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
• it acts via the GFRAL receptor

• acts on the brain stem centres via GFRAL receptors where it causes anorexia and nausea, and regulates appetite and body weight
• 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)
• in patients with metabolic dysfunction-associated steatohepatitis it can suppress liver inflammation and slow the progression of liver scarring independently of weight loss
  • GDF15 activates signalling from the brain to the nervous system independent of β-adrenergic signaling that leads to the release of glucocorticoids which help dampen inflammation in the liver and those protective effects occur independently of changes in food intake, body weight or liver fat ²⁾

• “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” ³⁾
• 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 ⁴⁾
• 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 ⁵⁾
  • 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 ⁶⁾