Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms

Abstract

People with Type 2 diabetes mellitus (T2DM) have reduced bone mineral density and an increased risk of fractures due to altered mesenchymal stem cell (MSC) differentiation in the bone marrow. This leads to a shift in the balance of differentiation away from bone formation (osteogenesis) in favour of fat cell development (adipogenesis). The commonly used anti-diabetic drug, metformin, activates the osteogenic transcription factor Runt-related transcription factor 2 (Runx2), which may suppress adipogenesis, leading to improved bone health. Here we investigate the involvement of the metabolic enzyme, AMP-activated protein kinase (AMPK), in these protective actions of metformin. The anti-adipogenic actions of metformin were observed in multipotent C3H10T1/2 MSCs, in which metformin exerted reciprocal control over the activities of Runx2 and the adipogenic transcription factor, PPARγ, leading to suppression of adipogenesis. These effects appeared to be independent of AMPK activation but rather through the suppression of the mTOR/p70S6K signalling pathway. Basal AMPK and mTOR/p70S6K activity did appear to be required for adipogenesis, as demonstrated by the use of the AMPK inhibitor, compound C. This observation was further supported by using AMPK knockout mouse embryo fibroblasts (MEFs) where adipogenesis, as assessed by reduced lipid accumulation and expression of the adipogeneic transcription factor, C/EBPβ, was found to display an absolute requirement for AMPK. Further activation of AMPK in wild type MEFS, with either metformin or the AMPK-specific activator, A769662, was also associated with suppression of adipogenesis. It appears, therefore, that basal AMPK activity is required for adipogenesis and that metformin can inhibit adipogenesis through AMPK-dependent or -independent mechanisms, depending on the cellular context.

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…In vitro, metformin also appears to protect against AGE‐induced cellular injury and cell death in osteoblastic cells, similar to described effects in other human and rodent complication‐affiliated cell types such as neurons, macrophages, cardiomyocytes, and renal tubular cells . In many cases, these effects are thought to be mediated by metformin activation of AMPK signaling pathways . Given that AMPK is a regulator of cellular energy sensing, a role for metformin in stimulating osteogenesis and inhibiting adipogenesis is conceptually consistent with its presumed systemic effects .…”

“…Examining both murine and human‐derived mesenchymal stem cell cultures, metformin exposure has been shown in several studies to induce an overall shift in mesenchymal stem cell differentiation toward the osteogenic pathway and away from adipogenesis . Further evidence of the osteogenic potential of metformin comes from studies utilizing a variety of osteoblast‐specific cell cultures, including UMR106 cells, MC3T3‐E1 cells, primary mouse calvarial cultures, and primary rat osteoblast cultures.…”

A novel berberine‐metformin hybrid compound exerts therapeutic effects on obese type 2 diabetic rats

“…Metformin (MET) has been used as the first‐line drug therapy for T2DM, due to its excellent inhibitory effect on hepatic glucose production . Berberine (BB) is an isoquinoline alkaloid originally isolated from Chinese herb Coptis chinensis (Huang lian), which exerts anti‐diabetic and anti‐inflammatory activities .…”

Berberine Inhibits Adipogenesis in Porcine Adipocytes via AMP‐Activated Protein Kinase‐Dependent and ‐Independent Mechanisms

“…The results are supported by previous studies in 3 T3‐L1 adipocytes (Jiang et al, , ; Li et al, ). On the contrary, recent conflicting reports involving the role of AMPK in adipogenesis showed that suppressing AMPK activity with compound C, a specific AMPK inhibitor, resulted in a decreased lipid accumulation and protein level of the adipogenic marker gene Perilipin a in adipogenic‐induced C3H10T1/2 mouse mesenchymal stem cells (MSC) (Chen et al, ). Moreover, knockout of Ampka in mouse embryonal fibroblasts (MEF) downregulated the expression of C/EBPβ protein and repressed adipogenic differentiation of the cells (Chen et al, ).…”

“…On the contrary, recent conflicting reports involving the role of AMPK in adipogenesis showed that suppressing AMPK activity with compound C, a specific AMPK inhibitor, resulted in a decreased lipid accumulation and protein level of the adipogenic marker gene Perilipin a in adipogenic‐induced C3H10T1/2 mouse mesenchymal stem cells (MSC) (Chen et al, ). Moreover, knockout of Ampka in mouse embryonal fibroblasts (MEF) downregulated the expression of C/EBPβ protein and repressed adipogenic differentiation of the cells (Chen et al, ). Furthermore, adipose tissue‐specific knockout of Ampka1 or Ampka2 in mice lead to an increased lipolysis and reduced triacylglycerol (TAG) content in adipocytes; meanwhile, the mice were lean (Kim et al, ).…”