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Reactive Oxygen Species and Hypothalamic Glucose Sensitive Neurons: a new mechanism in glucose homeostasis

Final Report Summary - NEUROSENS (Reactive Oxygen Species and Hypothalamic Glucose Sensitive Neurons: a new mechanism in glucose homeostasis)

State of the Art: Development of obesity and diabetes is the consequence of impaired glucose homeostasis regulation. The hypothalamus plays a critical role in detecting changes in blood glucose level and triggers appropriate physiological responses. High glucose-excited (HGE) neurons increase their electrical activity as glucose level rises. The molecular mechanisms involved in these glucose-sensitive neurons are not fully understood and the specific role of these neurons in the control of glucose homeostasis remains to be clearly demonstrated.

Hypothesis: Preliminary data generated in the laboratory showed that reactive oxygen species (ROS) produced in the hypothalamus in response to increased brain glucose level play a critical role in glucose homeostasis. In HGE neurons, the nature of the channel involved in their glucose sensitivity is unknown. Sub-types of the transient-receptor potential (TRP) channel super-family which present a non-selective cationic conductance (as seen in HGE neurons) have been shown to be ROS sensitive. Thus, the NeuROSens project hypothesized that ROS-TRP channels signaling is involved in hypothalamic HGE glucose sensitivity. The characterization of the channel involved in HGE neurons glucose sensitivity will allow determination of their physiological role in the control of glucose homeostasis.

Originality of the project: This project is highly original and innovative in regards of the hypothesis proposed and technical strategies used. Understanding molecular mechanisms and physiological roles of HGE neurons might significantly improve the knowledge in glucose homeostasis. This could lead to propose new targets against development of diabetes and obesity.

Results obtained: The first accomplishment of the NeuROSens project was the transfer of in vitro cellular imaging and ex vivo electrophysiology techniques to the host institution. The second is the results obtained. The four specific aims of the NeuROSens project are almost all completed. Dr. Fioramonti and his collaborators have collected a significant amount of data confirming our hypothesis. For instance, inhibition of ROS production decreases glucose response of HGE neurons in an in vitro preparation of dissociated hypothalamic neurons. Selective TRPC inhibitors show that TRPC3 channels play a critical role in HGE neurons glucose response. Using TRPC3 deficient mice, ongoing work shows that this channel is critical for the central control of glucose homeostasis. In addition, in making advancement beyond the state of the art in the field, they found that HGE neurons from rats fed high-fat/high-sucrose diet, in which central control of glucose homeostasis is altered, present an impaired response to glucose. These data confirm the involvement of HGE neurons in the control of glucose homeostasis since their response to glucose is altered in condition where glucose homeostasis is also impaired. Thus, the NeuROSens project highlights a new signaling pathway involved in the control of energy homeostasis and proposes a new target, hypothalamic TRPC3 channels, against the development of metabolic diseases.
It is noteworthy that, Dr. Fioramonti managed senior staff members, undergraduate students and a PhD student for the accomplishment of the NeuROSens project. Managing these persons gave Dr. Fioramonti the opportunity to lead his own research group, a necessary step for becoming group leader.

Impact: The impact of the NeuROSens project is double in term of scientific and technical impact. The idea of working on TRP channel in the control of energy homeostasis is new. In addition, as mentioned above, NeuROSens highlights a new signaling pathway involved in glucose homeostasis. Thus, our data open a new field of investigation which will beneficiate for both the host team, the institute and more generally European or international laboratories working in the field. The technical impact of the NeuROSens project is also significant since it combines both high standard in vitro and in vivo approaches. This is particularly interesting since Dr. Fioramonti is one of the few European researchers able to perform those techniques.

Dissemination: We have started disseminating our data; Dr. Fioramonti and the PhD student hired for this project presented their data at different national or international meetings through poster or oral communications. No scientific article directly related to the NeuROSens project has been published yet since we are waiting for final data to submit an article in a high ranked journal.
Dr. Fioramonti has developed collaborations with persons from the laboratory and outside our institution (in France or internationally) such as with his former postdoctoral mentor. These collaborations have already led to published articles and some other manuscripts are in the process to be submitted. These collaborations show the good integration of Dr. Fioramonti among respected scientists of the field.

Conclusion: In conclusion, we believe that being awarded from the Marie Curie CIG significantly boosted Dr. Fioramonti's scientific career to become an independent and respected researcher known internationally in his field. Awarding the NeuROSens was both benefic for him, the laboratory as well as for the hosts institutions : INRA and the University of Burgundy.