CIDEC Human

What is human CIDEC and what are its primary functions in metabolism?

CIDEC is a protein originally identified as a lipid droplet-associated protein in adipocytes that positively correlates with insulin sensitivity in humans . Though initially characterized for its role in adipose tissue, recent research has discovered that CIDEC is abundantly expressed in human endothelial cells where it regulates vascular function .

The protein plays multiple critical roles in metabolism:

• Regulation of adipose lipolysis and protection against high-fat diet-induced glucose intolerance

• Improvement of systemic insulin sensitivity and glucose homeostasis

• Enhancement of endothelium-dependent vascular relaxation

• Improvement of vascularization in metabolically active tissues including adipose tissue, skeletal muscle, and heart

• Mitigation of dyslipidemia associated with high-fat diets

Human studies consistently show a positive association between CIDEC expression and healthy metabolic phenotypes across multiple investigations .

How does endothelial CIDEC expression differ from adipose CIDEC expression in humans?

While CIDEC was first identified as an adipocyte-specific protein regulating lipolysis and insulin sensitivity, more recent discoveries have shown it is highly expressed in human endothelial cells . The protein appears to have distinct but complementary functions in these different tissue types:

In adipocytes:

• Associates with lipid droplets

• Regulates lipid metabolism pathways

• Influences whole-body glucose homeostasis through effects on adipose tissue

In endothelial cells:

• Improves endothelium-dependent vascular relaxation

• Enhances endothelial nitric oxide synthase activation

• Improves tissue vascularization

• Contributes to protection against diet-induced metabolic dysfunction

This dual expression pattern suggests CIDEC acts through multiple mechanisms to improve metabolic health, with both direct effects on lipid handling and indirect effects through vascular improvements.

What clinical correlations exist between CIDEC expression levels and metabolic disorders?

Multiple clinical investigations have established significant correlations between CIDEC and metabolic health parameters:

In obese humans, CIDEC expression in adipose tissue positively correlates with insulin sensitivity . Studies in obese populations show associations between CIDEC levels and various metabolic parameters:

Additionally, single nucleotide polymorphisms (SNPs) in the CIDEC gene are associated with metabolic syndrome components. Specifically, the minor allele of SNP rs2479 (A allele) is associated with elevated fasting plasma glucose and blood triglyceride levels, while both rs1053239 and rs2479 predict longitudinal deterioration of blood pressure .

What transgenic models are available for studying human CIDEC function, and what are their key characteristics?

Several innovative transgenic mouse models have been developed to study human CIDEC function:

Adipose-specific human CIDEC expression model (Ad-CIDECtg):

• Generated by inserting a floxed stop codon followed by the human CIDEC expression cassette into the mouse Rosa26 locus

• Bred with B6.FVB-Tg(Adipoq-cre)1Evdr/J mice expressing Cre recombinase under control of mouse adiponectin promoter/enhancer regions

• Expresses human CIDEC specifically in adipose tissue without altering endogenous mouse Cidec expression

• Shows improved AKT phosphorylation in perigonadal adipose tissue and skeletal muscle when fed high-fat diet

• Displays improved whole-body glucose homeostasis and insulin sensitivity

Endothelial-specific human CIDEC expression model (E-CIDECtg):

• Generated using floxed humanized mice with the human CIDEC transgene crossed with Tek-Cre mice

• Expresses human CIDEC specifically in endothelial cells

• Shows approximately twofold increase in combined CIDEC (human) and Cidec (mouse) protein levels in endothelial cells

• Demonstrates protection against high-fat diet-induced glucose intolerance, insulin resistance, and dyslipidemia

• Exhibits improved insulin signaling, enhanced endothelium-dependent vascular relaxation, and improved tissue vascularization

CIDEC mutant model:

• Expresses mutant human CIDEC (E186X) in adipose tissue

• Allows comparison with wild-type CIDEC to understand functional domains

These models enable targeted investigation of tissue-specific CIDEC effects and mechanisms while maintaining physiological relevance to human disease.

