protein, expression (3), suggesting a positive correlation between senescence of preadipocytes and adipose dysfunction. Analogous to aged preadipocytes, the preadipocytes isolated from obese animals and humans appear to exhibit senescence-like phenotypes and impaired adipogenic potential with elevated sensitivity to inflammatory cytokine-induced macrophage-like phenotypes (3-7). Although understanding the precise role of senescent preadipocytes in adipose aging still warrants further investigation, facilitated conversion of senescent preadipocytes to adipocytes appears to contribute to adipose development during aging.AGEs are a heterogeneous group of macromolecules that are formed by nonenzymatic glycation of proteins, lipids, or nucleic acids (7). Although exogenous AGEs are mainly generated during ...

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“…The mouse gene primer sequences used for PCR were: mRAGE, forward 5′-AAC ACA GCC CCC ATC CAA-3′, and reverse, 5′-GCT CAA CCA ACA GCT GAA TGC-3′ [14]; mICAM-1, forward 5′-CGC TGT GCT TTG AGA ACT GTG-3′ and reverse 5′-ATA CAC GGT GAT GGT AGC GGA-3′ [15]; mMCP-1, forward 5′-CTG AAG CCA GCT CTC TCT TCC T-3′ and reverse 5′-CAG GCC CAG AAG CAT GAC A-3′ [16] and mGAPDH, forward 5′-CAT GGC CTT CCG TGT TCC TA-3′and reverse 5′-GCG GCA CGT CAG ATC CA-3′ [17]. All samples were measured in triplicates for statistical analysis.…”

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