The expansion of fat mass in the obese state is due to increased adipocyte hypertrophy and hyperplasia. The molecular mechanism that drives adipocyte hyperplasia remains unknown. The NAD+-dependent protein deacetylase sirtuin 1 (SIRT1), a key regulator of mammalian metabolism, maintains proper metabolic functions in many tissues, counteracting obesity. Here we report that differentiated adipocytes are hyperplastic when SIRT1 is knocked down stably in mouse 3T3-L1 preadipocytes. This phenotype is associated with dysregulated adipocyte metabolism and enhanced inflammation. We also demonstrate that SIRT1 is a key regulator of proliferation in preadipocytes. Quantitative proteomics reveal that the c-Myc pathway is altered to drive enhanced proliferation in SIRT1-silenced 3T3-L1 cells. Moreover, c-Myc is hyperacetylated, levels of p27 are reduced, and cyclin-dependent kinase 2 (CDK2) is activated upon SIRT1 reduction. Remarkably, differentiating SIRT1-silenced preadipocytes exhibit enhanced mitotic clonal expansion accompanied by reduced levels of p27 as well as elevated levels of CCAAT/enhancer-binding protein β (C/EBPβ) and c-Myc, which is also hyperacetylated. c-Myc activation and enhanced proliferation phenotype are also found to be SIRT1-dependent in proliferating mouse embryonic fibroblasts and differentiating human SW872 preadipocytes. Reducing both SIRT1 and c-Myc expression in 3T3-L1 cells simultaneously does not induce the adipocyte hyperplasia phenotype, confirming that SIRT1 controls adipocyte hyperplasia through c-Myc regulation. A better understanding of the molecular mechanisms of adipocyte hyperplasia will open new avenues toward understanding obesity.

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the CFTR gene, with various clinical manifestations that affect pulmonary, digestive, exocrine and male reproductive functions as well as the bones and kidneys. This study aimed to reveal the spectrum of CFTR gene mutations in Arab CF patients and their corresponding clinical phenotypes among the 22 Arab countries. We searched four literature databases (PubMed, Science Direct, Web of Science and Scopus) from their times of inception to January 2018. All possible search terms were used to encompass the different clinical phenotypes, disease incidences, CFTR mutations, ages and consanguinity rates of CF patients in the 22 Arab countries. Our search strategy identified 678 articles; of these, 72 were eligible for this systematic review. We retrieved data from 18 Arab countries; only 1766 Arab patients with CF were identified, even after additional searches using Google and Google Scholar. The search uncovered a wide spectrum of mutations, some of which are shared with other ethnic groups and some unique to Arab patients. Although the clinical phenotypes of Arab patients were typical of CF, several distinct phenotypes were reported. Despite the rarity of genetic epidemiological studies of CF patients among the 22 Arab nations, the disease is frequently reported in Arab countries where consanguineous marriage is common. Therefore, significant attention should be paid to this problem by implementing carrier and premarital screening, newborn screening and genetic counselling.

Vascular endothelial dysfunction as the mechanism for the development of obesity Raja'a Dalloul, Tatiana Lobo, Hamid Massaeli, Nasrin Mesaeli Weill Cornell Medicine- Qatar, Qatar Foundation, Doha, Qatar Background: Obesity is one of the major public health issues in the world with a rapid increase in its prevalence. According to the last public health report from supreme public health in Qatar in 2012, 71.8 % of the women were overweight compared to 68.3% of men. Among the gulf region, Qatar has the 6th highest rate of obesity in young boys. Moreover, the WHO survey in 2009 showed 70% of the Qatari children were obese because of the nutritional changes and unhealthy lifestyle. Adipocytes are considered the only cells where their size can vary in physiological conditions. Adipose tissues grow as they store excess energy intake. It's well established that adipose tissue is highly vascularized. These vascular networks play a vital role in the adipogenesis process. The vasculature of adipose tissue provide oxygen, growth factors, nutrients, and cytokines to the progenitor cells that are differentiated into pre-adipocytes and vascular endothelial cells. Vascular endothelial cells form the inner barrier of the vessel and is responsible for maintaining the vascular vasodilation and constriction. Defect in the endothelial cell function has been shown to result as a consequence of different diseases such as obesity, diabetes and high blood pressure. An increase or decrease in the generation of the reactive oxygen is one of the main cause of endothelium dysfunction. The fluctuation in the balance of these factors in the endothelial has an influence in the adipocyte cells which is responsible for the formation of fats or fatty tissues which cause an impairment of adipocytes and may lead to obesity. Calreticulin (CRT) is a multifunctional protein that is expressed in the endoplasmic reticulum of all mammalian cells. The main functions of CRT are regulation of intracellular Ca2+ hemostasis and lectin like chaperone. As part of ongoing research in our lab, we have developed a mouse model overexpressing CRT in endothelial cells. One of the phenotypes of this mouse is the development of obesity and type II diabetes overtime. Therefore, the current research was to examine the hypothesis that endothelial specific overexpression of CRT in mice leads to endothelial dysfunction leading to obesity and diabetes. Methodology: A cell targeted transgenic mouse model overexpressing CRT in endothelial cells [will be referred to as (ECCRT+)] was developed in our lab and used in our study. One of the major phenotype of these mice is the development of visceral obesity and diabetes. To characterize these mice phenotype, 4 weeks old wild-type (wt) and transgenic (ECCRT+) litter mate mice were fed with special diet containing either high fat (60%) or low fat (10%) diet for different time points (8-24 weeks). Body weight and blood glucose was measured bi-weekly. At the end time point glucose tolerance test (GTT) was performed to determine the state of diabetes. Epididymal adipose tissues were collected from the wt and ECCRT+ mice. The tissues were embedded in paraffin, sectioned and stained using histological and immunohistochemical techniques to examine the phenotypic changes (shape and size) of adipocyte in ECCRT+ and wildtype mice. Results: Our results illustrated that these mice suffered from endothelial dysfunction. The GTT assay illustrated that ECCRT+ mice developed diabetes at 16 weeks of age when on regular diet (10% fat diet) and high fat diet expedited the development of diabetes. Fat to body weight ratios, and histological analysis of the fat from these wt and ECCRT+ mice showed significant changes in the fat volume, adipocyte size and adipocyte number suggesting a possible association between endothelial dysfunction and adipogenesis which correlate to the obesity and diabetic developed in these mice. Conclusion: Many studies have focused on how obesity induces endothelial dysfunction. Our study is the first to show an important role of endothelial dysfunction in the process of adipogenesis leading to the development of obesity and diabetes. Our data also highlights the importance of an endoplasmic reticulum chaperone in this process. Acknowledge: This project has been funded by NPRP07-208-3-046.