Intracellular receptor regulation of adipose metabolism by the isoflavone genistein

Abstract

than 50,000 μg/kg/day inhibit adipose deposition [2, 3] in male and female mice, and at 200 mg/kg/day, it shows an inhibitory effect comparable to that observed with the natural estrogen estradiol [4]. In the attempt to interpret the dose-dependent variations in adipose weight as are described by a Gaussian curve in mice fed genistein in the range of 50–200,000 μg/kg/ day [4, 5], we may look for a correlation with the dosedependent transcriptional regulation curve that is driven in vitro by ligand-activated nuclear receptors [6]. Genistein is an affinity ligand for a few NRs (ERs, AR, PPARg, LXRs and PXR and membrane-bound ERs and AR) [7–10], and the dose of this isoflavone together with its different affinity for different NRs is a critical element for its ability to regulate receptor-mediated cellular processes. Among the mentioned receptor systems which recognize genistein, the most characterized beyond the ERs, is PPARγ. PPARγ is a central switch for adipose metabolism. It does its work also by regulating estrogen-dependent modulatory functions through a negative cross-talk with the ERs [11]. Through regulating both the ERs and PPARγ, genistein can alter cell functions and modulate systemic homeostatic controls [12]. Experimental in vivo data indicate that the ERs and PPARγ-mediated transcriptional regulation of genistein depends on the dose and the tissue [4–6] and the different affinity for these receptors. Studying the adipose tissue in mice we have observed that at low doses, genistein induces enzymes directly involved in lipid storage such as the lipoprotein lipase (LPL), an effect that it is likely to be produced through the activation of PPARγ, a regulator of LPL. At higher supra-nutritional or pharmacological doses, it strongly inhibits the same enzymes, including LPL through a mechanism likely involving the ERs since its effects are very similar to that elicited by estradiol although not targeting the same promoters ([4], and the paper under discussion In the last few lines of his letter, Dr. Chirumbolo concludes that the complex action of genistein in the modulation of adipose metabolism and growth is dependent on several factors among which the most relevant are its plasma concentration, its nuclear receptor-mediated signaling and the gender. I would add that the dietary background is itself a factor that may shift the variable effect of genistein on adipose metabolism from negative (inhibitory control) to positive (stimulation), influencing the gut microbiota and intestinal metabolization, absorption and bioavailability. To investigate the effect of genistein on the adipose metabolism, experimental laboratory models have been established to reproduce the consumption of amounts of genistein as they are occurring in populations eating moderate-to-high quantity of soy or soy-derived products [1]. Dietary amounts of genistein are present in standard soy-containing rodent diets at average concentrations of 200 ppm which produce serum levels of about 70 ± 9 nM. This falls between the serum concentrations obtained in mice fed genistein at the nutritional doses of 500 and the 5,000 μg/ kg/day on an estrogen-free dietary background (66 ± 7, 74 ± 7 nM). At these doses, genistein induces a significant increase in the epididymal and renal fat pads of male mice. The same doses do not affect either the abdominal or the renal fat pads of intact females, thus indicating gender-specific effects of this isoflavone on adipos metabolism. Higher serum levels of genistein produced by feeding doses higher