Abstract
Insulin plays a central role in regulating metabolic homeostasis and guanine-nucleotide exchange factors of the cytohesin family have been suggested to be involved in insulin signal transduction. The Drosophila homolog of cytohesin-3, steppke, has been shown to be essential for insulin signaling during larval development. However, genetic evidence for the functional importance of cytohesin-3 in mammals is missing. We therefore analyzed the consequences of genetic cytohesin-3-deficiency on insulin signaling and function in young and aged mice, using normal chow or high-fat diet (HFD). Insulin-receptor dependent signaling events are significantly reduced in liver and adipose tissue of young cytohesin-3-deficient mice after insulin-injection, although blood glucose levels and other metabolic parameters remain normal in these animals. Interestingly, however, cytohesin-3-deficient mice showed a reduced age- and HFD-induced weight gain with a significant reduction of body fat compared to wild-type littermates. Furthermore, cytohesin-3-deficient mice on HFD displayed no alterations in energy expenditure, but had an increased lipid excretion instead, as well as a reduced expression of genes essential for bile acid synthesis. Our findings show for the first time that an intact cyth3 locus is required for full insulin signaling in mammals and might constitute a novel therapeutic target for weight reduction.
Highlights
Metabolic diseases like type 2 diabetes are widespread in western countries and are rapidly arising in developing countries
Deciphering all participants in the regulation of insulin receptor (IR)-signaling is important for future treatments and for the reduction of risk factors
We describe for the first time the in vivo requirement of cyth[3] for insulin signal transduction in liver and fat, as well as in body weight control in the mouse
Summary
Metabolic diseases like type 2 diabetes are widespread in western countries and are rapidly arising in developing countries. The basis of insulin signaling and the regulation of nutrient metabolism under different conditions i.e. starvation, food intake, high-fat diet, and aging are under intense investigation. This study provides the first metabolic analysis of cyth[3] full knockout mice (cyth3−/−). Phenotypic alterations of these animals were analyzed with respect to insulin signaling and the regulation of nutrient metabolism after metabolic changes like starvation and re-feeding, after insulin injection, during high-fat diet, and aging. Under aging conditions or on a high-fat diet, cyth3−/− mice exhibit reduced weight gain accompanied by decreased accumulation of body fat due to increased fat excretion. In conclusion we found cyth[3] to play an important role in insulin signaling and body fat regulation in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
