Brown and beige adipose tissue regulate systemic metabolism through a metabolite interorgan signaling axis

Anna Whitehead, Fynn N. Krause, Amy Moran, Amanda D. V. MacCannell, Jason L. Scragg, Ben D. McNally, Edward Boateng, Steven A. Murfitt, Samuel Virtue, John Wright, Jack Garnham, Graeme R. Davies, James Dodgson, Jurgen E. Schneider, Andrew J. Murray, Christopher Church, Antonio Vidal-Puig, Klaus K. Witte, Julian L. Griffin and Lee D. Roberts ()
Additional contact information
Anna Whitehead: University of Leeds
Fynn N. Krause: University of Cambridge
Amy Moran: University of Leeds
Amanda D. V. MacCannell: University of Leeds
Jason L. Scragg: University of Leeds
Ben D. McNally: University of Cambridge
Edward Boateng: University of Leeds
Steven A. Murfitt: University of Cambridge
Samuel Virtue: University of Cambridge
John Wright: University of Leeds
Jack Garnham: University of Leeds
Graeme R. Davies: Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca
James Dodgson: Phenotypic Screening and High Content Imaging, Antibody Discovery & Protein Engineering, R&D, AstraZeneca
Jurgen E. Schneider: University of Leeds
Andrew J. Murray: University of Cambridge
Christopher Church: Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca
Antonio Vidal-Puig: University of Cambridge
Klaus K. Witte: University of Leeds
Julian L. Griffin: University of Cambridge
Lee D. Roberts: University of Leeds

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: Abstract Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an interorgan signaling network. Using metabolomics, we identify 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. 3-methyl-2-oxovaleric acid and 5-oxoproline signal through cAMP-PKA-p38 MAPK and β-hydroxyisobutyric acid via mTOR. In humans, plasma and adipose tissue 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid concentrations correlate with markers of adipose browning and inversely associate with body mass index. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk.

Date: 2021
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DOI: 10.1038/s41467-021-22272-3

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