microRNA-induced recruitment of thermogenic adipocytes to combat obesity

Excessive energy intake and diminished energy expenditure are two sides of the same coin leading to overweight and obesity. Both disorders reach pandemic proportions globally with more than 1.5 billion adults overweight (BMI > 25 kg/m2) and at least 500 million of them clinically obese (BMI > 30 kg/m2). As controlling the side of energy intake pharmacologically has failed so far in promoting weight loss, enforcing the side of energy expenditure has recently attracted attention. Intriguingly, in contrast to early contention, healthy adult individuals possess not only energy-storing white adipocytes but also thermogenic adipocytes which are specialized in combustion of carbohydrates and fats for the purpose of heat production (non-shivering thermogenesis). These thermogenic adipocytes are characterized by multilocular lipid droplets, a high density of mitochondria, and the expression of uncoupling protein 1 (UCP1), a mitochondrial protein that plays the key role in heat production by uncoupling the activity of the respiratory chain from ATP synthesis. Thermogenic adipocytes constitute the brown adipose tissue and - upon cold stimulation - can be found in white adipose tissue, thereby called "brite" (brown-in-white) / "beige" adipocytes. We identified a microRNA that induces UCP1 expression in mature white human adipocytes, thus influencing the white-brite balance. Therefore we propose to characterize the microRNA-induced effects on adipocyte metabolism in vitro and in vivo. In particular, we first aim to generate a human in vitro model system with inducible expression or inhibition of this microRNA. While the inducible microRNA expression will enable us to investigate its thermogenic effects in mature human adipocytes, the inducible microRNA inhibition will provide insight into its regulatory interplay with substances known to influence the white-brite balance. To investigate the role of this microRNA in vivo, we generated a transgenic mouse model that enables an inducible microRNA overexpression exclusively in adipocytes. With these mice, we will investigate the impact of this microRNA on energy homeostasis and thermogenic adipocyte recruitment. We expect to generate novel insights into the regulation of energy expenditure via non-shivering thermogenesis in adipocytes, which may contribute to novel strategies to combat obesity and associated metabolic disorders.

Excessive energy intake and diminished energy expenditure are two sides of the same coin leading to overweight and obesity. Both disorders reach pandemic proportions globally with more than 1.5 billion adults overweight (BMI > 25 kg/m2) and at least 500 million of them clinically obese (BMI > 30 kg/m2). As controlling the side of energy intake pharmacologically has failed so far in promoting weight loss, enforcing the side of energy expenditure has recently attracted attention. Intriguingly, in contrast to early contention, healthy adult individuals possess not only energy-storing white fat cells but also thermogenic fat cells which are specialized in combustion of carbohydrates and fats for the purpose of heat production (non-shivering thermogenesis). However, these beneficial fat cells decline with increasing body weight and years of age. They are characterized by multilocular lipid droplets, a high density of mitochondria, and the expression of uncoupling protein 1 (UCP1), a mitochondrial protein that plays the key role in heat production (thermogenesis) by uncoupling the activity of the respiratory chain from ATP synthesis. Thermogenic fat cells constitute the brown adipose tissue and - upon cold stimulation - can be found in white adipose tissue, thereby called brite (brown-in-white) / beige fat cells. We have discovered and characterized the first human microRNA family miR-26 which is able to initiate energy expenditure in human white fat cells, thus representing a novel drug target for the treatment of obesity and diabetes. First findings in vivo confirm this function of miR-26a on the energy metabolism, further studies are in preparation. These results prove for the first time the hypothesis that microRNAs, in particular miR-26, can have a beneficial impact on the recruitment and function of energy dissipating fat cells in human. These insights into the control of energy metabolism via thermogenesis in fat cells, in combination with issued patents in Europe and USA, may pave the way to develop novel therapies against obesity and associated metabolic complications.