Abstract
Metformin has been reported to have body weight lowering effects while treating type 2 diabetes. However, limited studies examined the effects of metformin on adipogenesis in vitro, and available data are inconclusive and contradictory. In this study, we examined the effects of a variety of concentrations of metformin on adipocyte differentiation of 3T3-L1 preadipocytes and found metformin exhibits a dual effect on adipogenesis. Metformin at lower concentrations (1.25–2.5 mM) significantly induced adipogenesis while at higher concentrations (5–10 mM) metformin significantly inhibited adipogenesis in 3T3-L1 cells. The biphasic effect of different doses of metformin on adipogenesis was accompanied by increasing or decreasing the expression of adipogenic and lipogenic genes including peroxisome proliferator-activated receptor (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), and fatty acid synthase (FASN) at both messenger RNA (mRNA) and protein levels. Furthermore, only the higher concentrations of metformin induced the phosphorylation of adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), p38, and c-Jun N-terminal kinase (JNK) and reduced the phosphorylation of extracellular regulated protein kinases (ERK) and Akt. Pretreatment with compound C, a specific AMPK inhibitor, significantly countered high concentration of metformin-induced inhibition of adipogenesis. Taken together, these findings demonstrate that the effect of metformin on adipocyte differentiation is biphasic and dose-dependent. Lower concentrations of metformin induce adipogenesis, which could be mediated in an AMPK-independent manner, while higher concentrations of metformin inhibit adipogenesis via AMPK activation.
Highlights
Obesity is a worldwide epidemic as the prevalence of obesity among the adult population has increased rapidly in both developed and developing countries
We first examined whether metformin has an influence on cell proliferation of 3T3-L1 preadipocytes
A (3-(4,5-dimethylthia-zol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay revealed that metformin had no cytotoxicity to 3T3-L1 cells at concentrations lower than 20 mM, 30 mM of metformin significantly inhibited cell viability
Summary
Obesity is a worldwide epidemic as the prevalence of obesity among the adult population has increased rapidly in both developed and developing countries. Obesity is characterized by an excessive accumulation of fat in adipose tissue as well as in the liver, muscles, and other organs. Adipose tissue is a complex organ that regulates and coordinates energy homeostasis [2]. It has been well-established that excessive adipogenesis leads to obesity. According to the World Health Organization, an estimated 422 million adults worldwide (8.5%) are affected by T2DM, and this number is expected to rise to 592 million by 2035 [3]. It is worth noting that a majority of patients with T2DM are obese, and obese people are at a higher risk of developing T2DM [4]
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