Journal
NATURE METABOLISM
Volume 3, Issue 12, Pages 1633-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42255-021-00497-2
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Funding
- NIDDK Mouse Metabolic Phenotyping Centers (MMPC) [DK076169, DK115255]
- EFSD/Novo Nordisk Programme for Diabetes Research in Europ 2016 grant
- Fondation Leducq [TNE15004]
- Ministero dell'Istruzione, dell'Universita e della Ricerca [FIRB RBAP11Z3YA_005, PRIN 2017BF3PXZ]
- PRIN [2010329EKE_005]
- NanoBAT H2020 EU.1.3.3 MSCA-RISE-2015
- Ministry of Education, University and Research (MIUR) Progetto Eccellenza (2018-2022)
- Academy of Finland [335443, 314383, 272376]
- Finnish Medical Foundation
- Gyllenberg Foundation
- Novo Nordisk Foundation [NNF20OC0060547, NNF17OC0027232, NNF10OC1013354]
- Finnish Diabetes Research Foundation
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The study demonstrates that the mitochondrial cristae biogenesis protein Opa1 plays a role in cell-autonomous adipocyte browning through the regulation of the urea cycle. The findings suggest a potential therapeutic strategy for obesity and highlight the connection between the urea cycle and adipocyte browning.
Bean et al. provide evidence showing that the mitochondrial cristae biogenesis protein Opa1 facilitates cell-autonomous white to brown/beige adipocyte conversion, through a process dependent on the urea cycle. White to brown/beige adipocytes conversion is a possible therapeutic strategy to tackle the current obesity epidemics. While mitochondria are key for energy dissipation in brown fat, it is unknown if they can drive adipocyte browning. Here, we show that the mitochondrial cristae biogenesis protein optic atrophy 1 (Opa1) facilitates cell-autonomous adipocyte browning. In two cohorts of patients with obesity, including weight discordant monozygotic twin pairs, adipose tissue OPA1 levels are reduced. In the mouse, Opa1 overexpression favours white adipose tissue expandability as well as browning, ultimately improving glucose tolerance and insulin sensitivity. Transcriptomics and metabolomics analyses identify the Jumanji family chromatin remodelling protein Kdm3a and urea cycle metabolites, including fumarate, as effectors of Opa1-dependent browning. Mechanistically, the higher cyclic adenosine monophosphate (cAMP) levels in Opa1 pre-adipocytes activate cAMP-responsive element binding protein (CREB), which transcribes urea cycle enzymes. Flux analyses in pre-adipocytes indicate that Opa1-dependent fumarate accumulation depends on the urea cycle. Conversely, adipocyte-specific Opa1 deletion curtails urea cycle and beige differentiation of pre-adipocytes, and is rescued by fumarate supplementation. Thus, the urea cycle links the mitochondrial dynamics protein Opa1 to white adipocyte browning.
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