GDF15 D Human

What is GDF15 and what are its primary functions in human physiology?

GDF15 is a secreted protein and distant member of the transforming growth factor-β superfamily that functions as a stress-response cytokine/mitokine. In humans, GDF15 is expressed at relatively low levels in most tissues under basal conditions but becomes markedly upregulated during tissue injury or stress . Research has identified multiple physiological roles for GDF15:

• It serves as a heart-derived hormone that regulates body growth by inhibiting growth hormone signaling in the liver

• It influences food intake and body weight regulation through central nervous system mechanisms

• It functions as a marker of cellular stress that increases during various stressors including intense exercise, altitude, and metabolic stress

• It appears to increase during energy deprivation states, suggesting a role in metabolic adaptation

In healthy individuals, circulating GDF15 levels typically range between 200-1,200 pg/ml and increase with chronological age .

How does GDF15 exert its effects on appetite and metabolism?

Current research indicates that while GDF15 does not appear to play a significant role in day-to-day metabolic regulation in the context of a balanced diet, it becomes important during states of stress or energy deprivation . In pharmacological studies, GDF15 agonism in humans has been shown to cause nausea without accompanying weight loss, suggesting species differences in response mechanisms .

What is the H202D variant in GDF15 and how prevalent is it?

The H202D variant in GDF15 is a common coding polymorphism that changes residue 202 from histidine (H) to aspartate (D) . This variant is widely distributed across human populations with a reported minor allele frequency ranging from 14% to 35% across major continental groups . The high prevalence of this variant suggests it may have evolutionary significance or, alternatively, represents a neutral polymorphism.

Does the H202D variant affect GDF15 bioactivity or measurement?

• Comparing results across different studies that may use different assay platforms

• Interpreting associations between GDF15 levels and clinical outcomes

• Designing clinical trials that use GDF15 as a biomarker

This measurement discrepancy may explain some contradictions between pharmacological studies and Mendelian randomization approaches regarding GDF15's effects on metabolism and body weight .

What is known about human GDF15 knockouts and their phenotypes?

Recent research has identified and characterized human GDF15 knockouts—individuals with homozygous loss-of-function (LOF) variants . Key findings include:

• Eight homozygous carriers of GDF15 LOF variants (including stop gains, frameshifts, and the fully inactivating missense variant C211G) have been identified, ranging in age from 31 to 75 years

• These individuals are fertile, have multiple children, and show no consistent overt phenotypic abnormalities, including no evidence of metabolic dysfunction

• The existence of both male and female GDF15-null individuals who reached adulthood and had children suggests that complete functional genetic loss of GDF15 in at least one parent is compatible with life and fertility

These findings challenge earlier assumptions about the physiological necessity of GDF15 and suggest that therapeutic GDF15 inhibition might be well-tolerated .

How were GDF15 knockout humans identified and characterized?

The identification and characterization of human GDF15 knockouts utilized several methodological approaches:

• Whole exome sequencing through the Pakistan Genomic Resource (PGR) at the Center for Non-Communicable Diseases in Pakistan, which represents one of the world's largest exome biobanks of human homozygous LOF carriers

• Recall-by-genotype (RBG) studies with family-based recruitment of variant carrier probands

• Functional validation of naturally occurring GDF15 LOF variants to confirm their impact on protein function

• Testing for associations between GDF15 LOF and 97 quantitative traits and binary outcomes

This comprehensive approach enabled researchers to identify not only homozygous carriers ("knockouts") but also 227 heterozygous carriers of LOF alleles, including the C211G variant .

How does GDF15 respond to caloric deprivation and metabolic stress?

Research indicates that both total GDF15 (irrespective of genetic variants) and H-specific GDF15 (detected only in H202D-variant absence) increase in response to energy deprivation in humans . Key findings include:

• Total and H-specific GDF15 increase with acute starvation

• Total GDF15 increases with chronic energy deprivation compared with healthy subjects, regardless of leptin repletion

• Baseline GDF15 positively correlates with triglyceride-rich particles and lipoproteins

• During acute metabolic stress, GDF15 associations with metabolites/lipids appear to differ in subjects with the H202D variant

These observations suggest that GDF15 functions as a mitokine reflecting or mediating metabolic stress response rather than primarily driving weight loss .

