Formononetin, an isoflavone, activates AMP-activated protein kinase/β-catenin signalling to inhibit adipogenesis and rescues C57BL/6 mice from high-fat diet-induced obesity and bone loss

Abstract

Balance between adipocyte and osteoblast differentiation is the key link of disease progression in obesity and osteoporosis. We have previously reported that formononetin (FNT), an isoflavone extracted from Butea monosperma, stimulates osteoblast formation and protects against postmenopausal bone loss. The inverse relationship between osteoblasts and adipocytes prompted us to analyse the effect of FNT on adipogenesis and in vivo bone loss, triggered by high-fat diet (HFD)-induced obesity. The anti-obesity effect and mechanism of action of FNT was determined in 3T3-L1 cells and HFD-induced obese male mice. Our findings show that FNT suppresses the adipogenic differentiation of 3T3-L1 fibroblasts, through down-regulation of key adipogenic markers such as PPARγ, CCAAT/enhancer-binding protein alpha (C/EBPα) and sterol regulatory element-binding protein (SREBP) and inhibits intracellular TAG accumulation. Increased intracellular reactive oxygen species levels and AMP-activated protein kinase (AMPK) activation accompanied by stabilisation of β-catenin were attributed to the anti-adipogenic action of FNT. In vivo, 12 weeks of FNT treatment inhibited the development of obesity in mice by attenuating HFD-induced body weight gain and visceral fat accumulation. The anti-obesity effect of FNT results from increased energy expenditure. FNT also protects against HFD-induced dyslipidaemia and rescues deterioration of trabecular bone volume by increasing bone formation and decreasing bone resorbtion caused by HFD. FNT's rescuing action against obesity-induced osteoporosis commenced at the level of progenitors, as bone marrow progenitor cells, obtained from the HFD mice group supplemented with FNT, showed increased osteogenic and decreased adipogenic potentials. Our findings suggest that FNT inhibits adipogenesis through AMPK/β-catenin signal transduction pathways and protects against HFD-induced obesity and bone loss.

Red Clover (<i>Trifolium pratense</i> L.) Sprout Prevents Metabolic Syndrome

“…There are various reports of bean components that are related to anti-obesity and anti-hypolipidemia (9), and it is natural to assign the cause of these RC effects to formononetin. The trends after RC administration seem to be similar, although there are some differences such as no change in VLDL cholesterol and low L/H efficacy compared to formononetin administration alone (6).…”

“…Recently, in vivo experiments using C57BL/6 mice and 0.1 to 10 mg/ kg/d of formononetin added to a high-fat diet for 12 wk resulted in weight gain, visceral fat accumulation, hyperlipidemia, and bone density loss. Formononetin also had a strong effect on preventing obesity and bone loss caused by the high fat diet (6).…”

The negative adipogenesis regulator DLK1 is transcriptionally regulated by TIS7 (IFRD1) and translationally by its orthologue SKMc15 (IFRD2)

“…In TIS7 SKMc15 dKO mice we found inhibited PPARγ and C/EBPα levels, induced MEK/ERK pathway, and decreased expression of CD36 and DGAT1, all hallmarks of up regulated DLK-1. TIS7 and SKMc15 acted after the commitment to the preadipocyte stage since the elevated DLK-1 and β-catenin levels found in the white adipose tissue of TIS7 SKMc15 dKO mice are characteristic for the preadipocyte stage 44,63 . In addition, the lipid transport deficiency of intestinal enterocytes due to their lower CD36 expression levels also led to the impaired fat accumulation in TIS7 SKMc15 dKO mice.…”

Molecular Mechanisms of Adipogenesis: The Anti-Obesogenic Role of AMP-Activated Protein Kinase and Recently Reported Plant Products

“…Interest in the prevention of obesity by regulation of non-shivering thermogenesis in BAT and brite adipose tissue through phytochemicals has been increasing rapidly due to their potential for side-effect-minimal medication. Various phytochemicals have been reported ( [40] and Myricetin [41] have also been reported to cause browning of WAT by upregulating the genes and transcriptional factors specifically expressed in BAT. [48] iWAT; Inguinal white adipose tissue,…”