How do mouse and human CIDEC isoforms differ in their cellular and physiological effects?

Critical differences exist between mouse and human CIDEC isoforms that researchers must consider when designing experiments:

• Functional differences: Mouse and human CIDEC isoforms differ in their cellular and physiological effects, particularly regarding insulin signaling and glucose homeostasis

• Translational implications: Studies using mouse Cidec may not fully predict human CIDEC effects, necessitating humanized models for highest translational impact

• Conservation of positive metabolic effects: Despite differences between species, human studies consistently show positive associations between CIDEC and healthy metabolic phenotypes

Research approaches should account for these species differences by:

• Using humanized mouse models when possible

• Validating findings in human tissues and cells

• Considering potential divergence in regulatory pathways between species

• Focusing on pathways with conserved function across species

This species specificity underscores why researchers have developed transgenic models expressing human CIDEC rather than relying solely on endogenous mouse Cidec studies .

What molecular mechanisms underlie CIDEC's role in improving vascular function and metabolic health?

Research has identified several molecular mechanisms through which CIDEC improves vascular function and metabolic health:

In adipose tissue:

• Regulates lipid homeostasis pathways, confirmed by transcriptome analysis showing upregulation of genes associated with lipid metabolism

• Influences adipose lipolysis, with 670 downregulated and 761 upregulated differentially expressed genes identified in adipose tissue of Ad-CIDECtg mice

• Pathway analysis revealed 26 upregulated pathways and 12 downregulated pathways, with many upregulated genes associated with lipid metabolism

In endothelial cells:

• Enhances endothelial nitric oxide synthase activation

• Improves endothelium-dependent vascular relaxation

• Enhances vascularization of metabolically active tissues including adipose tissue, skeletal muscle, and heart

• Improves insulin signaling through enhanced AKT phosphorylation

Systemic effects:

• Protects against high-fat diet-induced glucose intolerance and insulin resistance

• Mitigates dyslipidemia associated with high-fat diets

• Improves whole-body glucose homeostasis, with transgenic mice showing lower basal insulin levels and maintaining glucose tolerance despite high-fat diet challenge

These mechanisms operate in concert to produce CIDEC's beneficial effects on both vascular function and metabolic health.

How do genetic variations in the human CIDEC gene influence metabolic syndrome components?

Single nucleotide polymorphisms (SNPs) in the CIDEC gene have significant associations with metabolic syndrome components:

rs2479 variant:

• The minor allele (A allele) is associated with elevated fasting plasma glucose and blood triglyceride levels

• Has a minor allele frequency (MAF) of 0.261 (0.252 for Han Chinese in Beijing)

• Confers increased risk for metabolic syndrome components with OR=1.353 (95% CI: 1.098, 1.666) for AG/AA genotypes compared to GG

rs1053239 variant:

• Has a minor allele frequency (MAF) of 0.409 (0.374 for Han Chinese in Beijing)

• Shows associations with metabolic parameters in some populations

Both rs2479 and rs1053239:

• Predict longitudinal deterioration of blood pressure

• Associated with high efficacy and cost-effectiveness for angiotensin II-targeted antihypertensive drugs

• May help identify individuals at higher risk for metabolic syndrome components

• Could guide genotype-directed application of antihypertensive therapy

These genetic variations are located within 3' untranslational regions (3' UTRs) of the CIDEC gene, suggesting they may affect post-transcriptional regulation of CIDEC expression.

What methodological approaches are recommended for assessing CIDEC function in experimental models?

