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Prolyl isomerase Pin1 regulates mouse embryonic fibroblast differentiation into adipose cells
Takafumi Uchida1, Kengo Furumai, Tomokazu Fukuda
1Molecular Enzymology, Department of Molecular Cell Science, Graduate School of Agricultural Science, Tohoku University, Miyagi, Japan. uchidat@biochem.tohoku.ac.jp
Background:
A peptidyl prolyl cis/trans isomerase, Pin1, regulates insulin signal transduction. Pin1 reduces responses to insulin stimulation by binding CRTC2 (CREB-regulated transcriptional co-activator 2) and PPARγ (peroxisome prolifereator- activated receptor γ), but conversely enhances insulin signaling by binding IRS-1 (insulin receptor substrate-1), Akt kinase, and Smad3. Therefore, it is still unclear whether Pin1 inhibits or enhances adipose cell differentiation.
Methodology/Principal Findings:
Pin1(-/-) and wild-type mice were fed with high fat diets and adipose tissue weight was measured. Compared to wild-type mice, Pin1(-/-) mice had lower adipose tissue weight, while the weight of other tissues was similar. Mouse embryo fibroblasts (MEFs), prepared from both groups of mice, were induced to differentiate into adipose cells by stimulation with insulin. However, the rate of differentiation of MEFs from Pin1(-/-) mice was less than that of MEFs from wild-type mice. The rate of insulin-induced MEF cell differentiation in Pin1(-/-) mice was restored by increasing expression of Pin1. We found that Pin1 binds to phosphoThr172- and phosphoSer271-Pro sites in CREB suppress the activity in COS-7 cells.
Conclusion And Significance:
Pin1 enhanced the uptake of triglycerides and the differentiation of MEF cells into adipose cells in response to insulin stimulation. Results of this study suggest that Pin1 down-regulation could be a potential approach in obesity-related dysfunctions, such as high blood pressure, diabetes, non-alcoholic steatohepatitis.
Insights
Pin1 enhances insulin-induced adipose cell differentiation and triglyceride uptake. Down-regulating Pin1 may offer a strategy for managing obesity-related conditions like diabetes and hypertension.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Research
Background:
- Pin1 (peptidyl prolyl cis/trans isomerase) has complex roles in insulin signaling, interacting with various proteins to either enhance or reduce pathway activity.
- The precise role of Pin1 in adipose cell differentiation remained unclear due to its dual regulatory functions.
Purpose of the Study:
- To elucidate the specific role of Pin1 in insulin-mediated adipose cell differentiation.
- To investigate the impact of Pin1 deficiency on adipose tissue development and insulin sensitivity.
Main Methods:
- Comparison of adipose tissue weight and insulin-induced differentiation of mouse embryo fibroblasts (MEFs) between wild-type and Pin1 knockout mice fed high-fat diets.
- Restoration of Pin1 expression in knockout MEFs to assess its effect on differentiation.
- Analysis of Pin1 binding sites in CREB (cAMP response element-binding protein).
Main Results:
- Pin1 knockout mice exhibited reduced adipose tissue weight compared to wild-type controls.
- MEFs from Pin1 knockout mice showed impaired insulin-induced differentiation, which was rescued by Pin1 re-expression.
- Pin1 was found to bind to specific phosphorylated sites on CREB.
Conclusions:
- Pin1 plays a crucial role in enhancing insulin-stimulated triglyceride uptake and adipose cell differentiation.
- Targeting Pin1 down-regulation presents a potential therapeutic avenue for metabolic disorders associated with obesity, including diabetes and hypertension.
