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.

Background: Common demographic risk factors are identified in colorectal cancer (CRC) and type 2 diabetes mellitus (DM), nevertheless, the molecular link and mechanism for CRC-DM comorbidity remain elusive. Dysregulated glycogen synthase kinase-3 beta under metabolic imbalance is suggested to accelerate CRC pathogenesis/progression via regulating collpasin response mediator protein-2 (CRMP2). Accordingly, roles of CRMP2 in CRC and CRC-DM patients were investigated for elucidating the molecular convergence of CRC and DM. Methods: CRMP2 profile in tumor tissues from CRC and CRC-DM patients was investigated to explore the link between CRC and DM etiology. Meanwhile, molecular mechanism of glucose to regulate CRMP2 profile and CRC characteristics was examined in vitro and in vivo. Results: CRMP2 was significantly lower in tumor lesions and associated with advanced tumor stage in CRC-DM patients. Physiological hyperglycemia suppressed CRMP2 expression/activity and augmented malignant characteristics of CRC cells. Hyperglycemia promotes actin de-polymerization, cytoskeleton flexibility and cell proliferation/metastasis by downregulating CRMP2 profile and thus contributes to CRC disease progression. Conclusions: This study uncovers molecular evidence to substantiate and elucidate the link between CRC and T2DM, as well as characterizing the roles of CRMP2 in CRC-DM. Accordingly, altered metabolic adaptations are promising targets for anti-diabetic and cancer strategies.

Type 2 diabetes mellitus (T2DM) is associated with chronic inflammation, suggesting the metabolic abnormalities are originated from or exacerbated by cytokine overproduction. Cytokines and counter-regulatory molecules are crucial in keeping the balance of immune responses and, therefore, are potential candidates involved in T2DM etiology, development and complications. Our previous reports identify several significant associations between the genotypes of cytokine genes and T2DM and/or the clinical lipid parameters, which strongly suggest the participation of immune-regulatory molecules in lipid metabolism. The aim of this study is to determine the distribution of gene encoding cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a T-cell negative regulator, in T2DM patients and health subjects. Genomic DNA was extracted from 287 Taiwanese T2DM patients and 278 ethnic- and age- matched healthy subjects, and two CTLA-4 polymorphisms (-318 C/T and +49 A/G) were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Intriguingly, CTLA-4 -318 genotype was associated with circulatory triglycerides in T2DM subjects (P=0.019) although no significant association between CTLA-4 -318 (P=0.119) and +49 (P=0.2) genotypes with T2DM was identified. In addition, CTLA-4 +49 genotype was significantly associated with the ratio between total cholesterol and high-density lipoprotein (P=0.004) in control subjects. Our results suggest that CTLA-4 may be involved in lipid metabolism and affect T2DM disease progression and/or the development of diabetic complications although this gene does not represent a major risk factor for T2DM.

Our previous studies demonstrated that collapsin response mediator protein 2 (CRMP2) is associated with obesity and, in addition, that hyperglycemia-suppressed CRMP2 augments malignant traits of colorectal cancer and is associated with advanced tumor stage. Regulation of CRMP2 profile was further explored in this study using 3T3-L1 pre-adipocyte adipogenesis as a study model for illustrating the roles of CRMP2 in metabolic homeostasis. Hyperglycemia inhibited expression of CRMP2, adipogenic machinery and adipocyte markers. CRMP2 displayed f-CRMP2 (62~66 kDa) and s-CMRP2 (58 kDa) isoforms at the growth arrest phase. Expression of s-CRMP2 was coupled with the mitotic clonal expansion (MCE) phase to direct cell proliferation and rapidly down-regulated in post-mitotic cells. In the late differentiation phase, f-CRMP2 was co-localized with tubulin in the cortical area. Insulin-enhanced CRMP2-glucose transporter 4 (GLUT4) co-localization and CRMP2 puncta on lipid droplets (LDs) suggested participation of CRMP2 in GLUT4 translocation and LD fusion. Collectively, the CRMP2 functional profile must be finely controlled to adjust cytoskeletal stability for meeting dynamic cellular needs. Manipulating the s-CRMP2/f-CRMP2 ratio and thus the cytoskeleton dynamics is anticipated to improve glucose uptake and insulin sensitivity. In summary, our data provide molecular evidence explaining the functions of CRMP2 in physiological, pathological and disease progression in metabolic homeostasis and disorders related to metabolic abnormalities, including cancer.