Based on published research, the following methodological approaches are recommended for comprehensive assessment of CIDEC function:

For transgenic model validation:

• PCR genotyping using specific primer pairs for human CIDEC and Cre recombinase to confirm transgene presence

• Measurement of CIDEC gene expression in target tissues using qPCR

• Western blot analysis using antibodies that bind both human and mouse isoforms to quantify protein levels

For metabolic phenotyping:

• Glucose tolerance testing with insulin level measurement before and after glucose injection

• Assessment of insulin sensitivity through measurement of AKT phosphorylation in response to insulin injection in multiple tissues

• Analysis of circulating lipid profiles including triglycerides, total cholesterol, HDL-C, and LDL-C

For vascular function assessment:

• Evaluation of endothelium-dependent vascular relaxation

• Measurement of endothelial nitric oxide synthase activation

• Assessment of tissue vascularization in adipose tissue, skeletal muscle, and heart

For molecular mechanism exploration:

• Transcriptome analysis to identify differentially expressed genes (DEGs)

• Pathway analysis of DEGs to identify affected biological processes

• Heat map visualization of altered genes associated with specific pathways

• Analysis of insulin signaling pathways in multiple tissues

These methodological approaches provide a comprehensive framework for investigating CIDEC function across multiple physiological systems.

How do research findings on CIDEC challenge or complement existing paradigms in obesity and cardiovascular research?

The emerging research on CIDEC challenges several existing paradigms in obesity and cardiovascular research:

Integration of adipose and vascular biology:

• Challenges the traditional separation between adipose tissue research and vascular biology

• Demonstrates that CIDEC functions in both adipocytes and endothelial cells, suggesting coordinated regulation of metabolism and vascular function

• Emphasizes that diseases like diabetes and obesity cannot be disassociated from cardiovascular disease due to their close physiological relationships

Prevention versus management paradigm:

• Shifts focus from disease management toward prevention and potential cures

• As researchers note: "Discoveries like this one allow us to not only manage the disease but work to cure it and help fight any related disorders"

Tissue-specific versus systemic effects:

• Shows how tissue-specific expression of a single protein (CIDEC) can have profound systemic metabolic effects

• Demonstrates that targeted interventions in specific tissues can influence whole-body physiology

Personalized medicine applications:

• Genetic variations in CIDEC predict response to specific antihypertensive medications

• Provides evidence for genotype-guided therapeutic applications, particularly for angiotensin II-targeted therapy

These findings suggest that integrated approaches targeting both metabolic and vascular pathways may be more effective for treating cardiometabolic diseases than approaches focused on single aspects of pathophysiology.

What are the current limitations and contradictions in CIDEC research that require further investigation?

Several important limitations and contradictions exist in the current CIDEC research landscape:

Translational gaps between mouse and human biology:

• Mouse and human CIDEC isoforms differ in their cellular and physiological effects

• Most mechanistic studies rely on mouse models, which may not fully recapitulate human CIDEC function

• Despite humanized transgenic models, further validation in human tissues is needed

Limited understanding of blood pressure regulation:

• Limited human data exist on the relation of CIDEC with blood pressure regulation

• Genetic studies show CIDEC SNPs predict blood pressure changes, but mechanisms remain unclear

• How CIDEC in endothelial cells directly influences blood pressure regulation requires further investigation

Tissue-specific versus systemic effects:

• It remains unclear how tissue-specific CIDEC expression coordinates systemic metabolic improvements

• Cross-talk mechanisms between CIDEC in adipose tissue and endothelial cells are not fully elucidated

• The relative contributions of adipose versus endothelial CIDEC to metabolic health are difficult to dissect

Genetic variation effects across populations:

• Most genetic studies focus on specific populations (e.g., Chinese Han cohort)

• Population differences in CIDEC SNP frequencies and effects require broader investigation

• Whether findings on CIDEC SNPs apply universally across ethnic groups needs confirmation

Therapeutic development challenges:

• Despite promising findings, translating CIDEC research into therapeutic interventions remains challenging

• Methods to selectively enhance CIDEC function in specific tissues require development

• Long-term safety and efficacy of CIDEC-targeted approaches need extensive evaluation

Addressing these limitations will require integrated research approaches combining human studies with advanced experimental models and comprehensive physiological assessments.