Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes

Human obesity has become a global health epidemic, with few safe and effective pharmacological therapies currently available. The systemic loss of ovarian estradiol (E2) in women after menopause greatly increases the risk of obesity and metabolic dysfunction, revealing the critical role of E2 in this setting. The salutary effects of E2 are traditionally attributed to the classical estrogen receptors ERα and ERβ, with the contribution of the G protein–coupled estrogen receptor (GPER) still largely unknown. Here, we used ovariectomy- and diet-induced obesity (DIO) mouse models to evaluate the preclinical activity of GPER-selective small-molecule agonist G-1 (also called Tespria) against obesity and metabolic dysfunction. G-1 treatment of ovariectomized female mice (a model of postmenopausal obesity) reduced body weight and improved glucose homeostasis without changes in food intake, fuel source usage, or locomotor activity. G-1–treated female mice also exhibited increased energy expenditure, lower body fat content, and reduced fasting cholesterol, glucose, insulin, and inflammatory markers but did not display feminizing effects on the uterus (imbibition) or beneficial effects on bone health. G-1 treatment of DIO male mice did not elicit weight loss but prevented further weight gain and improved glucose tolerance, indicating that G-1 improved glucose homeostasis independently of its antiobesity effects. However, in ovariectomized DIO female mice, G-1 continued to elicit weight loss, reflecting possible sex differences in the mechanisms of G-1 action. In conclusion, this work demonstrates that GPER-selective agonism is a viable therapeutic approach against obesity, diabetes, and associated metabolic abnormalities in multiple preclinical male and female models.

Role of Ghrelin in Postmenopausal obesity

Objectives: Obesity is considered a worldwide important health problem with continuously increasing prevalence, particularly among postmenopausal women. Weight gain is one of the major concerns of menopause. Understanding the contributing factors to postmenopausal obesity helps to reduce its incidence and thus its associated health complications. The present study aimed to review the role of ghrelin in mediating postmenopausal obesity. Methods: A literature review was done to understand the possible association between ghrelin levels and obesity in postmenopausal women. Results: It was found that the lack of estrogen during menopause increases the serum ghrelin level. In addition, the results revealed that ghrelin stimulates appetite, changes food preference, and causes an accumulation of visceral fat resulting in weight gain. On the other hand, ghrelin was found to have many protective effects as an anti-inflammatory and a neuroprotective agent. Conclusions: In general, the ghrelin hormone is a double-edged sword as it mediates the increase of body weight in postmenopausal women. More importantly, it plays a considerable role in protecting postmenopausal women from cardiovascular and neurodegenerative diseases. The selective blockage of appetite-stimulating and metabolic effects of ghrelin may be of a potential prophylactic or therapeutic effect for postmenopausal overweight and obesity.

Molecular Targeted Therapy for Breast Cancer: A New Frontiers

ABSTRACT: Cancer has become a major public health problem worldwide. Researches focus on the new approaches for cancer treatments that involve the specific targets of the cancer disease. Breast cancer is the most frequent type of cancer among women, and it causes approximately 25% of the deaths in women below the age of 35. Multiple environmental and hereditary factors are responsible for breast cancer such as age, family history, postmenopausal obesity, early menarche, late menopause, alcohol consumption, pregnancy and the use of exogenous hormones. Treatment of breast cancer patients relies primarily on surgery followed by radiotherapy and systemic therapy. Several molecules expressed and secreted by breast cancer cells have been identified by their interactions, invasion and metastasis. These molecular interactions appear to maintain the cancer cells’ survival and growth. The improvement in understanding of the molecular basis of breast cancer will provide possible targets for novel therapies. Therefor, this review focuses on the molecular and cellular basis of the breast cancer treatment.