Projects / Programmes
Role of ventromedial hypothalamic nucleus as central glucose sensor
| Code |
Science |
Field |
Subfield |
| 7.00.00 |
Interdisciplinary research |
|
|
| Code |
Science |
Field |
| B001 |
Biomedical sciences |
General biomedical sciences |
| Code |
Science |
Field |
| 4.03 |
Agricultural and Veterinary Sciences |
Veterinary science |
Mouse, hypothalamus, ventromedial nucleus, glucose, obesity, energy balance, steroidogenic factor 1
Researchers (8)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
23415 |
PhD Jurij Dolenšek |
Metabolic and hormonal disorders |
Researcher |
2016 - 2018 |
233 |
| 2. |
28405 |
PhD Marko Gosak |
Physics |
Researcher |
2016 - 2018 |
287 |
| 3. |
24348 |
PhD Neža Grgurevič |
Veterinarian medicine |
Researcher |
2016 - 2018 |
58 |
| 4. |
13330 |
PhD Gregor Majdič |
Veterinarian medicine |
Head |
2016 - 2018 |
577 |
| 5. |
12266 |
PhD Marjan Slak Rupnik |
Metabolic and hormonal disorders |
Researcher |
2016 |
350 |
| 6. |
32132 |
PhD Andraž Stožer |
Metabolic and hormonal disorders |
Researcher |
2016 - 2018 |
425 |
| 7. |
34286 |
Nina Šterman |
|
Technical associate |
2016 - 2018 |
0 |
| 8. |
19487 |
PhD Malan Štrbenc |
Veterinarian medicine |
Researcher |
2016 - 2018 |
87 |
Organisations (2)
Abstract
Body weight regulation is a tightly regulated process requiring close interplay between the peripheral and central sensing and regulating centres. The main regulator of energy availability in the periphery is pancreas with secretion of glucagon and insulin, which modulate glucose storage in different tissues and glucose utilization from the energy stores when needed. Central nervous system has also important roles in the energy balance regulation. It is well established that hypothalamus is the main site of autonomous mechanisms for body weight regulation, with arcuate (ARC) nucleus and paraventricular nucleus (PVN) probably being the most important sites. Beside ARC and PVN, dorsomedial hypothalamic nucleus, ventromedial hypothalamic nucleus (VMH) and lateral hypothalamus have important roles in the body weight regulation, although their roles are less clear. VMH has been long thought to be a satiety centre as studies in the seventies have shown that damage to the VMH causes obesity due to hyperphagia. This has been challenged recently by several papers, including one from the PI of this proposal, showing that VMH disruption has more severe effects on physical activity, and perhaps metabolism, than on appetite. Our studies with SF-1 knockout mice that have specifically disrupted only VMH have shown that these mice develop late onset obesity due to severely reduced physical activity levels. Mechanisms regulating motivation to perform physical activity are much less explored than mechanisms regulating appetite and therefore, we still do not understand what causes obesity in mice with the disrupted VMH. Several studies in recent years have suggested the role of VMH in glucose sensing and even implied VMH as the main glucosensor in the brain. Although this has not been universally accepted, there are several studies strongly supporting this theory and if VMH does act as a glucose sensing centre, this could explain the obesity in SF-1 KO (and other similar) mice model(s). If glucose sensing in such animals is disrupted and they are not able to sense levels of glucose, their central nervous system might want to save the energy through the reduction in physical activity, being made to believe that there is not enough energy (glucose) in the bloodstream. Consequently, this may lead to obesity as unused energy would be stored as adipose tissue. In the proposed studies, we will therefore explore the function of the VMH from glucosensing perspective in SF-1 KO and WT mice. We will aim to determine if defective glucosensing in the VMH is the cause of obesity in SF-1 KO mice, if obese phenotype could be rescued by transplantation of VMH cells from WT mice into SF-1 KO mice brain, if adult downregulation of SF-1 gene affects body weight, physical activity and glucosensing in the VMH and if pancreas is affected in SF-1 KO mice as some studies have suggested direct connections between VMH and pancreas. We will use immunocytochemistry with specific antibodies against proteins involved in glucosensing, live calcium imaging in live brain slices to detect glucose sensing, live brain cell transplantation to rescue obese phenotype in SF-1 KO mice, siRNA mediated SF-1 gene silencing of SF-1 gene in adult WT mice to determine the role of SF-1 in the adult brain, and calcium imaging in live pancreatic slices to examine pancreas function in SF-1 KO mice.
