Lipokines from browning adipose tissue regulate systemic metabolism to resist obesity
Lead Research Organisation:
University of Leeds
Department Name: School of Medicine
Abstract
Obesity is characterised by high levels of body fat leading to a body mass index of over 30. Over 650 million people worldwide are living with obesity. Obesity increases the risk of cardiovascular disease, some cancers and type 2 diabetes (T2D). Given the number of people affected, the impact on their quality of life and the burden on healthcare, finding new treatments is essential.
Energy balance is a key concept behind our understanding of metabolism and metabolic diseases like obesity. The balance between energy uptake (food intake), and energy expenditure (everyday biological processes / physical activity) determines whether a person is lean or obese. A chronic imbalance in energy, with excess uptake in combination with reduced expenditure, leads to increased storage of energy as fats within white fat cells in white fat tissue and can lead to metabolic diseases including obesity and T2D.
Many biological processes relevant to the development or treatment of obesity involve fat tissue. White fat tissue, once considered only as an energy-storage depot, is now known to be the source of key biological signals, known as adipokines, which are released into the blood and communicate to other organs to regulate whole-body metabolism. Not all fat cells are the same, however. A second group of fat cells, known as brown fat cells, regulate body temperature by "burning" stored fats to produce heat. A third group, known as beige fat cells, can switch from behaving like a white fat cell (storing fat) to functioning like a brown fat cell (burning fat), in a process known as "browning". In humans, beige fat makes up the majority of this heat producing tissue but is also found within white fat tissue and once activated has anti-obesity effects. Recent studies, including our own, suggest several of the anti-obesity properties of beige fat may occur by non-heat producing effects through the release of signals into the blood which communicate with other tissues such as the liver and muscle to alter their metabolism. We recently discovered metabolite signals released from browning adipose tissue that activate beige cells in white fat tissue and cause muscle tissue to burn fat. The metabolites had anti-obesity properties, highlighting a mechanism in which metabolites signal between tissues to influence energy balance.
This proposal builds on our findings by investigating whether browning of white fat tissue results in the release of a type of fat molecule that also has signalling properties (known as a lipokine). The capacity of this lipokine to induce browning in areas of neighbouring white fat tissue and to enter into the blood, signalling to other organs such as the liver and muscle to change their metabolic characteristics, will be investigated. This research will identify beige cell-specific lipokine signals, the way in which fat cells produce and release the lipokine signal, and the importance of this lipokine in human obesity. The lipokine will be evaluated for its capacity to improve metabolic health and protect against obesity.
This research will improve our understanding of how fat tissue communicates with other tissues such as liver and muscle in regulating whole-body energy balance, and help to define its contribution to obesity development. Novel beige fat signals identified in these studies may prove to be useful treatments for the global obesity epidemic, or highlight new treatment targets and so contribute to anti-obesity drug development. This study will highlight areas of further research by identifying novel signals communicating between fat tissue and other organs that may contribute, through their activity or disruption, to metabolic disease. The proposed research may contribute to prevention of metabolic disease; since many fats found within our diets overlap with those found within the body, the identification of lipokines with beneficial metabolic effects may help inform healthy dietary choices.
Energy balance is a key concept behind our understanding of metabolism and metabolic diseases like obesity. The balance between energy uptake (food intake), and energy expenditure (everyday biological processes / physical activity) determines whether a person is lean or obese. A chronic imbalance in energy, with excess uptake in combination with reduced expenditure, leads to increased storage of energy as fats within white fat cells in white fat tissue and can lead to metabolic diseases including obesity and T2D.
