Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans

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Abstract

Metformin, a widely used first-line treatment for type 2 diabetes (T2D), is known to reduce blood glucose levels and suppress appetite. Here we report a significant elevation of the appetite-suppressing metabolite N-lactoyl phenylalanine (Lac-Phe) in the blood of individuals treated with metformin across seven observational and interventional studies. Furthermore, Lac-Phe levels were found to rise in response to acute metformin administration and post-prandially in patients with T2D or in metabolically healthy volunteers.

Abstract

Metformin treatment was found to be associated with acute increases in the appetite-suppressing metabolite Lac-Phe in several human observational and interventional studies.

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Organization of GC/MS and LC/MS metabolomics data into chemical libraries

Corey DeHaven, Anne M Evans, Hongping Dai … (2010)

Background Metabolomics experiments involve generating and comparing small molecule (metabolite) profiles from complex mixture samples to identify those metabolites that are modulated in altered states (e.g., disease, drug treatment, toxin exposure). One non-targeted metabolomics approach attempts to identify and interrogate all small molecules in a sample using GC or LC separation followed by MS or MSn detection. Analysis of the resulting large, multifaceted data sets to rapidly and accurately identify the metabolites is a challenging task that relies on the availability of chemical libraries of metabolite spectral signatures. A method for analyzing spectrometry data to identify and Qu antify I ndividual C omponents in a S ample, (QUICS), enables generation of chemical library entries from known standards and, importantly, from unknown metabolites present in experimental samples but without a corresponding library entry. This method accounts for all ions in a sample spectrum, performs library matches, and allows review of the data to quality check library entries. The QUICS method identifies ions related to any given metabolite by correlating ion data across the complete set of experimental samples, thus revealing subtle spectral trends that may not be evident when viewing individual samples and are likely to be indicative of the presence of one or more otherwise obscured metabolites. Results LC-MS/MS or GC-MS data from 33 liver samples were analyzed simultaneously which exploited the inherent biological diversity of the samples and the largely non-covariant chemical nature of the metabolites when viewed over multiple samples. Ions were partitioned by both retention time (RT) and covariance which grouped ions from a single common underlying metabolite. This approach benefitted from using mass, time and intensity data in aggregate over the entire sample set to reject outliers and noise thereby producing higher quality chemical identities. The aggregated data was matched to reference chemical libraries to aid in identifying the ion set as a known metabolite or as a new unknown biochemical to be added to the library. Conclusion The QUICS methodology enabled rapid, in-depth evaluation of all possible metabolites (known and unknown) within a set of samples to identify the metabolites and, for those that did not have an entry in the reference library, to create a library entry to identify that metabolite in future studies.

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Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems.

Anne M Evans, Corey DeHaven, Tom Barrett … (2009)

To address the challenges associated with metabolomics analyses, such as identification of chemical structures and elimination of experimental artifacts, we developed a platform that integrated the chemical analysis, including identification and relative quantification, data reduction, and quality assurance components of the process. The analytical platform incorporated two separate ultrahigh performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS(2)) injections; one injection was optimized for basic species, and the other was optimized for acidic species. This approach permitted the detection of 339 small molecules, a total instrument analysis time of 24 min (two injections at 12 min each), while maintaining a median process variability of 9%. The resulting MS/MS(2) data were searched against an in-house generated authentic standard library that included retention time, molecular weight (m/z), preferred adducts, and in-source fragments as well as their associated MS/MS spectra for all molecules in the library. The library allowed the rapid and high-confidence identification of the experimentally detected molecules based on a multiparameter match without need for additional analyses. This integrated platform enabled the high-throughput collection and relative quantitative analysis of analytical data and identified a large number and broad spectrum of molecules with a high degree of confidence.

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GDF15 mediates the effects of metformin on body weight and energy balance

Anthony P. Coll, Michael A Chen, Pranali Taskar … (2019)

Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.

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Author and article information

Contributors

Lydia Lynch:

ORCID: http://orcid.org/0000-0002-4273-4681

llynch@bwh.harvard.edu

Journal

Journal ID (nlm-ta): Nat Metab

Journal ID (iso-abbrev): Nat Metab

Title: Nature Metabolism

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2522-5812

Publication date (Electronic): 18 March 2024

Publication date PMC-release: 18 March 2024

Publication date (Print): 2024

Volume: 6

Issue: 4

Pages: 651-658

Affiliations

[1 ]School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, ( https://ror.org/02tyrky19) Dublin, Ireland

[2 ]GRID grid.38142.3c, ISNI 000000041936754X, Division of Endocrinology, , Brigham and Women’s Hospital, Harvard Medical School, ; Boston, MA USA

[3 ]School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, ( https://ror.org/02tyrky19) Dublin, Ireland

Author information

Barry Scott http://orcid.org/0000-0002-8841-3525

Emily A. Day http://orcid.org/0000-0003-3245-5715

John Scanlan http://orcid.org/0009-0001-9559-4731

David K. Finlay http://orcid.org/0000-0003-2716-6679

Lydia Lynch http://orcid.org/0000-0002-4273-4681

Article

Publisher ID: 1018

DOI: 10.1038/s42255-024-01018-7

PMC ID: 11052712

PubMed ID: 38499765

SO-VID: b445daa9-1a06-43ac-8b4c-0022374bb612

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 23 January 2024

Date accepted : 22 February 2024

Funding

Funded by: FundRef https://doi.org/10.13039/100000060, U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID);

Award ID: R01AI134861 Supplement

Award ID: R01AI134861

Award Recipient : Aine Ni Scannail Lydia Lynch

Funded by: FundRef https://doi.org/10.13039/501100001602, Science Foundation Ireland (SFI);

Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)

Funded by: FundRef https://doi.org/10.13039/100011199, EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013));

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Keywords: metabolomics,type 2 diabetes,metabolism,mechanism of action

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Keywords: metabolomics, type 2 diabetes, metabolism, mechanism of action

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Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans

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Horses and Humans Research Foundation

Most cited references 31

Organization of GC/MS and LC/MS metabolomics data into chemical libraries

Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems.

GDF15 mediates the effects of metformin on body weight and energy balance

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Cited by 4

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