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

Anna Whitehead,Andrew J Murray,Samuel Virtue,Graeme R Davies,James Dodgson,Fynn N Krause,Klaus K Witte,Jack Garnham,Chris Church ,Edward Amoah Boateng ,John W Wright ,Jürgen Schneider ,Jason L Scragg,Julian L Griffin,Antonio Vidal–Puig ,Amanda D V Maccannell,Ben D Mcnally,Steven A Murfitt,Amy L Moran ,Lee D Roberts

doi:10.1038/s41467-021-22272-3

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.

Highlights

Brown and beige adipose tissue are emerging as distinct endocrine organs
Adipocyte browning was induced in primary adipocytes differentiated from the stromal vascular fraction of subcutaneous white adipose tissue (WAT) of mice using two distinct canonical signaling mechanisms, an adenylate cyclase activator, and peroxisome proliferator-activated receptor δ (Pparδ) agonist (GW0742)[17]
To define the physicochemical nature of the small molecule mediators, aqueous-soluble metabolites were extracted from media conditioned on activated beige adipocytes using solvent partition

Summary

Introduction

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. 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. A discrete panel of small molecule metabolite paracrine and endocrine signals, secreted from both beige and brown adipocytes, is identified These metabokines increase adipose tissue, skeletal muscle, and systemic energy metabolism. We propose these brown and beige adipokine-like small molecules function in an adipose–adipose and adipose–skeletal muscle interorgan signaling axis

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Conclusion