MOLMET
865
S2212-8778(19)30619-2
10.1016/j.molmet.2019.08.011
The Authors
Original Article
Metformin prevents the pathological browning of subcutaneous white adipose tissue
Christopher
Auger
1
Carly M.
Knuth
2
Abdikarim
Abdullahi
2
Osai
Samadi
2
Alexandra
Parousis
1
Marc G.
Jeschke
1
2
∗
marc.jeschke@sunnybrook.ca
1
Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, M4N 3M5, Canada
Ross Tilley Burn Centre
Sunnybrook Health Sciences Centre
Toronto
Ontario
M4N 3M5
Canada
Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, M4N 3M5, Canada
2
University of Toronto, Toronto, Ontario, M5S 1A1, Canada
University of Toronto
Toronto
Ontario
M5S 1A1
Canada
University of Toronto, Toronto, Ontario, M5S 1A1, Canada
∗
Corresponding author. Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, M4N 3M5, Canada. Fax: +416 480 6763.
Ross Tilley Burn Centre
Sunnybrook Health Sciences Centre
Toronto
Ontario
M4N 3M5
Canada
Abstract
Objective
Browning, the conversion of white adipose tissue (WAT) to a beige phenotype, has gained interest as a strategy to induce weight loss and improve insulin resistance in metabolic disorders. However, for hypermetabolic conditions stemming from burn trauma or cancer cachexia, browning is thought to contribute to energy wasting and supraphysiological nutritional requirements. Metformin's impact on this phenomenon and underlying mechanisms have not been explored.
Methods
We used both a murine burn model and human ex vivo adipose explants to assess metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)'s effects on the development of subcutaneous beige adipose. Enzymes involved in fat homeostasis and browning, as well as mitochondrial dynamics, were assessed to determine metformin's effects.
Results
Treatment with the biguanide metformin lowers lipolysis in beige fat by inducing protein phosphatase 2A (PP2A) independently of adenosine monophosphate kinase (AMPK) activation. Increased PP2A activity catalyzes the dephosphorylation of acetyl-CoA carboxylase (Ser 79) and hormone sensitive lipase (Ser 660), thus promoting fat storage and the “whitening” of otherwise lipolytic beige adipocytes. Moreover, co-incubation of metformin with the PP2A inhibitor okadaic acid countered the anti-lipolytic effects of this biguanide in human adipose. Additionally, we show that metformin does not activate this pathway in the WAT of control mice and that AICAR sustains the browning of white adipose, offering further evidence that metformin acts independently of this cellular energy sensor.
Conclusions
This work provides novel insights into the mechanistic underpinnings of metformin's therapeutic benefits and potential as an agent to reduce the lipotoxicity associated with hypermetabolism and adipose browning.
Graphical abstract
Image 1
Highlights
•
Metformin prevents the catabolism of murine iWAT tissue post-burn injury.
•
Mitochondrial respiration and uncoupling in adipose are decreased by metformin.
•
Metformin, independently of AMPK, reduces adipose lipolysis and β-oxidation via PP2A.
•
AICAR treatment activates AMPK in peripheral adipose leading to sustained browning.
•
PP2A is directly induced by metformin in scWAT, lowering ACC/HSL phosphorylation.
Keywords
Trauma
Oxidative phosphorylation
Metformin
Burns
Mitochondria
Uncoupling
KBJ00000000011542
2019-10-26T18:47:15
S300.1
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S2212-8778(19)30619-2
10.1016/j.molmet.2019.08.011
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2212-8778
865
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2019-08-20T14:16:36Z
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