Investigating the mechanisms in sympathetic neurons that link sleep to obesity
Lead Research Organisation:
University of Oxford
Department Name: Physiology Anatomy and Genetics
Abstract
Obesity is a major health problem that affects many people worldwide. Unfortunately, there are limited options available to treat obesity, including surgery and medications that suppress appetite, which can be expensive and irreversible. Lifestyle changes and dieting are less expensive but often ineffective because they can lead to a compensatory decrease in energy expenditure, making it difficult to lose weight in the long term. This is because when we reduce our food intake, our body's metabolism adapts to save energy, which can counteract weight loss during dieting.
To overcome this problem, we are trying to understand the biological mechanisms behind metabolic adaptation to fasting. One important aspect of this research is to investigate the role of thermogenesis, a process that dissipates energy in the form of heat, and how it is affected by rest and sympathetic neurons. Recent studies in humans and mice have shown that adrenergic beta 2 (adrb2) agonists can boost thermogenesis and energy expenditure, potentially making it easier to lose weight.
The goal of this research proposal is to better understand the molecular mechanisms behind metabolic adaptation to fasting and the role of adrb2 in thermogenesis and energy expenditure. The research will use mice to investigate whether adrb2 agonism can mitigate metabolic adaptation to fasting, and whether this effect is dependent on the function of adrb2 in sympathetic neurons that control thermogenic adipose tissue. We also aim to understand whether lack of rest, consequence of sleep deprivation, alters metabolic adaptation to fasting and whether this is connected to lower adrb2 signaling in sympathetic neurons and sympathetic neurodegeneration within thermogenic adipose tissue. We think that this is important to study because it is well known that humans and animals that are sleep deprived gain more weight.
Overall, this research aims to provide insights into new approaches to treat obesity that are effective, safe, and affordable. By understanding the molecular mechanisms behind metabolic adaptation to fasting and the role of adrb2 in thermogenesis, other researchers may be able to develop new medications or therapies that can help people lose weight and maintain a healthy lifestyle.
To overcome this problem, we are trying to understand the biological mechanisms behind metabolic adaptation to fasting. One important aspect of this research is to investigate the role of thermogenesis, a process that dissipates energy in the form of heat, and how it is affected by rest and sympathetic neurons. Recent studies in humans and mice have shown that adrenergic beta 2 (adrb2) agonists can boost thermogenesis and energy expenditure, potentially making it easier to lose weight.
The goal of this research proposal is to better understand the molecular mechanisms behind metabolic adaptation to fasting and the role of adrb2 in thermogenesis and energy expenditure. The research will use mice to investigate whether adrb2 agonism can mitigate metabolic adaptation to fasting, and whether this effect is dependent on the function of adrb2 in sympathetic neurons that control thermogenic adipose tissue. We also aim to understand whether lack of rest, consequence of sleep deprivation, alters metabolic adaptation to fasting and whether this is connected to lower adrb2 signaling in sympathetic neurons and sympathetic neurodegeneration within thermogenic adipose tissue. We think that this is important to study because it is well known that humans and animals that are sleep deprived gain more weight.
Overall, this research aims to provide insights into new approaches to treat obesity that are effective, safe, and affordable. By understanding the molecular mechanisms behind metabolic adaptation to fasting and the role of adrb2 in thermogenesis, other researchers may be able to develop new medications or therapies that can help people lose weight and maintain a healthy lifestyle.
Technical Summary
Obesity is a rapidly increasing global epidemic with unresolved scientific questions.
Treatments include expensive and irreversible bariatric surgery, injectable biologics that suppress appetite, lifestyle changes, and dieting. However, these options are often ineffective due to metabolic adaptation to fasting, where reductions in food intake lead to a compensatory decrease in energy expenditure. The molecular mechanisms behind this process are unknown.
Humans and mice rely on thermogenesis, which dissipates energy as heat, but during fasting, thermogenesis is blunted to save energy. As with sleep deprivation, lack of rest promotes obesity and diabetes, and it is unclear if it worsens metabolic adaptation to fasting.
The grant proposal aims to uncover the fundamental biological mechanisms behind metabolic adaptation to fasting and their relation to rest and sympathetic neurons.
Recent studies show that adrenergic beta 2 (adrb2) agonists can boost thermogenesis and energy expenditure.
We hypothesize that a subpopulation of adrb2+ sympathetic neurons innervating thermogenic adipose tissues contributes to the beneficial effect of adrb2 agonism on energy expenditure and thermogenesis. Our observation of a subpopulation of nearly 45% sympathetic neurons expressing the beta 2 adrenergic receptor in ganglia supports this hypothesis. The conditional knockout of these neurons' adrb2 facilitates the temperature reduction response to fasting and precipitates obesity without increasing food intake. Our single-cell sequencing analysis supports the tissue specificity of the conditional knock, and adrb2 agonism promotes neuronal/axonal growth in vitro.
We aim to determine if adrb2 agonism can rescue metabolic adaptation to fasting, whether it is connected to lower adrb2 signalling in sympathetic neurons and sympathetic neuropathy within brown adipose tissue, and how lack of rest alters metabolic adaptation to fasting.
Treatments include expensive and irreversible bariatric surgery, injectable biologics that suppress appetite, lifestyle changes, and dieting. However, these options are often ineffective due to metabolic adaptation to fasting, where reductions in food intake lead to a compensatory decrease in energy expenditure. The molecular mechanisms behind this process are unknown.
Humans and mice rely on thermogenesis, which dissipates energy as heat, but during fasting, thermogenesis is blunted to save energy. As with sleep deprivation, lack of rest promotes obesity and diabetes, and it is unclear if it worsens metabolic adaptation to fasting.
The grant proposal aims to uncover the fundamental biological mechanisms behind metabolic adaptation to fasting and their relation to rest and sympathetic neurons.
Recent studies show that adrenergic beta 2 (adrb2) agonists can boost thermogenesis and energy expenditure.
We hypothesize that a subpopulation of adrb2+ sympathetic neurons innervating thermogenic adipose tissues contributes to the beneficial effect of adrb2 agonism on energy expenditure and thermogenesis. Our observation of a subpopulation of nearly 45% sympathetic neurons expressing the beta 2 adrenergic receptor in ganglia supports this hypothesis. The conditional knockout of these neurons' adrb2 facilitates the temperature reduction response to fasting and precipitates obesity without increasing food intake. Our single-cell sequencing analysis supports the tissue specificity of the conditional knock, and adrb2 agonism promotes neuronal/axonal growth in vitro.
We aim to determine if adrb2 agonism can rescue metabolic adaptation to fasting, whether it is connected to lower adrb2 signalling in sympathetic neurons and sympathetic neuropathy within brown adipose tissue, and how lack of rest alters metabolic adaptation to fasting.
