Mitochondrial protein OPA1 can promote autonomous browning of white fat
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Mitochondrial protein OPA1 can promote autonomous browning of white fat.
Nature Metabolism: Scientists discover for the first time that mitochondrial protein OPA1 can promote autonomous browning of white fat
Adipose tissue metabolism disorders are associated with many diseases prevalent in the world, such as obesity, type 2 diabetes, cardiovascular disease, and certain tumors. As an important part of the endocrine system, adipose tissue secretes many key hormones, and its dysfunction also affects distant cells and tissues [1].
In mammals, white adipose tissue (WAT) stores energy, while brown adipose tissue (BAT) converts energy into heat through uncoupling protein 1 (Ucp1)-mediated thermogenesis.
For adults, brown fat can fight obesity and diabetes . Since BAT is scarce in the human body, scientists have thought of “browning” white fat as a possible therapeutic strategy to address obesity and metabolic diseases .
Mitochondria are a key organelle involved in fat metabolism and play a key role in brown fat energy expenditure.
Electron transport chain activity, fatty acid oxidation (FAO) deficiency, and abnormal mitochondrial morphology are all associated with obesity and metabolic diseases, while the role of the mitochondrial fusion protein OPA1 in the inner mitochondrial membrane in adipose tissue is unclear [2].
On December 6, a team led by Luca Scorrano from the Department of Biology, University of Padova, Italy, published important research results in the famous journal Nature Metabolism.
They found that OPA1 protein in the inner mitochondrial membrane can promote the autonomous browning of adipocytes, and this promotion is produced by affecting the urea cycle [3].
In past work, researchers have identified mitochondrial dysfunction in adipose tissue in the development of obesity through genetic analysis [4].
However, mitochondrial dysfunction is a broad concept that does not draw conclusions about differences in adipose tissue between lean and obese individuals.
While some studies have identified the importance of mitochondria in adipose tissue, it has not been clear what role mitochondria play in obesity.
Since obesity is determined by a variety of genetic and environmental factors, Luca Scorrano’s team took identical twins as research subjects and adopted a unified method to measure mitochondrial protein levels in obese patients to explore the relationship between obesity and OPA1 expression in adipose tissue.
They studied identical twins with discordant body mass index to see if there were differences in key factors regulating mitochondrial morphology, and found that OPA1 expression was significantly downregulated in the subcutaneous adipose tissue of the heavier twins .
To understand how adipose tissue OPA1 levels affect adipose tissue metabolism, they generated a mild OPA1-overexpressing mouse model by targeting a transgene ( Opa1 tg ) and analyzed its adipose tissue metabolism.
They found that Opa1 tg mice had significantly reduced subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) size and weight, as well as adipocyte size , in Opa1 tg mice compared with WT mice ; Increased tolerance and increased insulin sensitivity were also observed in high-fat diet-fed (HFD) mice .
▲ Size, weight andH&E stainingWT andOpa1 tg mice
So what causes the altered metabolism of adipose tissue in Opa1 tg mice?
Luca Scorrano’s team attributed this to a change in WAT. They observed that the expression of Ucp1 in the subcutaneous fat of HFD Opa1 tg mice was higher than that of littermate WT mice; and Ucp1 is a key protein in mediating BAT thermogenesis, suggesting that OPA1 may promote WAT browning .
A more in-depth study found that brown adipose tissue marker genes and OPA1 were more expressed in subcutaneous adipose tissue than in visceral adipose tissue; Ucp1 transcription was detected in subcutaneous adipose tissue of mice exposed to cold environment, and Opa1 tg Transcription of Ucp1 was increased 28-fold compared to WT mice .
These findings further suggest that OPA1 promotes WAT browning and that OPA1 levels are positively correlated with WAT browning .
▲ WT and Opa1 tgImmunoblotting and fold changes of Ucp1 transcripts in mice exposed to room temperature or cold
To understand the complex mechanism by which OPA1 promotes WAT browning, Luca Scorrano’s team discovered the browning pathway of the Jumanji family group demethylating protease Kdm3a mediated by Ucp1 transcription by studying the differentiation of primary OPA1 white preadipocytes .
Subsequent transcriptomic, metabolomic, and metabolic flux analysis (MFA) in preadipocytes revealed that the mitochondrial fusion protein Opa1 promotes WAT-autonomous browning by affecting the urea cycle and Kdm3a .
Therefore, Luca Scorrano’s team proposes that the uremic cycle of adipose tissue can be reactivated as a strategy for the treatment of obesity.
However, whether this function of OPA1 is based on mitochondrial fusion remains to be explored, but Luca Scorrano’s team is inclined to believe that OPA1 function is independent of its mitochondrial fusion-promoting function .
Because other mitochondrial fusion genes were not observed to be associated with metabolic health, they suggested that OPA1 has independent roles in mitochondrial biology and metabolism in addition to promoting mitochondrial fusion.
Overall, this study is the first to identify the role of the mitochondrial protein OPA1 in the browning of white fat and to elucidate the mechanism of action.
Based on this progress, it may be possible to develop new treatments for obesity and metabolic diseases, let us wait and see.
references:
1.Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004 Jun;89(6):2548-56. doi: 10.1210/jc.2004-0395. PMID: 15181022.
2. Giacomello M, Pyakurel A, Glytsou C, Scorrano L. The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol. 2020 Apr;21(4):204-224. doi: 10.1038/s41580-020-0210 -7. Epub 2020 Feb 18. PMID: 32071438.
3. Bean C, Audano M, Varanita T, Favaretto F, Medaglia M, Gerdol M, Pernas L, Stasi F, Giacomello M, Herkenne S, Muniandy M, Heinonen S, Cazaly E, Ollikainen M, Milan G, Pallavicini A , Pietiläinen KH, Vettor R, Mitro N, Scorrano L. The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites. Nat Metab. 2021 Dec 6. doi: 10.1038/s42255-021-00497-2. Epub ahead of print. PMID: 34873337.
4. Pietiläinen KH, Naukkarinen J, Rissanen A, Saharinen J, Ellonen P, Keränen H, Suomalainen A, Götz A, Suortti T, Yki-Järvinen H, Oresic M, Kaprio J, Peltonen L. Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med. 2008 Mar 11;5(3):e51. doi: 10.1371/journal.pmed.0050051. PMID: 18336063; PMCID: PMC2265758.
Mitochondrial protein OPA1 can promote autonomous browning of white fat
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