Growth/differentiation factor 15 / GDF15

Where it participates (unsigned role)

1. Metformin increased circulating GDF15 in mice and humans, but studies in wild-type, GDF15-knockout and GFRAL-knockout mice suggested that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance.

   Experimental Gdf15-null mouse genotype → Body weight source_derived_draftungraded
   Experimental context and source evidence

   availability_state

   machinery_impairment Imported condition classification; unverified.

   evidence_span

   {"source_cache": "artifacts/metformin-research/36001956.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457", "start_char": 0, "end_char": 979, "text_sha256": "b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457"}

   experimental_model

   Wild-type, GDF15-knockout and GFRAL-knockout mice with human measurements

   exposure

   Metformin in knockout and wild-type mice

   limitations

   A direct replication attempt reaching the opposite conclusion on necessity, while confirming the GDF15 rise itself.

   nutrient_topic

   Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

   organism

   Mouse and human

   plain_language

   A second group removed the same hormone and still saw the weight effect.

   primary_references

   [metformin-p36001956] The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. (2022). https://pubmed.ncbi.nlm.nih.gov/36001956/ DOI: 10.1016/j.celrep.2022.111258

   tissue_or_cell_type

   Whole-body energy balance

   trigger_kind

   machinery_impairment Imported condition classification; unverified.

   Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 814–825

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Wild-type, GDF15-knockout and GFRAL-knockout mice with human measurements · source_derived_draft · unverified_draft

   ### metformin-gdf15-dispensable Metformin increased circulating GDF15 in mice and humans, but studies in wild-type, GDF15-knockout and GFRAL-knockout mice suggested that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: A second group removed the same hormone and still saw the weight effect. organism: Mouse and human tissue_or_cell_type: Whole-body energy balance experimental_model: Wild-type, GDF15-knockout and GFRAL-knockout mice with human measurements limitations: A direct replication attempt reaching the opposite conclusion on necessity, while confirming the GDF15 rise itself. exposure: Metformin in knockout and wild-type mice evidence_span: {"source_cache": "artifacts/metformin-research/36001956.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457", "start_char": 0, "end_char": 979, "text_sha256": "b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457"} [metformin-p36001956] The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. (2022). https://pubmed.ncbi.nlm.nih.gov/36001956/ DOI: 10.1016/j.celrep.2022.111258

   Complete structured claim and evidence

2. In two independent randomised controlled trials metformin increased circulating GDF15, and in wild-type mice oral metformin increased circulating GDF15 with expression rising predominantly in the distal intestine and the kidney.

   Metformin → Circulating GDF15 concentration source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/metformin-research/31875646.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a", "start_char": 0, "end_char": 1454, "text_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a"}

   experimental_model

   Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice

   exposure

   Oral metformin; high-fat diet in mice; GFRAL-antagonist antibody

   limitations

   The weight mechanism is separable from the glucose mechanism in this work; the mouse knockouts carry the causal claim, the human trials the GDF15 rise. A publisher correction was issued for this paper (Nature 2020;578:E24, PMID 32051582); its notice body was not available, so its impact on these records has not been assessed.

   nutrient_topic

   Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

   organism

   Human and mouse

   plain_language

   The drug raises a hormone that is made mostly in the gut and kidney.

   primary_references

   [metformin-p31875646] GDF15 mediates the effects of metformin on body weight and energy balance. (2020). https://pubmed.ncbi.nlm.nih.gov/31875646/ DOI: 10.1038/s41586-019-1911-y

   tissue_or_cell_type

   Distal intestine, kidney and brainstem receptor

   Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 775–786

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice · source_derived_draft · unverified_draft

   ### metformin-gdf15-rise In two independent randomised controlled trials metformin increased circulating GDF15, and in wild-type mice oral metformin increased circulating GDF15 with expression rising predominantly in the distal intestine and the kidney. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug raises a hormone that is made mostly in the gut and kidney. organism: Human and mouse tissue_or_cell_type: Distal intestine, kidney and brainstem receptor experimental_model: Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice limitations: The weight mechanism is separable from the glucose mechanism in this work; the mouse knockouts carry the causal claim, the human trials the GDF15 rise. A publisher correction was issued for this paper (Nature 2020;578:E24, PMID 32051582); its notice body was not available, so its impact on these records has not been assessed. exposure: Oral metformin; high-fat diet in mice; GFRAL-antagonist antibody evidence_span: {"source_cache": "artifacts/metformin-research/31875646.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a", "start_char": 0, "end_char": 1454, "text_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a"} [metformin-p31875646] GDF15 mediates the effects of metformin on body weight and energy balance. (2020). https://pubmed.ncbi.nlm.nih.gov/31875646/ DOI: 10.1038/s41586-019-1911-y

   Complete structured claim and evidence