"Nature Metabolism" scientists find for the first time a protein that can promote the autonomous browning of white fat!

Disorders of adipose tissue metabolism are associated with many diseases prevalent in the world, such as obesity, type 2 diabetes, cardiovascular disease and certain tumors

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

Mitochondria are important organelles 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 related to obesity and metabolic diseases, while the role of the mitochondrial fusion protein OPA1 in the inner mitochondrial membrane of adipose tissue is unclear [2]

On December 6, a research team led by Luca Scorrano from the Department of Biology at the University of Padova in Italy published important research results in the prestigious journal Nature Metabolism

They found that OPA1 protein in the inner mitochondrial membrane promotes adipocyte-autonomous browning by affecting the urea cycle [3]

In past work, researchers have identified mitochondrial dysfunction in adipose tissue during obesity development 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 is unclear what role mitochondria play in obesity

Since obesity is determined by a variety of genetic and environmental factors, Luca Scorrano's team used identical twins as research objects, and adopted a unified method to measure mitochondrial protein levels in obese patients to explore the relationship between obesity and op1 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

To understand how adipose tissue OPA1 levels affect adipose tissue metabolism, they generated a mildly overexpressed mouse model of OPA1 by targeting a transgene (OPA1 tg) and analyzed its adipose tissue metabolism

They found that subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) size and weight, and adipocyte size were significantly reduced in OPA1 tg mice compared with WT mice; Increased tolerance and insulin sensitivity were also observed in mice

So what causes the altered adipose tissue metabolism in OPA1 tg mice?

Luca Scorrano's team attributed this to a change in WAT

A more in-depth study found that brown adipose tissue marker genes and OPA1 were expressed at higher levels in subcutaneous adipose tissue than in visceral adipose tissue; transcription of Ucp1, Opa1 tg of Ucp1 was detected in subcutaneous adipose tissue of mice in a cold environment Transcript levels were 28-fold higher than in WT mice

These findings further suggest that OPA1 promotes WAT browning and that OPA1 levels are positively correlated with WAT browning
.
  

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 preadipocyte transcriptomic, metabolomic and metabolic flux analysis (MFA) revealed that the mitochondrial fusion protein OPA1 promotes WAT-autonomous browning by affecting the urea cycle and Kdm3a
.

Therefore, they propose that the uremic cycle in adipose tissue can be reactivated as a strategy for treating 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 functions independently of its mitochondrial fusion-promoting function
.

Since no other mitochondrial fusion genes were observed to be associated with metabolic health, they suggest that OPA1 has an independent role in mitochondrial biology and metabolism beyond promoting mitochondrial fusion
.

In conclusion, this study is the first to identify the role of the mitochondrial protein OPA1 in white fat browning and to clarify its mechanism of action
.

Based on this progress, it is possible to develop new treatments for obesity and metabolic diseases, and we will 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 , Pietil?inen KH, Vetttor 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.
Pietil?inen KH, Naukkarinen J, Rissanen A, Saharinen J, Ellonen P, Ker?nen H, Suomalainen A, G?tz A, Suortti T, Yki-J?rvinen 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.