Strategy for improving clinical obesity therapeutics
Lead Research Organisation:
University of Manchester
Department Name: School of Medical Sciences
Abstract
Obesity is a global health problem affecting millions of people. It contributes to various health problems like heart disease, diabetes, and even certain types of cancer. Intuitively, this has huge societal and economic implications costing about £6 billion annually to the NHS alone, a figure projected to rise to about £10 billion each year by 2050. While healthy diet and exercise are the first line of intervention and should be promoted, they are often insufficient, and medical interventions become necessary for a significant number of people. One of the most effective treatments so far has been weight-loss surgery, but it is invasive, costly, and not practical when considering the epidemic proportion of the obesity problem. Therefore, finding an affordable, less invasive, and more universally applicable solutions is crucial.
In this context, our team is set to explore a promising new drug, called Tirzepatide. This medication, originally developed for type 2 diabetes, has shown extraordinary results in helping people lose weight. In fact, its effects are almost comparable to those of weight-loss surgery, and superior to any other drug so far tested clinically. However, the exact way by which Tirzepatide achieves these remarkable results are currently unknown.
That is where our research comes in. We aim to delve into the mechanisms through which Tirzepatide achieve its remarkable clinical outcomes, focusing particularly on its effects on the brain, as we believe that this is where the drug acts to exert its major impact on body weight. We will be using a 'reverse translational' approach, which means we start with what we already know from patient experiences and clinical trials, then work backward using laboratory mouse models to uncover the underlying biological processes.
We will be using advanced genetic tools, which can be thought of as advanced biological controls, to find the specific brain cells that the drug interacts with to help people lose weight. These tools give us the power to flip these cells on or off whenever we want, just like switching a light on or off using a remote control. This will help us understand what exactly these cells are doing where the drug is working. In simpler terms, we are trying to find and study the 'weight loss' cells in the brain that this drug talks to.
The goal of this research is to gain a thorough understanding of how Tirzepatide interacts with the body's systems to cause weight loss. We believe that this knowledge will be critical not only for a better-informed use of Tirzepatide itself, but also guiding the development of new treatments. Additionally, by pinpointing the specific 'weight loss' brain cells that this drug interacts with, we are also likely to gain a deeper understanding of the fundamental processes controlling body weight and how these processes go awry in obesity. This knowledge could offer hope for the development of more personalised and effective treatments in the future. As such, our research holds the potential to provide a more comprehensive understanding of obesity, and, importantly, to inform the development of more efficient, scalable, and affordable solutions to combat this widespread health challenge.
In this context, our team is set to explore a promising new drug, called Tirzepatide. This medication, originally developed for type 2 diabetes, has shown extraordinary results in helping people lose weight. In fact, its effects are almost comparable to those of weight-loss surgery, and superior to any other drug so far tested clinically. However, the exact way by which Tirzepatide achieves these remarkable results are currently unknown.
That is where our research comes in. We aim to delve into the mechanisms through which Tirzepatide achieve its remarkable clinical outcomes, focusing particularly on its effects on the brain, as we believe that this is where the drug acts to exert its major impact on body weight. We will be using a 'reverse translational' approach, which means we start with what we already know from patient experiences and clinical trials, then work backward using laboratory mouse models to uncover the underlying biological processes.
We will be using advanced genetic tools, which can be thought of as advanced biological controls, to find the specific brain cells that the drug interacts with to help people lose weight. These tools give us the power to flip these cells on or off whenever we want, just like switching a light on or off using a remote control. This will help us understand what exactly these cells are doing where the drug is working. In simpler terms, we are trying to find and study the 'weight loss' cells in the brain that this drug talks to.
The goal of this research is to gain a thorough understanding of how Tirzepatide interacts with the body's systems to cause weight loss. We believe that this knowledge will be critical not only for a better-informed use of Tirzepatide itself, but also guiding the development of new treatments. Additionally, by pinpointing the specific 'weight loss' brain cells that this drug interacts with, we are also likely to gain a deeper understanding of the fundamental processes controlling body weight and how these processes go awry in obesity. This knowledge could offer hope for the development of more personalised and effective treatments in the future. As such, our research holds the potential to provide a more comprehensive understanding of obesity, and, importantly, to inform the development of more efficient, scalable, and affordable solutions to combat this widespread health challenge.
Technical Summary
The escalating obesity epidemic necessitates the development of novel, scalable and affordable interventions. Tirzepatide, a promising dual GLP-1R/GIPR agonist, has shown significant weight loss in the clinic, approaching that of bariatric surgery. However, its mechanisms of action remain unknown. In our objectives, through a reverse translational approach, we propose to use mouse models to dissect the neural pathways that underpin the efficacy of dual GLP-1R/GIPR agonism.
We will tag and manipulate the specific neuronal ensemble that are responsive to different incretin mimetics, including dual GLP1-R/GIPR and GLP1-R monotherapies allowing us to study their physio-pathological significance and their role in mediating the effects of the drugs. We also aim to clarify the specific role of GIPR in the efficacy of dual GLP-1R/GIPR agonists. We will probe the function of this receptor in specific neuronal populations, using independent loss-of-function and rescue approaches to test both necessity and sufficiency. Lastly, we will explore how GLP1R agonist effects are differentially mediated by distinct, genetically defined neurons, and assess the impact of these neurons on the effectiveness of dual GLP-1R/GIPR agonists.
Our proposed research has the potential to provide crucial insights that could inform the optimisation and advancement of obesity treatments, as well as to significantly enhance our understanding of body-weight regulation and the mechanisms contributing to obesity.
We will tag and manipulate the specific neuronal ensemble that are responsive to different incretin mimetics, including dual GLP1-R/GIPR and GLP1-R monotherapies allowing us to study their physio-pathological significance and their role in mediating the effects of the drugs. We also aim to clarify the specific role of GIPR in the efficacy of dual GLP-1R/GIPR agonists. We will probe the function of this receptor in specific neuronal populations, using independent loss-of-function and rescue approaches to test both necessity and sufficiency. Lastly, we will explore how GLP1R agonist effects are differentially mediated by distinct, genetically defined neurons, and assess the impact of these neurons on the effectiveness of dual GLP-1R/GIPR agonists.
Our proposed research has the potential to provide crucial insights that could inform the optimisation and advancement of obesity treatments, as well as to significantly enhance our understanding of body-weight regulation and the mechanisms contributing to obesity.