Results of the proposed studies will importantly contribute to our understanding of energy balance regulation in mammals. In particularly, these results will provide important advancements in understanding the function of the ventromedial hypothalamus in the body weight regulation, general molecular mechanisms regulating physical activity and will help to clarify the role of VMH as glucosensing organ. The results will have very important implications for human health as they could lead to the development of new methods/drugs to increase motivation for physical activity in people prone to sedentary
Significance for science
Mechanisms of body weight regulation are extremely important for survival of organisms in the environment. In the last 20 years, since the discovery of leptin in 1992, there was a large progress in our understanding of body weight regulation mechanisms. However, beside many studies, these processes are still not completely understood. Although we understand quite well molecular pathways regulating appetite, it is much less known about the molecular mechanisms regulating energy consumption and in particularly about the mechanisms influencing the drive for physical activity. In our proposed studies we will carefully examine the role of ventromedial hypothalamus and also an SF-1 gene in the regulation of glucose sensing and physical activity. Results of proposed studies will contribute importantly to the understanding of processes regulating energy balance and in particular physical activity in mammals. Expected results will shed light on understanding how physical activity is autonomously regulated in mammalian central nervous system and will be important contribution to our understanding of regulation of physical activity drive in humans. Our results will clarify the role of ventromedial hypothalamic nucleus in the regulation of physical activity and will therefore in the future contribute to the development of new drugs for treatment of obesity and associated health problems in inactive/sedentary people. Additionally, our results will also clarify the role of ventromedial hypothalamic nucleus in the development and function of pancreas, what will be undoubtedly important for better understanding of type 2 diabetes, which is becoming one of the major health problems in the world. Results of the proposed studies will also clarify the role of SF-1 gene in the development and function of the hypothalamus. Currently ,we do not know if SF-1 gene is needed only for proper development of the ventromedial hypothalamic nucleus or perhaps also for its function in adult life. If our results will reveal that SF-1 gene has important role in the function of adult ventromedial hypothalamic nucleus and in the regulation of energy balance, this would make SF-1 gene a very interesting target gene for drugs to treat obesity and consequently help in obesity associated problems.
Significance for the country
Obesity is becoming one of the major health problems in many countries including Slovenia. Obesity is presenting a very large burden for public health care as it is closely associated with many other serious health problems such as type 2 diabetes, cardiovascular diseases, stroke, some cancers etc. Despite 20 years of intensive research, we still don't have good tools to fight the obesity epidemics and its associated health problems. Although it is clear that unhealthy lifestyle, too much highly caloric food and not enough physical activity are the main reasons for increasing incidence of obesity, it is difficult to motivate people to become more physically active. Since we do not yet understand the molecular mechanisms that autonomously regulate physical activity, it is also difficult to intervene in these autonomous processes. SF-1 KO mice are very interesting model that develop obesity due to hypoactivity, which is present before mice become obese. This suggests the existence of internal drives for physical activity, which, if discovered also in humans, could be potentially activated and would increase the desire/drive for being physically active. Our studies are aimed to determine the causes of hypoactivity in SF-1 KO mice and once these molecular mechanisms are discovered, this could lead to further studies that would more carefully examine how such systems could be activated. Once these molecular mechanisms will be understood, it would be possible to develop drugs that would specifically activate drives for physical activity and such drugs could have many beneficial effects on human health. It is well known that physical activity has many beneficial effects for human health, not just in reduction of body weight but also, for example, direct beneficial effects in type 2 diabetes through modulating insulin resistance. Interestingly, the number one choice drug used today for treatment of early type 2 diabetes is Metformin, a drug that activates AKC kinase, which is normally activated during physical activity. Unfortunately, Metformin has many sideffects and drugs that could potentially activate drive for physical activity would undoubtedly be more healthy way to increase physical activity and achieve associated benefits. Such drugs could have a major impact on the health of the society, as well as on public healthcare costs as it could potentially majorly reduce the incidence of obesity and its associated health problems.
However, development of such drugs would be only possible if we would first understand the mechanisms in the central nervous system that regulate physical activity, what is the major aim of our proposed studies. Therefore in long term, the results of propsoed project could have direct benefits for the society by reducing the incidence of obesity and induce more healthy lifestyle, as well as for economy through reducing healthcare expenditure due to reduced incidence of obesity associated health problems.
Most important scientific results
Interim report,
final report
Most important socioeconomically and culturally relevant results
Interim report,
final report
