Nutraceuticals in Brown Adipose Tissue Activation.

Obesity and its associated comorbidities have become pandemic, and challenge the global healthcare system. Lifestyle changes, nutritional interventions and phamaceuticals should be differently combined in a personalized strategy to tackle such a public health burden. Altered brown adipose tissue (BAT) function contributes to the pathophysiology of obesity and glucose metabolism dysfunctions. BAT thermogenic activity burns glucose and fatty acids to produce heat through uncoupled respiration, and can dissipate the excessive calorie intake, reduce glycemia and circulate fatty acids released from white adipose tissue. Thus, BAT activity is expected to contribute to whole body energy homeostasis and protect against obesity, diabetes and alterations in lipid profile. To date, pharmacological therapies aimed at activating brown fat have failed in clinical trials, due to cardiovascular side effects or scarce efficacy. On the other hand, several studies have identified plant-derived chemical compounds capable of stimulating BAT thermogenesis in animal models, suggesting the translational applications of dietary supplements to fight adipose tissue dysfunctions. This review describes several nutraceuticals with thermogenic properties and provides indications, at a molecular level, of the regulation of the adipocyte thermogenesis by the mentioned phytochemicals.

RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives.

RANKL/RANK/OPG system consists of three essential signaling molecules: i) the receptor activator of nuclear factor (NF)-kB-ligand (RANKL), ii) the receptor activator of NF-kB (RANK), and iii) the soluble decoy receptor osteoprotegerin (OPG). Although this system is critical for the regulation of osteoclast differentiation/activation and calcium release from the skeleton, different studies have elucidated its specific role in mammary gland physiology and hormone-driven epithelial proliferation during pregnancy. Of note, several data suggest that progesterone induces mammary RANKL expression in mice and humans. In turn, RANKL controls cell proliferation in breast epithelium under physiological conditions typically associated with higher serum progesterone levels, such as luteal phase of the menstrual cycle and pregnancy. Hence, RANKL/RANK system can be regarded as a major downstream mediator of progesterone-driven mammary epithelial cells proliferation, potentially contributing to breast cancer initiation and progression. Expression of RANKL, RANK, and OPG has been detected in breast cancer cell lines and in human primary breast cancers. To date, dysregulation of RANKL/RANK/OPG system at the skeletal level has been widely documented in the context of metastatic bone disease. In fact, RANKL inhibition through the RANKL-blocking human monoclonal antibody denosumab represents a well-established therapeutic option to prevent skeletal-related events in metastatic bone disease and adjuvant therapy-induced bone loss in breast cancer. On the other hand, the exact role of OPG in breast tumorigenesis is still unclear. This review focuses on molecular mechanisms linking RANKL/RANK/OPG system to mammary tumorigenesis, highlighting pre-clinical and clinical evidence for the potential efficacy of RANKL inhibition as a prevention strategy and adjuvant therapy in breast cancer settings.