Abstract
As emerging evidence suggesting neurodegenerative diseases and metabolic diseases have common pathogenesis, we hypothesized that the neurite outgrowth-controlling collapsin response mediator protein 2 (CRMP2) was involved in energy homeostasis. Therefore, putative roles of CRMP2 in adipocyte differentiation (adipogenesis) and lipid metabolism were explored and addressed in this study. CRMP2 expression profiles were in vitro and in vivo characterized during adipogenic process of 3T3-L1 pre-adipocytes and diet-induced obese (DIO) mice, respectively. Effects of CRMP2 on lipid metabolism and deposits were also analyzed. Our data revealed that CRMP2 expression pattern was coupled with adipogenic stages. CRMP2 overexpression inhibited cell proliferation at MCE phase, and significantly reduced lipid contents by down-regulating adipogenesis-driving transcription factors and lipid-synthesizing enzymes. Interestingly, GLUT4 translocation and the lipid droplets fusion were disturbed in CRMP2-silencing cells by affecting actin polymerization. Moreover, adipose CRMP2 was significantly increased in DIO mice, indicating CRMP2 is associated with obesity. Accordingly, CRMP2 exerts multiple functions in adipogenesis and lipid deposits through mediating cell proliferation, glucose/lipid metabolism and cytoskeleton dynamics. The present study identifies novel roles of CRMP2 in mediating adipogenesis and possible implication in metabolic disorders, as well as provides molecular evidence supporting the link of pathogenesis between neurodegenerative diseases and metabolic abnormalities.
Highlights
Global type 2 diabetes mellitus (T2DM) prevalence has been exponentially increasing over the past 3 decades
We previously provide the molecular evidence addressing the linkage between Parkinson’s disease (PD) and T2DM comorbidity by uncovering the roles of PTEN-induced kinase 1 (PINK1)-presenilin associated rhomboid-like protein (PARL)-PINK1-Parkin system in adipocyte differentiation and energy metabolism [17]
The above results strongly suggest that collapsin response mediator protein 2 (CRMP2) suppresses adipocyte differentiation through inhibiting the machinery required for adipogenesis, including cell proliferation at MCE phase, the expression of critical adipogenic transcription factors leading to the decreased adipogenic markers, and the critical lipid-synthesizing enzymes resulting in the reduced lipid contents in the mature adipocytes
Summary
Global type 2 diabetes mellitus (T2DM) prevalence has been exponentially increasing over the past 3 decades. In addition to serving as one of the major target molecules of insulin in modulating energy homeostasis, GSK-3β is the critical enzyme controlling microtubule dynamics via mediating the activity of collapsin response mediator protein 2 (CRMP2) [6,7,8]. CRMP2 is the most studied member among the CRMP family proteins, which regulates multiple physiological activities including microtubule dynamics, neuronal outgrowth and polarity, and vehicle transportation [6,7,8]. GSK-3β the major regulator controlling CRMP2 activities and microtubule dynamics in neuronal cells, is the important insulin downstream signaling molecule modulating metabolic homeostasis. Our results demonstrate that CRMP2 exerts multiple functions in adipogenesis and determines lipid deposits through mediating cell proliferation, glucose/lipid metabolism, and cytoskeleton dynamics
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