Role of glycated proteins and its associated pathways in adipose development
Abstract
Glycated proteins, known as advanced glycation end products (AGEs) are formed in Maillard reaction, mainly during food processing. Endogenous AGEs occur spontaneously in human body, particularly accumulating during hyperglycemic conditions and aging. However, the function of AGEs in adipose development and aging is unclear. Here, we demenstrated that a role for AGEs in pro-adipogenesis, particularly in senescent preadipocytes. We identified that high pasaged 3T3-L1 cells displayed a defect in adipogenic ability characterizing senescent cells. Interestingly, AGEs treatment restored impaired adipogenic potential of senescent preadipocytes in vitro and ex vivo, while the control (BSA) had little effect on promoting adipogenesis. This is likely through an induction of its receptor, RAGE, and RAGE-suppressed p53 expression and its function. As previous studies have been reported an inhibitory role of p53 in adipogenesis, our results suggested that AGEs-induced RAGE-53-dependent pathway restores adipogenic potential in senescent preadipocytes. We further elucidated the direct function of RAGE in adipocyte differentiation using lentiviral-shRNA mediated RAGE knockdown (KD) system. We found RAGE KD resulted in a reduction of lipid accumulation through impaired the mitotic clonal expansion (MCE) program in the early stage of adipogenesis. Similar to the senescent preadipocytes, RAGE KD preadipocytes showed an alteration in p53 function. Moreover, RAGE KD in preadipocytes resulted in lowering basal levels of inflammation and reactive oxygen species (ROS) production when compared to control cells. Additionally, these RAGE knockdown cells were resistant to lipopolysaccharide-stimulated inflammation and pro-oxidant-initiated ROS generation. The requirement of functional RAGE for adipogenesis was next tested using high-mobility group box protein 1 (HMGB1), an endogenous RAGE ligand and known as a pro-inflammatory cytokine. In analogous to RAGE activation, we observed that HMGB1 knockdown preadipocytes showed a decrease of lipid accumulation and a delay of the cell cycle with impaired MCE. Consequently, we propose a conceptual framework for considering how AGEs and their associated RAGE-dependent pathways in preadipocytes may modulate p53 function to lead to altering adipogenesis. As obesity (adiposity) and adipose aging are positively correlated with increased cellular accumulation of AGEs and RAGE expression, regulation of AGEs/RAGE/HMGB1 could become an effective intervention in obesity development.
Degree
Ph.D.
Advisors
Kim, Purdue University.
Subject Area
Molecular biology|Aging|Nutrition
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