Metformin prevents the pathological browning of subcutaneous white adipose tissue

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.

Management of Cancer Cachexia: Attempting to Develop New Pharmacological Agents for New Effective Therapeutic Options

“…In a preclinical setting, Etoxomir was shown to effectively rescue human myotubes in vitro as well as muscle mass and body weight of cachectic mice (210). Yet, Metformin was shown to prevent WAT browning by increasing PP2A activity, with subsequent dephosphorylation of acetyl-CoA carboxylase and HSL (211). Targeting of hepatic peroxisome proliferator-activated receptor-α (PPARα) by PPARα agonists has also show a considerable potential.…”

ASCs derived from burn patients are more prone to increased oxidative metabolism and reactive oxygen species upon passaging

“…It has been recently shown that the sustained hypermetabolism seen in burned patients is, in part, due to the browning of the subcutaneous adipose tissue [ 23 ]. Both in the acute and chronic time frames, this tissue displays increased oxidative phosphorylation, mitochondrial mass, and mitochondrial uncoupling that is associated with higher expression of the adipose-specific uncoupling protein 1 (UCP1) [ 24 , 25 ]. Interestingly, ASCs from burned patients did not display increased oxygen consumption in the basal or the leak states when compared to ASCs from non-burned patients.…”

Recent Advances in Experimental Burn Models

“…Therefore, most radiation-inflicted injury models require laborious pilot experiments to determine the unique adjustments needed for each experimental setting. Furthermore, human or porcine ex vivo and in vitro skin models have been established to study the immediate local response to thermal burns or novel treatments [44,[49][50][51][52]73].…”