pancreatic islet; energy homeostasis; Argonaute2; diabetes; obesity; microRNA
570 Biowissenschaften; Biologie
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.
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