Abstract
Extracellular matrix (ECM), as an essential component of adipose tissue, not only provides mechanical support for adipocyte growth, but also participates in ECM-adipocyte communication via various secreted proteins, including highly enriched collagens. Collagen XV (ColXV) is a secreted non-fibrillar collagen within ECM Basement Membrane (BM) zones and well recognized as a tumor suppressor. However, the role of ColXV in adipose tissue is still unknown. In this study, high fat diet (HFD) fed mice were used as obese model, in which we deeply investigated the interaction between ColXV and adipocyte differentiation or adipose metabolism. We found great elevated ColXV expression and positive effect of ColXV on lipid deposition during adipocyte differentiation or obesity both in vitro and in vivo. cAMP response element binding protein (CREB) is a cellular transcription factor that can inhibit adipogenesis and promote lipolysis. Here we proposed ColXV as a newly discovered downstream gene of CREB. We further proved that CREB can repress adipocyte differentiation and enhance lipolysis by negatively regulating ColXV transcription. Mechanistic studies showed ColXV enhanced adipocyte differentiation and lipid deposition through reducing its DNA methylation and repressing the cAMP/PKA signaling pathway. Collectively, our study identified ColXV as a novel downstream gene for CREB and could promote adipocyte differentiation, inhibit lipolysis through repressing cAMP/PKA signaling pathway and positively regulating adipogenic markers expressions by repressing the activity of maintenance methyltransferase Dnmt1. Our data discovered a novel role of ColXV in adipocyte differentiation and provide insight into obesity and related metabolic diseases.
Highlights
The increasing obesity and obesity-related diseases such as insulin resistance and type II diabetes are closely associated with excessive fat deposition [1,2,3]
Followed by elevated adipogenic markers peroxisome proliferator activated receptor γ (PPARγ), FABP4 and decreased thermogenic gene UCP1 in high fat diet (HFD) fed mice (Figure 1C), Collagen XV (ColXV) mRNA level was robustly increased in mouse brown adipose tissue (BAT), inguinal white adipose tissue (iWAT) and epididymis white adipose tissue (eWAT) (Figure 1B)
ColXV expression was positively correlated with PPARγ and FABP4 in iWAT and eWAT, but negatively correlated with UCP1 in BAT (Figure 1D–1F)
Summary
The increasing obesity and obesity-related diseases such as insulin resistance and type II diabetes are closely associated with excessive fat deposition [1,2,3]. Adipose tissues, which mainly consist of adipocytes, are important in balancing systemic energy levels. Two general classes of adipose tissues are found in mammals: white and brown. Adipose tissue grows through hyperplasia and/or hypertrophy, which results in increasing adipocytes number and differentiating into fat-laden adipocytes. CCAAT/ enhancer-binding proteins (C/EBPs) and peroxisome proliferator activated receptor γ (PPARγ) are considered as central engine for adipocyte differentiation [4]. Studies implicated activated PKA directly phosphorylates the transcription www.impactjournals.com/oncotarget factor cyclic AMP responsive element binding protein (CREB), which promotes the expressions of lipolysis and thermogenic genes such as peroxisome proliferator γ-activated receptor coactivator 1-α (Pgc-1α) and uncoupling protein 1 (Ucp1) in adipocytes [5, 6]
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