Phytochemicals Added to the Feed of Ovariectomized Adult Rats Increase Brown Adipose Activity

Background: Brown adipose tissue (BAT) uncouples respiration, using lipids as an energy source while dissipating heat. Increases in BAT activity are protective against obesity, thus compounds that increase BAT activation may help prevent weight gain. Resveratrol (R) increases BAT activity by upregulating thermogenic genes. As phytochemicals have synergistic properties, our research strategy has included investigation of the efficacy of relatively low concentrations of phytochemical blends on BAT activation. Methods: Previously, we showed that R combined with genistein (G) and quercetin (Q) reduced weight gain in aged ovariectomized (OVX) female rats. In the current study, OVX rats were fed diets containing doses of phytochemicals with vitamin D (diet 1: 1000 mg/kg G; diet 2: 500 mg/kg G, 200 mg/kg R, and 1000 mg/kg Q; diet 3: 1000 mg/kg G, 400 mg/kg R, and 2000 mg/kg Q). Results: After 16 weeks, rats in the high dose group had a significantly smaller scapular BAT depot compared to non-OVX controls (0.74 g v 0.92 g;

Basis for resveratrol\u27s potential prevention and treatment of obesity osteoporosis

Higher levels of adiposity are associated with increased risk for development of numerous adverse health conditions including type-two diabetes, bone disorders and cancer. Phytochemicals and combinations of phytochemicals are potential supplements for humans to suppress differentiation of preadipocytes, stimulate lipolysis, and induce apoptosis of existing adipocytes, thereby providing a preventive and treatment for adiposity. Resveratrol decreases adipogenesis and viability in maturing preadipocytes which has been shown to be through down-regulating adipocyte specific transcription factors and enzymes and gene products that change mitochondrial function. Furthermore, resveratrol increases fat mobilization and synthesis in mature adipocytes. Potentially of special importance is that resveratrol combined with other natural products produces synergistic activities from the modulation of multiple biotargets throughout the life cycle of adipocytes. It was reported that mice treated with resveratrol alone reduced weight gain caused by a high fat diet. Because mesenchymal stem cells are precursors for both adipocytes and osteoblasts and the differentiation to adipocytes dominates over the differentiation to osteoblasts in bone marrow of aging humans, there is an increased propensity for osteoporosis and bone fracutres. Resveratrol, and other phytochemicals, act on several biotargets in adipocytes and osteoblasts leading to a decrease in adipocyte number and size and an increase in osteogenesis. In a post-menopausal animal model, aged ovariectomized rats, dietary supplementation using a combination of resveratrol with vitamin D, quercetin and genistein decreased weight gain and inhibited bone loss. Combining several phytochemicals, including especially resveratrol, is likely to lead to combinations that are efficacious for the prevention and treatment of obesity and osteoporosis through targeted decrease in adipogenesis, enhanced apoptosis and lipolysis in adipocytes and increased osteogenesis in osteoblasts. © 2013 by Nova Science Publishers, Inc. All rights reserved

Phytochemicals and regulation of the adipocyte life cycle

Natural products have potential for inducing apoptosis, inhibiting adipogenesis and stimulating lipolysis in adipocytes. The objective of this review is to discuss the adipocyte life cycle and various dietary bioactives that target different stages of adipocyte life cycle. Different stages of adipocyte development include preadipocytes, maturing preadipocytes and mature adipocytes. Various dietary bioactives like genistein, conjugated linoleic acid (CLA), docosahexaenoic acid, epigallocatechin gallate, quercetin, resveratrol and ajoene affect adipocytes during specific stages of development, resulting in either inhibition of adipogenesis or induction of apoptosis. Although numerous molecular targets that can be used for both treatment and prevention of obesity have been identified, targeted monotherapy has resulted in lack of success. Thus, targeting several signal transduction pathways simultaneously with multiple natural products to achieve additive or synergistic effects might be an appropriate approach to address obesity. We have previously reported two such combinations, namely, ajoene+CLA and vitamin D+genistein. CLA enhanced ajoene-induced apoptosis in mature 3T3-L1 adipocytes by synergistically increasing the expression of several proapoptotic factors. Similarly, genistein potentiated vitamin D\u27s inhibition of adipogenesis and induction of apoptosis in maturing preadipocytes by an enhanced expression of VDR (vitamin D receptor) protein. These two examples indicate that combination therapy employing compounds that target different stages of the adipocyte life cycle might prove beneficial for decreasing adipose tissue volume by inducing apoptosis or by inhibiting adipogenesis or both. © 2008 Elsevier Inc. All rights reserved

