Insulin secretion by pancreatic β-cells is primarily regulated by glucose; however, hormones and additional nutrients, such as long-chain fatty acids, also play an important role in adjusting insulin output to physiologic needs. To examine the role of short-chain fatty acids (SCFAs) in β-cell function, we analyzed mouse models of gain and loss of function of GPR41 (FFAR3), a receptor for SCFAs, vs. wild-type control mice. GPR41 gain of function [GPR41-overexpressing transgenic (41 Tg) model] and GPR41 loss of function [GPR41-knockout (KO 41) model] resulted in complementary changes in glucose tolerance, without significant effects on insulin sensitivity. KO 41 mice showed fasting hypoglycemia, which was consistent with increased basal and glucose-induced insulin secretion by islets in vitro Mirroring this, 41 Tg islets showed impaired glucose responsiveness in vitro Microarray analysis of islets from 41 Tg mice indicated significant alterations in gene expression patterns; several of the altered genes were chosen for further analysis and were also observed to change upon incubation of islets‏‏ and cultured β-cells with SCFAs in a GPR41-dependent manner. Taken together, our results indicate that GPR41 and its ligands, SCFAs, may play an important role in the fine-tuning of insulin secretion in fed and fasting states.-Veprik, A., Laufer, D., Weiss, S., Rubins, N., Walker, M. D. GPR41 modulates insulin secretion and gene expression in pancreatic β-cells and modifies metabolic homeostasis in fed and fasting states.

The basis for the vivid color of carotenoids and their antioxidant activity is the multiple conjugated double bonds, which are characteristic for these phytonutrients. Moreover, the cleavage of these oxidation-prone double bonds leads to the formation of apocarotenoids. A large number of carbonyl-containing oxidation products are expected to be produced as a result of carotenoid oxidation and these can be further metabolized into the corresponding acids and alcohols. As discussed in this review, many, but not all, of these potential products have been detected and identified in plants as well as in human and animal plasma and tissues. Some of these compounds were found to be biologically active as anticancer agents. In addition to the inhibition of cancer cell proliferation, several carotenoid metabolites were shown to modulate the activity of various transcription systems. These include ligand-activated nuclear receptors, such as the retinoic acid receptor, retinoid X receptor, peroxisome proliferator-activated receptor and estrogen receptor, as well as other transcription systems that have an important role in cancer, such as the electrophile/antioxidant response element pathway and nuclear factor-κB. Therefore, apocarotenoids can be considered as natural compounds with multifunctional, rather than monofunctional, activity and, thus, can be useful in the prevention of cancer and other degenerative diseases.

Evidence from epidemiologic studies has suggested that carotenoids, and lycopene in particular, decrease the risk of cancer: however, not all studies support this view. To gain insight into the molecular mechanisms whereby lycopene and other carotenoids may exert their chemoprotective effects, we and others performed a series of studies that used a large panel of cancer cell lines of different lineages and animal models of human cancer. In this review we address some of the mechanisms proposed for the cancer-preventive activity of tomato lycopene, focusing on the induction of the antioxidant response element transcription system and the inhibition of the transcriptional activity of sex hormones, such as estrogens and androgens, and the activity of growth factors, such as insulin-like growth factor. We also considered the modulation by lycopene of the transcription factors peroxisome proliferator-activated receptor, retinoid X receptor, liver X receptor, and activating protein-1. The ligands and the phytonutrient regulators of these transcription systems contain electrophilic active groups, whereas lycopene and nonxanthophylic carotenoids are devoid of them. Thus, we suggest that at least some of the cellular effects of carotenoids are mediated through their derivatives formed either by chemical oxidation or by enzymatic cleavage inside the cells. This review highlights findings that pertain to this exciting avenue of research, which is currently under intense scrutiny in several laboratories worldwide.

No abstract

-While exposure to estrogens is a major risk factor of breast and endometrial cancer, it well established that estrogens are beneficial for bone health. We have previously shown that carotenoids inhibit estrogen signaling in breast and endometrial cancer cells. The aim of this study was to compare the effects of various phytonutrients, (carotenoid derivatives, polyphenols, isothiocyanates) on estrogenic activity in breast cancer cells and osteoblast-like cells. All the tested phytonutrients inhibited estrogen response element (ERE) transactivation in breast cancer cells. In contrast, these compounds either did not affect or enhanced ERE activity and the expression of several bone-forming genes. These results were obtained using two osteoblast-like cell lines, MG-63 human osteosarcoma cells stably transfected with estrogen receptor-␣ (ER␣) and MC3T3-E1 mouse calvaria-derived cells expressing endogenous ER. Phytonutrients-induced ERE inhibition in breast cancer cells, and its potentiation in osteoblast-like cells were associated both with a decrease and a rise in total and nuclear ER␣ levels, respectively. Phytonutrients activated the electrophile/antioxidant response element (EpRE/ARE) transcription system to various extents in both cancer and bone cell lines. Overexpression of Nrf2, the major EpRE/ ARE activating transcription factor, mimicked the effects of phytonutrients, causing inhibition and enhancement of ERE transactivation in breast cancer cells and in osteoblast-like cells, respectively. Moreover, reduction in Nrf2 levels by RNAi led to a decrease in the phytonutrient potentiation of ERE activity transactivation in osteoblast-like cells. These findings suggest that the enhancement and inhibition of estrogen signaling by phytonutrients in bone-derived cells and breast cancer cells, respectively, is partially mediated by the activation of the Nrf2/ARE system. Nrf2; estrogen receptor; osteoblasts; antioxidant response element; lycopene; curcumin INCIDENCE RATES of breast and endometrial cancer have been rising in the last decades, due to increased exposure to estrogens resulting from changes in lifestyle (19,39). Thus, reduction of estrogen receptor activity is a major strategy for prevention of hormone-dependent malignancies. This preventive approach, however, must be implemented by taking into consideration that estrogens are beneficial to bone health. Women who enter menopause are at high risk for osteoporosis due to low blood levels of estrogens (42). Thus, since women today live longer after menopause than in a reproductive state, osteoporosis has become a serious threat to their health. To prevent hormone-dependent cancer without compromising bone health, specific estrogen receptor modulators (SERMs) have been developed (41). SERMs such as tamoxifen and raloxifen were successfully used for prevention of breast cancer in women who are at high risk for the disease and were also found to reduce the incidence of bone fractures (11, 54). However, for long-term prevention in the general population, dietary...