#	Pagina
attuale pagina	/open-h2020/projects/209051/results.html
-1	/open-h2020/projects/223870/index.html
-2	/open-h2020/projects/200057/index.html

Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CNS-Insuin-Res (How insulin resistance in the dorsal vagal complex affects glucose metabolism and feeding behaviour)

Teaser

Summary

The Dorsal Vagal Complex (DVC) is an area on the brain that can sense changes in the levels of circulating hormones like insulin, GLP1(Glucagon-Like peptide), glucagon, etc. The DVC can respond to these changes by regulating the way in which we eat, and also by controlling the way in which the liver release glucose in the blood. Altogether these events can regulate the food intake, body weight and blood glucose levels. We are interested in understanding how the DVC senses insulin to regulated feeding behavior, body weight, and blood glucose levels and we try to understand what happened when this part of the brain is not able to respond to insulin. With obesity and type 2 diabetes, in fact, the brain stops sensing insulin and its ability to regulate metabolic functions like food intake body weight and glucose levels are lost. Understanding the molecular mechanism that triggers insulin resistance in the brain could be and important step in developing new treatments to counteract obesity and diabetes.

The mitochondria are important organelles presents in every cell and are responsible for producing energy. They work hard and become big by fusing together (mitochondria fusion) when we are in need of energy and they
work less and become small (Mitochondria fission) when we have too much energy. We discovered that giving rodent a diet rich in fat for as short as 3 days is sufficient to cause insulin resistance in the DVC and prevent insulin to regulate feeding behavior and blood glucose levels. This loss of insulin sensitivity is due to the fact that the mitochondria become smaller and less active (increase in mitochondria fission).

In this fellowship, we aimed to:
WP1) Identify the molecular mechanism by which HFD-dependent mitochondria fission causes insulin resistance in the DVC and deregulation of glucose metabolism
WP2) Understand whether the increase of mitochondria fission in the DVC can affect the feeding behaviour of the rodent
WP3) Identify the neuronal networks involved in the DVC-insulinâ€“dependent regulation of HGP and feeding behaviour.

Work performed

\"
In this fellowship, we showed that by simply increasing mitochondria fission in the DVC we cause insulin resistance, hyperphagia, and body weight gain while inhibition of mitochondria fission on the DVC of high-fat diet-fed, insulin resistant, rats protects from developing insulin resistance, decreases body weight and food intake. This data makes mitochondria fission and the protein that regulates it (DRP1) a potential target for restoring insulin sensitivity in obese and diabetic individuals.
With mitochondria fission, we also see an increase in the levels of a protein called inducible Nitric oxide synthase (iNOS). This is an enzyme that can regulate the activity of many different proteins and is involved in changes in insulin signalling. With this fellowship, we also discovered that by decreasing iNOS levels in high-fat diet-fed rats, we can prevent the development of insulin resistance, decrease body weight and food intake. This also makes iNOS a potential drug target to fight insulin resistance in obesity and diabetes.

We have a manuscript in preparation that contains the aforementioned results and that we hope to submit soon.

The DVC is an important brain centre that receives signals from the peripheral organs and relays these signal to higher areas of the brain. In addition, the DVC can also receive signals from other brain areas and relay them to the peripheral organs. Due to his nature, the DVC has a highly diversified group of neuronal cells. An important question that is still unanswered is which neuronal population in the DVC is involved in insulin sensing and regulates feeding behaviour. In the attempt to address this question we performed a histochemical characterization of the DVC neuronal populations. The data we obtained will be used in the future to target specific neuronal cell types in the DVC in order to understand their involvement in sensing insulin.

This work was presented in a series of scientific meetings:
Invited seminar and talks:
Mitochondria Form and Function, 14-15 September 2017, London, sponsored by the physiological society. I was part of the organization committee that selected the theme and the speakers and I also gave a talk: Filippi B.M.: Mitochondria fission in the dorsal vagal complex induces insulin resistance. Mitochondria: Form and Function meeting, 14 -15 September 2017, London, UK (Invited Speaker)
Filippi B.M.: Mitochondria fission in the dorsal vagal complex induces insulin resistance. Institute of Hepatology, 14 November 2017, London, UK) (Invited seminar)
Posters presentations:
Future Physiology, University of Leeds, LS2 9JT, Inhibition of Drp1 in the Dorsal Vagal Complex of the Brain Reduces Food Intake in Insulin Resistant Rats PC47 (Nov 17)
Mitochondrial Medicine, Wellcome Genome Campus, Hinxton,CB10 1SA: Inhibition of mitochondrial fission in the Dorsal Vagal Complex of the Brain prevents Hyperphagia in High Fat Diet Fed Rats P69 (May 18)
Europhysiology, QEII, London, SW1P 3EE: Inhibition of mitochondrial fission in the Dorsal Vagal Complex of the Brain prevents Hyperphagia in High Fat Diet Fed Rats PCA299 (Sep 18)
SFN, San Diego Convention Centre, San Diego, CA 92101: Inhibition of mitochondrial fission in the Dorsal Vagal Complex of the Brain prevents Hyperphagia in High Fat Diet Fed Rats XX3 (Nov 18)
Public engagement:
When we show our data to the public we create awareness about the danger of being overweight and having an unhealthy lifestyle and the negative effect that this has on the brain and consequently in the body. I presented these findings in public events:
- In the \"\"Pint of Science\"\" I interacted with an adult audience and talked about the brain and how it regulated metabolic functions. I disseminate awareness of the dangers of obesity and insulin resistance and how they can lead to the development of diabetes.
- In the be Curious (A day event at the University of Leeds open to children and families), we had a stall in which we interacted with the yo\"

Final results

The grant was focused on understanding the molecular mechanisms that cause insulin resistance in the brain. None of the findings will be of immediate use for people with obesity and diabetes, but these findings highlight how the brain
is a very important regulator of metabolic functions and how targetting the brain could be beneficial in individuals with altered metabolic functions.
With this study, we showed how the brain is an important regulator of metabolic functions. and we highlighted how changes in mitochondria dynamics and in iNOS levels can affect insulin sensitivity, feeding behaviour and body weight. Understanding how it works will give us new means to develop novel pharmacological approaches to treat obesity and diabetes.

With our public engagement, we aimed to make the public aware of the dangers related to obesity and diabetes and of the fact that the brain can be compromised by unhealthy habits and cause metabolic imbalance. The aim is to create an impact in the society by increasing awareness of the problems and explaining how compromising brain function can be deleterious for many different biological events.