MicroRNAs and Adipose Tissue
MicroRNAs and Adipose tissue
Throughout the industrialized world, the obesity pandemic poses a significant health burden with more than 300 millions adults diagnosed as clinically obese (WHO). Weight-intervention approaches often include reductions in caloric intake and surgical interventions. These often fail to significantly lower body weight due to metabolic adaptations such as reductions in energy expenditure and food intake. Opposing approaches, which aim at increasing basal metabolic rates and thus the turnover of ingested calories are less stringently accompanied by metabolic adaptations and thus harbor a high potential as anti-obesity treatment. In this regard, activation of brown adipose tissue (BAT) has moved into focus as potential anti-obesity treatment. This is exemplified by the intriguing fact that seemingly negligible amounts of brown fat significantly increase energy expenditure and basal metabolic rates. It has been estimated that as a little as 50g of additional BAT would combust 20% more of calories ingested per day in humans. Thus, identifying novel regulatory Noncoding RNAs that control BAT differentiation, activation and function is of critical importance. Our ultimatate goal is to define novel sequence-specific anti-ncRNAs therapeutics for anti-obesity intervention.
Dicer1-microRNA328-Bace1 Signaling governs Brown Adipose Tissue Function in Obesity and Ageing
Recent, we could show that ageing- and obesity-associated dysfunction of brown fat coincides with global microRNA down-regulation due to reduced expression of the microRNA processing node Dicer1. Consequently, heterozygosity of Dicer1 in BAT aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose metabolism. Analyses of differential microRNA-expression during preadipocyte commitment and mouse models of progeria, longevity and DIO, identified miR-328 as a regulator of BAT differentiation. Reducing miR-328 blocked preadipocyte commitment while miR-328 over-expression instigated BAT differentiation and impaired muscle progenitor commitment - partly via silencing of the ß-Secretase Bace1. Bace1 loss enhanced brown preadipocyte specification in vitro while Bace1 was over-expressed in BAT of obese and progeroid mice. In vivo Bace1 inhibition delayed DIO-induced weight gain and improved glucose tolerance and insulin sensitivity. These experiments reveal Dicer1-miR-328-Bace1 signaling as a determinant of BAT function and define Bace1-inhibition as therapeutic approach to not only improve neurodegenerative diseases but also ageing- and obesity-associated impairments of BAT function.