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Profiling Mouse Brown and White Adipocytes to Identify Metabolically Relevant Small ORFs and Functional Microproteins

View ORCID ProfileThomas F. Martinez, Sally Lyons-Abbott, Angie L. Bookout, View ORCID ProfileCynthia Donaldson, Joan M. Vaughan, Calvin Lau, Ariel Abramov, Arian F. Baquero, Karalee Baquero, Dave Friedrich, Justin Huard, Ray Davis, Bong Kim, Ty Koch, View ORCID ProfileAaron J. Mercer, Ayesha Misquith, Sara A. Murray, Sakara Perry, View ORCID ProfileLindsay K. Pino, Christina Sanford, Alex Simon, Yu Zhang, Garrett Zipp, View ORCID ProfileMaxim N. Shokhirev, Andrew J. Whittle, View ORCID ProfileBrian C. Searle, View ORCID ProfileMichael J. MacCoss, Alan Saghatelian, View ORCID ProfileChristopher A. Barnes
doi: https://doi.org/10.1101/2022.03.12.484025
Thomas F. Martinez
1Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA
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Sally Lyons-Abbott
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Angie L. Bookout
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Cynthia Donaldson
3Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA, USA
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Joan M. Vaughan
3Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA, USA
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Calvin Lau
3Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA, USA
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Ariel Abramov
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Arian F. Baquero
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Karalee Baquero
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Dave Friedrich
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Justin Huard
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Ray Davis
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Bong Kim
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Ty Koch
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Aaron J. Mercer
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Ayesha Misquith
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Sara A. Murray
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Sakara Perry
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Lindsay K. Pino
4Department of Genome Sciences, University of Washington, Seattle, WA, USA
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Christina Sanford
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Alex Simon
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Yu Zhang
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Garrett Zipp
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Maxim N. Shokhirev
3Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA, USA
6Razavi Newman Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, CA, USA
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Andrew J. Whittle
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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Brian C. Searle
5Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA
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Michael J. MacCoss
4Department of Genome Sciences, University of Washington, Seattle, WA, USA
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Alan Saghatelian
3Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA, USA
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  • For correspondence: cpba@novonordisk.com asaghatelian@salk.edu
Christopher A. Barnes
2Novo Nordisk Research Center Seattle, Inc. Seattle, WA, USA
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  • For correspondence: cpba@novonordisk.com asaghatelian@salk.edu
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SUMMARY

The absence of thousands of recently annotated small open reading frame (smORF)-encoded peptides and small proteins (microproteins) from databases has precluded their analysis in metabolism and metabolic disease. Given the outsized importance of small proteins and peptides such as insulin, leptin, amylin, glucagon, and glucagon-like peptide-1 (GLP-1) in metabolism, microproteins are a potentially rich source of uncharacterized metabolic regulators. Here, we annotate smORFs in primary differentiated brown, white, and beige mouse adipose cells. Ribosome profiling (Ribo-Seq) detected a total of 3,877 unannotated smORFs. Analysis of RNA-Seq datasets revealed diet-regulated smORF expression in adipose tissues, and validated the adipose translation of the feeding-neuron marker gene Gm8773. Gm8773 encodes the mouse homolog of FAM237B, a neurosecretory protein that stimulates food intake and promotes weight gain in chickens. Testing of recombinant mFAM237B produced similar orexigenic activity in mice further supporting a role for FAM237B as a metabolic regulator and potentially part of the brain-adipose axis. Furthermore, we demonstrated that data independent acquisition mass spectrometry (DIA-MS) proteomics can provide a sensitive, flexible, and quantitative platform for identifying microproteins by mass spectrometry. Using this system led to the detection of 58 microproteins from cell culture and an additional 33 from mouse plasma. The proteomics data established the anti-inflammatory microprotein AW112010 as a circulating factor, and found that plasma levels of a microprotein translated from a FRS2 uORF is elevated in older obese mice. Together, the data highlight the value of this database in examining understudied smORFs and microproteins in metabolic research and identifying additional regulators of metabolism.

Competing Interest Statement

All authors affiliated with the Novo Nordisk Research Center Seattle, Inc. have worked for a for-profit commercial pharmaceuticals company that produces and sells medicines for the treatment of obesity and diabetes. The MacCoss Lab at the University of Washington has a sponsored research agreement with Thermo Fisher Scientific, the manufacturer of the instrumentation used in this research. Michael J MacCoss is also a paid consultant for Thermo Fisher Scientific. Alan Saghatelian is a paid consultant for and cofounder of Exo Therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 14, 2022.
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Profiling Mouse Brown and White Adipocytes to Identify Metabolically Relevant Small ORFs and Functional Microproteins
Thomas F. Martinez, Sally Lyons-Abbott, Angie L. Bookout, Cynthia Donaldson, Joan M. Vaughan, Calvin Lau, Ariel Abramov, Arian F. Baquero, Karalee Baquero, Dave Friedrich, Justin Huard, Ray Davis, Bong Kim, Ty Koch, Aaron J. Mercer, Ayesha Misquith, Sara A. Murray, Sakara Perry, Lindsay K. Pino, Christina Sanford, Alex Simon, Yu Zhang, Garrett Zipp, Maxim N. Shokhirev, Andrew J. Whittle, Brian C. Searle, Michael J. MacCoss, Alan Saghatelian, Christopher A. Barnes
bioRxiv 2022.03.12.484025; doi: https://doi.org/10.1101/2022.03.12.484025
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Profiling Mouse Brown and White Adipocytes to Identify Metabolically Relevant Small ORFs and Functional Microproteins
Thomas F. Martinez, Sally Lyons-Abbott, Angie L. Bookout, Cynthia Donaldson, Joan M. Vaughan, Calvin Lau, Ariel Abramov, Arian F. Baquero, Karalee Baquero, Dave Friedrich, Justin Huard, Ray Davis, Bong Kim, Ty Koch, Aaron J. Mercer, Ayesha Misquith, Sara A. Murray, Sakara Perry, Lindsay K. Pino, Christina Sanford, Alex Simon, Yu Zhang, Garrett Zipp, Maxim N. Shokhirev, Andrew J. Whittle, Brian C. Searle, Michael J. MacCoss, Alan Saghatelian, Christopher A. Barnes
bioRxiv 2022.03.12.484025; doi: https://doi.org/10.1101/2022.03.12.484025

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