Hepatic Gene Expression Profiles Are Altered by Genistein Supplementation in Mice with Diet-Induced Obesity

Abstract

We reported previously that genistein enhances the expression of genes involved in fatty acid catabolism through activation of peroxisome proliferator-activated receptor (PPAR) alpha in HepG2 cells, suggesting that genistein holds great promise for therapeutic applications to lipid abnormalities such as obesity and hyperlipidemia in humans. In this study, we examined the changes in hepatic transcriptional profiles using cDNA microarrays in mice with high-fat diet (HFD)-induced obesity supplemented with genistein. C57BL/6J male mice (n = 10/group) were fed a low-fat diet (LFD), a HFD, or a HFD supplemented with 2 g/kg genistein (HFD+GEN) for 12 wk. Mice fed the HFD had abnormal lipid profiles and significantly greater body weight and visceral fat accumulation than the LFD-fed group. Genistein supplementation improved lipid profiles and hepatic steatosis and attenuated the increases in body weight and visceral fat in HFD-fed mice. The cDNA microarrays revealed marked alterations in the expression of 107 genes in the mice fed the HFD and/or the HFD+GEN. Of 97 transcripts altered in the HFD-fed group, 84 genes were normalized by genistein supplementation. However, several genes involved in fatty acid catabolism were not normalized but were still upregulated in the HFD+GEN-fed group, relative to the LFD-fed group. Furthermore, carnitine O-octanoyltransferase, which accelerates fatty acid oxidation, was not affected by the HFD, but was induced by genistein supplementation. These results are consistent with our previous study showing that genistein is an activator of PPAR alpha in vitro. This study showed beneficial effects of genistein supplementation in preventing the development of obesity and metabolic abnormalities in mice with diet-induced obesity. Our results also provide interesting information about the genes associated with the beneficial effects of genistein as well as the mechanisms underlying the development and maintenance of the obesity phenotype in vivo.

Genistein Derivatization – From a Dietary Supplement to a Pharmaceutical Agent

“…In general, microarray data published so far supports existing hypotheses on the mechanisms of action of genistein, both beneficial for human health (i.e. reduction of cancer risk, amelioration of postmenopausal syndrome and decrease of bone resorption in postmenopausal women, lipid metabolism, cardiovascular homeostasis) (Kim et al, 2005;Lee et al, 2007;Pie et al, 2006;Rice et al, 2007) and unfavorable (as estrogen-dependent cancer cell proliferation and adverse effects on the reproductive organs or involution of thymus and auto-immune disorders) (Lee et al, 2007;Naciff et al, 2002;Selvaraj et al, 2005). Those homeostasis-maintaining or homeostasis-affecting effects are often observed at low concentrations of genistein, essentially not exceeding 5 M.…”

“…7OH group of genistein forms hydrogen bonds with the glutamate in helix 3, the arginine in helix 5, and a water molecule; 4'OH group forms hydrogen bond with H398. Adapted and reprinted by permission from American Association for Cancer Research, Suetsugi et al 2003, Molecular Cancer Research Vol.1, No.13, 981-991. Other members of nuclear receptor family activated by genistein are peroxisome proliferatorsactivated receptor  (PPAR) (Dang et al, 2003) and PPAR (Kim et al, 2004;Kim et al, 2005). The main role of PPAR is to control the genes involved in adipocyte differentiation and lipid storage.…”

“…Those homeostasis-maintaining or homeostasis-affecting effects are often observed at low concentrations of genistein, essentially not exceeding 5 M. Functional categorization of genes affected by genistein on transcriptional level repeatedly indicates genes involved in cell growth, cell cycle, apoptosis, cell signals transduction, angiogenesis, tumor cell invasion and metastasis, cholesterol synthesis and lipid metabolism (Kim et al 2005;Li et al, 2004;Li & Sarkar, 2002;Niculescu et al, 2007;Pie et al, 2006;Rice et al, 2007;Selvaraj et al, 2005). Among the genes regulated by genistein is a group of genes with common mechanism of regulation by nuclear receptors: estrogen receptors (Selvaraj et al, 2005) and androgen receptor (Rice et al, 2007).…”

“…Among non-reproductive organs in which strong changes of expression profile occurred in estrogen receptor-dependent manner after treatment with genistein are bones (Pie et al, 2006), liver and adipose tissue (Kim et al, 2005), thymus (Selvaraj et al, 2005), lymphocytes (Niculescu et al, 2007), brain (Lyou et al, 2002), endothelial cells (Rimbach et al, 2008), cardiovascular system and muscles (Velders et al, 2010). It has to be noted that the expression profile influenced by high genistein uptake may not depend on genistein directly, but on the ability of individuals to metabolize genistein to equol (Niculescu et al, 2007).…”

Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism

“…15 Besides these results, our hepatic transcript profiles showed that daidzein supplementation reduced hepatic lipid levels through the activation of ACAS and ACAD, which are involved in fatty acid b-oxidation, [42][43][44][45][46][47] and this activation was due to the upregulation of PPARa, their upstream gene. 48 Daidzein supplementation also functions as hepatic antisteatotic materials by the regulation of adipocyte metabolism. Recently, adiponectin has been shown to exert protective effects against NAFLD in obese ob/ob mice, 49 hepatic injury or fibrogenesis in mice to whom lipopolysaccharide or CCl 4 were administered.…”