Phytochemicals and adipogenesis

Obesity is an increasing health problem all over the world. Phytochemicals are potential agents to inhibit differentiation of preadipocytes, stimulate lipolysis, and induce apoptosis of existing adipocytes, thereby reducing the amount of adipose tissue. Flavonoids and stilbenoids represent the most researched groups of phytochemicals with regards to their effect on adipogenesis, but there are also a number of in vitro and in vivo studies with phenolic acids, alkaloids, and vitamins, as well as other plant compounds. Although phytochemicals like epigallocatechin-3-gallate, genistein, and resveratrol reduce lipid accumulation and induce adipocyte apoptosis in vitro and reduce body weight and adipose tissues mass in animal models of diet-induced obesity, well-conducted clinical trials are lacking. Pharmacological doses are often used in vitro and when applied in physiological doses in animals or humans, the phytochemicals are often ineffective in affecting adipogenesis. However, by combining several phytochemicals or using them as templates for synthesizing new drugs, there is a large potential in targeting adipogenesis using phytochemicals. © 2010 International Union of Biochemistry and Molecular Biology, Inc

Enhanced effects of xanthohumol plus honokiol on apoptosis in 3T3-L1 adipocytes

Objective: To study the effects of xanthohumol (XN), a flavonoid found in hops (Humulus lupulus) and honokiol (HK), a lignan isolated from Magnolia officinalis, alone and in combination, on apoptotic signaling in 3T3-L1 adipocytes. Methods and Procedures: 3T3-L1 mature adipocytes were incubated with various concentrations of XN and HK alone and in combination. Viability and apoptosis were quantified using an MTS-based cell viability assay and single-stranded DNA assay, respectively. Expression of apoptosis related proteins including cleaved poly(ADP-ribose) polymerase (PARP), cytochrome c, Bcl-2, caspase-3/7, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Akt was analyzed by western blotting. Results: Combinations of XN and HK significantly decreased viability and induced apoptosis in a dose-dependent manner and more than the additive responses to XN and HK alone. Western blot analysis showed an increase in cleaved PARP and cytochrome c release and decrease in expression of Bcl-2 protein by XN plus HK, whereas XN and HK individually had no effect. Furthermore, the combination of XN and HK activated PTEN and inactivated Akt by decreasing levels of phosphorylated PTEN and phosphorylated Akt. Discussion: We demonstrated that although XN and HK showed little or no effect as individual compounds, in combination (XN plus HK) they showed enhanced activity in inducing apoptosis via the cytochrome c/caspase-3/PARP and PTEN/Akt pathways in 3T3-L1 adipocytes. © 2008 The Obesity Society

Novel molecular targets for prevention of obesity and osteoporosis

Evidence from both epidemiological studies and basic research suggests that obesity and osteoporosis are interrelated. Though there is an increase in the prevalence of these disorders, a limited number of treatments are available, one of the reasons being the complexity of the pathways involved and difficulty in identifying a single molecular target. Due to adverse effects of pharmaceuticals, intake of herbal drugs by patients without a physician\u27s recommendation is increasing globally. Lack of success with targeted monotherapy has encouraged scientists to determine whether combinations of phytochemicals that interfere with numerous cell-signaling pathways can be a more effective approach to treat complex diseases. For example, evidence is emerging that specific combinations of phytochemicals are far more effective than single compounds in decreasing adipogenesis and promoting bone formation. Since multiple pathways are dysfunctional in obesity and osteoporosis, an ideal approach for preventing and treating these diseases may be to use a combination of phytochemicals to address several targets simultaneously. © 2011 Elsevier Inc

Effect of xanthohumol and isoxanthohumol on 3T3-L1 cell apoptosis and adipogenesis

