AbstractsBiology & Animal Science

MicroRNAs (miRNAs) belong to a class of small non-coding RNAs that are implicated in the post-transcriptional regulation of gene expression. Many insights have been made during the past decade into the regulatory function of the miRNA pathway in health and disease. In the present study, we established Argonaute2 (Ago2), a central mediator of the miRNA pathway, as an important regulator of beta cell function. Loss of Ago2 resulted in decreased proliferation of beta cells and increased glucose-stimulated insulin secretion (GSIS). Furthermore, we could show that Ago2 mediates the function of miR- 375, a highly abundant miRNA in beta cells, further highlighting the close relationship between these two genes. A small-scale siRNA-based screen revealed that multiple target genes of miR-375 orchestrate GSIS. Furthermore, using a SILAC based quantitative mass spectrometry approach, we could identify about 50 unique proteins that are co-secreted along with insulin that may have autocrine or paracrine functions. Among the numerous predicted targets of miR-375, the cell adhesion molecule 1 (Cadm1) emerged as a suppressor of beta cell proliferation. Interestingly, Cadm1 also exhibits an important regulatory role in the central regulation of glucose homeostasis. Loss of Cadm1 in Vglut2-positive neurons resulted in decreased body weight, increased hepatic insulin sensitivity, increased energy expenditure and protected from diet as well as genetically induced obesity. To our knowledge, we for the first time established a role for a cell adhesion molecule as an important regulator of glucose homeostasis by modulating neuronal circuits and the composition of the active zone within synapses. Furthermore, we could highlight that Cadm1 expression is regulated in response to changes in insulin sensitivity in the hippocampus, emphasizing the adaptive responses of tissues to maintain energy homeostasis. Future studies will address how changes in circulating hormones and nutrients translate into tissue-specific adaptive responses in gene expression and shed light on the complex network between different cell types in order to maintain energy balance. Lastly, the biological significance of the miRNA pathway in these processes remains to be studied in greater detail that may be crucial for therapeutic intervention. MicroRNAs (miRNAs) gehören zu der Klasse nicht-kodierender RNAs und sind an der post-translationalen Regulation der Genexpression beteiligt. Verschiedene Arbeiten konnten bereits zeigen, dass miRNAs eine wichtige Rolle bei der Aufrechterhaltung der Zellfunktion haben und auch an der Entstehung von Krankheiten beteiligt sind. In der hier vorgelegten Arbeit konnten wir zeigen, dass Argonaute2 (Ago2), ein wichtiger Bestandteil des miRNA Signalweges, an der Regulation des Betazellfunktion beteiligt ist. Der Verlust von Ago2 Expression in Mäusebetazellen resultierte in verringerter Zellproliferation und verstärkter Freisetzung von Insulin nach Stimulation mit Glukose. Darüber hinaus konnten wir…