The role of microRNA in body weight maintenance

• Applicant: Professor Dr. Nikolaus Rajewsky
• Subject Area: Pediatric and Adolescent Medicine ; Endocrinology, Diabetology, Metabolism
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 101434729

MicroRNAs (miRNAs) are now known as a large class of small non-coding RNAs, which post-transcriptionally regulate the expression of a large fraction of all animal genes. Due to this ability, miRNAs are important in a wide range of biological processes. Notably, miRNAs are known regulators of metabolic processes such as insulin secretion, and have recently been implicated in the regulation of diet-induced obesity in mice. The presence of circulating miRNAs in patient serum has attracted considerable amount of interest (1; 2). This is due to the fact, that –surprisingly- the stability of such serum-miRNAs is rather high and is likely caused by exosomes or other forms of microvesicles, which bind to miRNAs. Another reason for the high interest in circulating serum-miRNAs is the finding that individual miRNAs can correlate with specific disease states (such as HPV-infection, coronary heart disease and others). Yet, in most of these cases little is known, where these miRNAs originate from, or if they are functional. We have sequenced serum-miRNAs of mouse and man and have uncovered an astonishing degree of conservation of miRNA expression levels between these species. The number of known and unknown miRNAs in the different mouse and human sera surpassed the expectation and is larger than in any other available data sets. Importantly, the profiles of the serum-miRNA from lean and obese mice strongly support our hypotheses that miRNA can serve as obesity-related biomarkers. As a next step the clinical relevance of this finding shall be determined by analyzing if such obesity-related serum miRNAs are conserved in mouse and human serum. If conserved individual miRNAs or miRNA patterns are identified it will be possible to predict the prospective targets and the matching signaling pathways. Moreover, we wish to analyze in greater detail, if single miRNAs are associated with long-term outcome of weight maintenance after weight loss in the two patient cohorts of the Z-project. In addition the immense depth of our currently established data, shall also be used cooperatively to establish if miRNAs in the hypothalamus (as a central relais of the leptin-signal), are specifically regulated. Moreover, we will establish animal models to follow our hypotheses of a new endocrine function of serum miRNAs. In particular we will follow the question where the serum miRNAs that are associated with weight regulating parameters originate from, where their targets are and which physiological functions they might have.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 218: Hormonal Regulation of Body Weight Maintenance
• Participating Person: Professor Dr. Heiko Krude