growth differentiation factor 15 (GDF15)

see also:

• hormones
• innate immunity
• cachexia
• anorexia

• the peptide hormone growth differentiation factor 15 (GDF15) wa discovered in 1997 and has been found to have a range of roles in physiology and pathophysiologic processes
• it was previously known as MIC1, NAG1, PLAB, or PTGFB
• it belongs to the TGF-β superfamily based on a characteristic seven cysteine region
• GDF15 circulates as a 25kDa dimer linked by a single inter-chain disulphide bond
• GDF15 likely evolved in the common ancestor of jawed vertebrates
• there is a high level of conservation observed in the C-terminal region of the protein that represents the mature peptide in mammals, reptiles, amphibians, bony fish, and birds.
• the human GDF15 gene is located on the forward strand of the short arm of chromosome 19 (19p13.11), flanked by the pyroglutamyl-peptidase I (PGPEP1) and leucine rich repeat containing 25 (LRRC25) genes upstream and downstream, respectively ¹⁾
• expression of its gene is one of the genes enriched in a model system of macrophage activation

• acts on the brain stem centres via GFRAL receptors where it causes anorexia and nausea
• potential important regulatory actions on embryogenesis in keeping with its placental origin
• inhibits the secretion of tumor necrosis factor-α (TNF-α) from macrophages in response to lipopolysaccharide (LPS)

• “Under normal non-pregnant physiological conditions, circulating GDF15 levels are low, typically less than 1000 pg/ml, but are increased by a wide range of acute stressors such as sepsis and inflammation, and are characteristically persistently elevated in a number of chronic disease states, for example reaching levels of 10,000–100,000 pg/ml in patients with advanced cancers” “ It is markedly elevated at birth at concentrations of 3000 pg/ml, declining to levels within the healthy adult normal range within the first 4 months of life” ²⁾
• GDF15 levels were not significantly altered following a glucose tolerance test
• short- to medium-term imposed caloric deficits have modest or no effect on GDF15 levels
• sustained caloric excess consisting of high-fat feeding for 7 days or an additional 40% of weight maintenance energy requirements for 8 weeks did not alter circulating GDF15
• GDF15 levels increase with chronic over-nutrition (perhaps via adipose tissue inflammatory response and released from macrophages) or with specific nutritional deficits such as amino-acid imbalanced diets
• intense exercise increases GDF15 levels by about a third by 1hr and by about 2/3rds by 2hrs (4-fold increases after an ultra-marathon)
• high altitude increases GDF15 levels
• increasing age: GDF15 levels changed by 11% on average after 5 years of follow-up, and is a biomarker of age

• pregnancy - produced by the feto-placental unit in large amounts and in those with prenatally low levels of GDF15 and thus sensitive to higher levels, are at higher risk of developing hyperemesis gravidarum ³⁾
• patients with beta thallaesaemia
• metformin - elevates circulating GDF15 chronically in humans and the weight loss caused by this drug appears to be dependent on the rise in GDF15
• as part of the cellular integrated stress response (ISR)
  • cellular stress results in phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) which remodels cellular translation, suppressing global protein synthesis while simultaneously activating transcription of an adaptive gene program via the ISR-effector, activating transcription factor 4 (ATF4) with the net effect of repartitioning of nutrients and the biosynthetic machinery to specific pathways that adapt cells to stress - this pathway is a potent regulator of GDF15 in a variety of cell types ⁴⁾
  • toxin exposure (drugs and industrial toxins) on rats have demonstrated upregulation of GDF15 expression, primarily in the kidney
  • GDF15 is also upregulated in human duodenal mucosa from patients suffering from cholera infection
  • smoking increases GDF15 secretion
• atherosclerotic cardiovascular disease
• congestive cardiac failure
• acute kidney injury (AKI) / acute renal failure (ARF) and chronic renal failure
• mitochondrial diseases
• critical illness due to acute infection (sepsis, ARDS, etc)
• obesity
• over-expression of p53 in cancers - causing cachexia
  • other stimuli that have been suggested to utilize p53 to induce GDF15 include C-reactive protein in endothelial cells and vitamin D in prostate cancer cell lines
• EGR1 may be a direct transcriptional regulator of GDF15 (eg. over-expressed in colonic cancers)
• frailty

• ponsegromab
  • monoclonal antibody which blocks GDF15
  • 2024 trial for cancer patients with cachexia - seems to have less side effects than common appetite stimulants and increased weight gain and overall activity level and reduced cachexia symptoms ⁵⁾