Xanthohumol (XN), the chalcone from beer hops has several biological activities. XN has been shown to induce apoptosis in cancer cells and also has been reported to be involved in lipid metabolism. Based on these studies and our previous work with natural compounds, we hypothesized that XN and its isomeric flavanone, isoxanthohumol (IXN), would induce apoptosis in adipocytes through the mitochondrial pathway and would inhibit maturation of preadipocytes. Adipocytes were treated with various concentrations of XN or IXN. In mature adipocytes both XN and IXN decreased viability, increased apoptosis and increased ROS production, XN being more effective. Furthermore, the antioxidants ascorbic acid and 2-mercaptoethanol prevented XN and IXN-induced ROS generation and apoptosis. Immunoblotting analysis showed an increase in the levels of cytoplasmic cytochrome c and cleaved poly (ADP-ribose) polymerase (PARP) by XN and IXN. Concomitantly, we observed activation of the effectors caspase-3/7. In maturing preadipocytes both XN and IXN were effective in reducing lipid content, XN being more potent. Moreover, the major adipocyte marker proteins such as PPARγ, C/EBPα, and aP2 decreased after treatment with XN during the maturation period and that of DGAT1 decreased after treatment with XN and IXN. Taken together, our data indicate that both XN and IXN inhibit differentiation of preadipocytes, and induce apoptosis in mature adipocytes, but XN is more potent. © 2007 Springer Science+Business Media, LLC

Emerging role of apelin as a therapeutic target in cancer: A patent review

Since tumors cannot grow or spread without forming new blood vessels, inhibiting angiogenesis is an excellent approach for the treatment of cancer. Further, inhibitors of angiogenesis have mild side effects since they act on endothelial cells, which eliminate the possibility of developing resistance or tolerance in tumor cells, unlike that seen with chemotherapy drugs. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab acts by preventing new blood vessel formation in solid tumors and is approved by FDA to treat colorectal, lung, breast, glioblastoma and kidney cancers. The registration of this drug and its ongoing success in the clinic has validated the targeting of angiogenesis as an important approach to the treatment of solid tumors. Apelin is a novel angiogenic factor and recent studies indicate that apelin promotes angiogenesis, lymphangiogenesis and tumor growth in vivo and the angiogenic potential of apelin is similar to that of VEGF. Also, apelin expression is upregulated and has been shown to be associated with clinical outcome in certain human cancers. Thus, inhibition of apelin activity might lead to a new class of anti-angiogenesis drugs which should be more efficacious than those currently on the market due to their ability to be both anti-angiogenic as well as anti-lymphangiogenic. There are very few patents on the angiogenic effects of apelin and this review article focuses on these patented claims related to inhibiting apelin signaling and sheds more light on how blocking apelin signaling might open doors to a new class of angiogenic inhibitors. © 2011 Bentham Science Publishers

Octanoate and decanoate induce apoptosis in 3T3-L1 adipocytes

The effect of octanoate and decanoate, respectively, eight- and 10-carbon medium-chain fatty acids (MCFAs), on apoptotic signaling in 3T3-L1 adipocytes was investigated. 3T3-L1 adipocytes were treated with various concentrations of octanoate or decanoate. Cell viability, apoptosis, and expression of apoptosis-related proteins were investigated. Results indicated that both octanoate and decanoate decreased viability, increased apoptosis, and increased reactive oxygen species production. Immunoblotting analysis showed an increase in the levels of cytoplasmic cytochrome c and cleaved poly(ADP-ribose) polymerase by octanoate and decanoate. Concomitantly, we observed that pro-caspase-3 was decreased, resulting in the induced accumulation of the cleaved form of caspase-3 by both octanoate and decanoate. In addition, both octanoate and decanoate increased the expression of pro-apoptotic Bax with an accompanied decrease of anti-apoptotic Bcl-2. These results show that octanoate and decanoate mediate adipocyte apoptosis via a caspase-dependent mitochondrial pathway in 3T3-L1 adipocytes. MCFAs thus decrease adipocyte number by initiating the apoptotic process in 3T3-L1 adipocytes. © Mary Ann Liebert, Inc