Hypermetabolism is a chronic physiological response to severe trauma such as burns. Trademarks of this phenomenon include increases in resting energy expenditure, supraphysiological nutritional requirements, and the systemic wasting of adipose tissue reserves and muscle tissue. In this context, the preservation of white adipose tissue is seen as a valuable strategy to improve patient outcomes. Auger and colleagues demonstrate that metformin directly affects adipose tissue, independently of systemic effects, and that activation of protein phosphatase 2A in burns, owing to the anti-lipolytic action of this enzyme, appears to be a viable strategy for adipose preservation.
Metformin prevents the pathological browning of subcutaneous white adipose tissue
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.