Mechanisms of conversion of human white to brown adipocytes – miRBAT

The increase in the frequency of overweight/obese people has reached a qualified epidemic stage with more than one billion overweight (IMC > 25 kg/m2) and at least 300 millions clinically obese (BMI > 30 kg/m2) with tremendous costs for health care systems. A positive energy balance, which is accompanied by an increase in body weight due to increase in the white adipose tissue (WAT) mass, is resulting from an imbalance between energy intake and energy expenditure. During the last two decades, the major scientific and financial contributions have focused on studies of genetic factors in response to an ‘’obesogenic'' environment. This approach now appears rather disappointing in terms of Public Health. Regarding energy expenditure, brown adipose tissue (BAT) has been long known in rodents to dissipate caloric excess through diet-induced thermogenesis. In contrast to early contention, healthy adult humans possess BAT with a potential for metabolic significance. During the 3 last years, active BAT was found in small amounts in healthy adult human localized in various anatomical sites (supra-clavicular area, neck, para-vertebral area). Therefore, the identification of factors leading to increased mass/activity of human BAT are of great interest for the treatment of overweight and obesity as well as for associated diseases. For that purpose, we set up a unique cellular model, i.e. multipotent stem cells derived from human adipose tissue (hMADS cells), which differentiate into white adipocytes and are also able to convert into functional brown adipocytes upon chronic activation of PPAR?, a nuclear receptor of the PPAR family (Peroxisome proliferator-activated receptor) (Elabd et al, 2009). Moreover, one class of small regulators – microRNA (miRNA)- was identified and showing a functional activity in several biological processes and associated diseases. At the present time, more than 900 mature microARN were identified and predict to control at least 50% of the whole set of genes. Although, low number of miRNA have been implicated in the differentiation of human white adipocyte, no miRNA has been described so far to play a role in the conversion of white into brown adipocytes and in the regulation of key metabolic pathways.
In order to identify miRNAs and mRNAs involved in the regulation of the conversion of human white to brown adipocytes and in that of the key metabolic pathways, we will perform in vitro studies and are proposing the following aims: 1) to identify miRNAs and mRNAs responding to the activation of PPAR? during the conversion of the human white into brown adipocytes; 2) to identify miRNAs and mRNAs responding to the activation of PPARa in white and brown adipocytes; 3) to analyze key metabolic pathways and mitochondriogenesis in white versus brown adipocytes and to assess the effects of the identified candidates and 4) to validate the functional role of identified miRNAs and mRNAs. The results thus obtained will bring an important contribution to the identification miRNAs and mRNAs as gatekeepers in the conversion of white to brown adipocytes and metabolic pathways involved in energy expenditure, with a special emphasis on weight gain/obesity issues, thereby paving a way for the development of new therapies and commercial applications.