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Exosome-Based Interorgan Transport of Mitochondria from Energetically Stressed Adipocytes

ABSTRACT: Samples are small extracellular vesicles isolated from the serum of control mice (WTexo) and adipo-FtMT mice (TGexo) fed a high fat diet with doxycycline for 3 weeks. The adipo-FtMT mouse is a model of doxycycline-inducible, adipocyte-specific overexpression of mitochondrial ferritin (FtMT) to induce mitochondrial dysfunction and oxidative stress

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Philipp E. Scherer

PROVIDER: MSV000085896 | MassIVE | Mon Aug 03 09:36:00 BST 2020

REPOSITORIES: MassIVE

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Project description:Purpose: To investigate alterations in subcutaneous white adipose gene expression induced by genetic AMPK activation in vivo, in mice fed a chow or a high-fat diet. Methods: Subcutaneous white adipose tissue mRNA profiles of wild-type transgenic (WT-Tg) mice and mice expressing a gain-of-function AMPK mutant gamma1 subunit (D316A-Tg) were generated by deep sequencing. Results: RNA sequencing revealed over 3000 differentially expressed genes between WT-Tg and D316A-Tg subcutaneous white adipose tissue (WATsc) from mice fed a high fat diet (HFD), of which many were classified as 'skeletal muscle-associated'. Interestingly, uncoupling protein 1 (UCP1), associated with 'beige' adipocyte formation in WATsc, was not differentially expressed. On a chow diet, many differentially expressed genes were also identified, with gene ontology analysis identifiying glycolysis, TCA cycle and brown fat differentiation as highly enriched; key features of brown adipocyte identity. HFD-associated skeletal-muscle associated gene expression was either not significantly altered, or significantly down-regulated on a chow diet, indicating a diet-induced gene signature in D316A-Tg WATsc. Conclusions: Our study revealed gene signatures indicative of brown adipocyte development on a chow diet, where no overt metabolic phenotype was observed in gain-of-function animals. When fed a HFD, WATsc from D316A-Tg mice displayed a muscle-like gene signature, expressing key components of creatine and calcium thermogenic cycles including Ckmt2 (creatine kinase, mitochondrial 2) Atp2a1 (SERCA1-sarco/endoplasmic reticulum ATPase 1) and ryr1 (ryanodine receptor 1). UCP1 expression was not altered between WT-Tg and D316A-Tg mice fed a HFD. Our findings suggest a novel role for AMPK in the regulation of white adipocyte identity and a potentially novel cell population that, when metabolically challenged, preferrentially utilise muscle-like thermogenic futile cycles independent of UCP1 to mediate whole organism energy expenditure.

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Exosome-Based Interorgan Transport of Mitochondria from Energetically Stressed Adipocytes

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