What is the relationship between GDF15 and cardiac function?

GDF15 has been identified as a heart-derived hormone that regulates body growth, particularly in the context of pediatric heart disease . Research shows that:

• Pediatric heart disease induces GDF15 synthesis and secretion by cardiomyocytes

• Circulating GDF15 acts on the liver to inhibit growth hormone (GH) signaling and body growth

• GDF15 inhibits liver STAT5 phosphorylation without altering JAK2 phosphorylation, decreases liver expression of STAT5 target genes, and reduces plasma IGF1 and IGFBP3 concentrations

• Plasma GDF15 is increased in children with concomitant heart disease and failure to thrive (FTT)

These findings reveal an endocrine mechanism by which the heart coordinates cardiac function and body growth, potentially explaining the clinical observation that children with heart diseases often develop FTT .

What methodological considerations are important when measuring GDF15 levels in research studies?

When designing studies measuring GDF15 levels, researchers should consider several important factors:

• Assay selection: The choice of immunoassay can significantly impact results, particularly due to the H202D variant's interference with certain antibody combinations

• Genotyping participants: When possible, genotyping participants for the H202D variant allows for more accurate interpretation of GDF15 measurements

• Diurnal variation: Consider whether GDF15 levels exhibit circadian patterns

• Age-related changes: Account for the natural increase in GDF15 with chronological age

• Stress indicators: Document potential stressors that might acutely elevate GDF15 (exercise, fasting, illness)

• Pregnancy status: Note that GDF15 naturally increases during pregnancy, which appears to be a primate-specific phenomenon

Researchers should clearly report the specific assay methodology used and acknowledge potential limitations related to variant detection.

How should researchers interpret discrepancies in GDF15 levels between different studies?

When interpreting discrepancies in reported GDF15 levels across different studies, researchers should consider:

• Assay differences: Different immunoassays may have varying abilities to detect the H and D isoforms of GDF15

• Population genetics: The frequency of the H202D variant differs across populations, potentially introducing systematic biases

• Study conditions: Acute stressors, fasting status, and other physiological conditions can significantly affect GDF15 levels

• Sample handling: Pre-analytical factors such as sample collection, processing time, and storage conditions may affect measured GDF15 concentrations

When comparing studies, researchers should ideally standardize measurements or develop correction factors based on the specific assays used and population characteristics.

What are the implications of GDF15 research for therapeutic development?

Current research on GDF15 has significant implications for therapeutic development in several areas:

• Treatment of cachexia and anorexia: GDF15 antagonism is being tested in clinical trials to treat cachexia and anorexia, with the existence of healthy human GDF15 knockouts supporting the potential safety of this approach

• Potential weight management applications: While GDF15 agonism causes nausea without accompanying weight loss in humans, refined approaches might exploit its metabolic effects

• Pregnancy-related conditions: Human genetics point to a role for GDF15 in hyperemesis gravidarum, suggesting potential therapeutic targets

• Cardiac conditions: Understanding GDF15's role as a heart-derived hormone suggests potential applications in pediatric heart disease and associated growth issues

The discovery that GDF15 knockouts show no consistent overt phenotypes indicates that therapeutic inhibition of GDF15 may be well-tolerated, though pharmacological intervention is not equivalent to genetic variation .

How do genetic and pharmacological studies of GDF15 complement or contradict each other?

Genetic and pharmacological studies of GDF15 have yielded some apparently contradictory results that require careful interpretation:

• Pharmacological GDF15 agonism in animal models promotes weight loss, while Mendelian randomization studies suggest genetically determined increases in GDF15 might predispose to obesity

• Pharmacological GDF15 agonism in humans causes nausea without accompanying weight loss, suggesting species differences in responses

• The existence of healthy GDF15 knockout humans contradicts some predictions from animal models regarding GDF15's physiological necessity

These discrepancies may be explained by:

• Measurement issues related to the H202D variant affecting interpretation of genetic association studies

• Compensatory mechanisms during development in genetic knockouts that are absent in acute pharmacological interventions

• Species differences in GDF15 signaling and physiological roles

• Context-dependent GDF15 functions that differ between health and disease states