Many biological processes relevant to the development or treatment of obesity involve fat tissue. White fat tissue, once considered only as an energy-storage depot, is now known to be the source of key biological signals, known as adipokines, which are released into the blood and communicate to other organs to regulate whole-body metabolism. Not all fat cells are the same, however. A second group of fat cells, known as brown fat cells, regulate body temperature by "burning" stored fats to produce heat. A third group, known as beige fat cells, can switch from behaving like a white fat cell (storing fat) to functioning like a brown fat cell (burning fat), in a process known as "browning". In humans, beige fat makes up the majority of this heat producing tissue but is also found within white fat tissue and once activated has anti-obesity effects. Recent studies, including our own, suggest several of the anti-obesity properties of beige fat may occur by non-heat producing effects through the release of signals into the blood which communicate with other tissues such as the liver and muscle to alter their metabolism. We recently discovered metabolite signals released from browning adipose tissue that activate beige cells in white fat tissue and cause muscle tissue to burn fat. The metabolites had anti-obesity properties, highlighting a mechanism in which metabolites signal between tissues to influence energy balance.
This proposal builds on our findings by investigating whether browning of white fat tissue results in the release of a type of fat molecule that also has signalling properties (known as a lipokine). The capacity of this lipokine to induce browning in areas of neighbouring white fat tissue and to enter into the blood, signalling to other organs such as the liver and muscle to change their metabolic characteristics, will be investigated. This research will identify beige cell-specific lipokine signals, the way in which fat cells produce and release the lipokine signal, and the importance of this lipokine in human obesity. The lipokine will be evaluated for its capacity to improve metabolic health and protect against obesity.
This research will improve our understanding of how fat tissue communicates with other tissues such as liver and muscle in regulating whole-body energy balance, and help to define its contribution to obesity development. Novel beige fat signals identified in these studies may prove to be useful treatments for the global obesity epidemic, or highlight new treatment targets and so contribute to anti-obesity drug development. This study will highlight areas of further research by identifying novel signals communicating between fat tissue and other organs that may contribute, through their activity or disruption, to metabolic disease. The proposed research may contribute to prevention of metabolic disease; since many fats found within our diets overlap with those found within the body, the identification of lipokines with beneficial metabolic effects may help inform healthy dietary choices.
Technical Summary
Globally, 650 million people live with obesity, a leading risk factor for cardiovascular diseases, diabetes, and several cancers. Obesity's severe socioeconomic impact means new treatments are essential.
Browning, the induction of a brown adipose-like phenotype in white adipose tissue (WAT), increases beta-oxidation, mitochondrial biogenesis and thermogenesis. Brown adipocyte-like cells (beige adipocytes) are interspersed within WAT, and alter systemic energy balance with anti-obesity effects. Recent studies suggest brown/beige adipocytes influence systemic metabolism through endocrine/paracrine signals in the adipocyte secretome. We identified a bioactive lipid (lipokine), released from browning adipocytes, with endocrine signalling properties.
We aim to identify Brown AT / beige adipocyte lipokines that regulate systemic energy balance with anti-obesity effects through interorgan action on skeletal muscle, adipose tissue and liver metabolism.
Our objectives are: 1) Characterise the anti-obesity effects of a putative lipokine on WAT, muscle, liver and systemic metabolism. Identify the adipocyte mechanism of lipokine 2) synthesis and 3) secretion. 4) Determine the lipokine-mediated mechanisms regulating target tissue metabolism. 5) Define the relationship of the lipokine to human obesity.
An interdisciplinary approach will combine molecular biology, physiology, imaging and lipidomics. The lipokine's effect on systemic and tissue-specific metabolism will be defined with state-of-the-art metabolic profiling of mouse obesity models (metabolic cages, high-resolution respirometry, mass spectrometry). Lipokine synthesis and secretion mechanisms and their pathophysiological relevance will be determined using tissue-specific transgenic mice. The lipokine's mechanism of action and relevance to human obesity will be defined with human primary cells and tissues.
Lipokine-mediated interorgan signalling will be established as a therapeutic target for obesity
Browning, the induction of a brown adipose-like phenotype in white adipose tissue (WAT), increases beta-oxidation, mitochondrial biogenesis and thermogenesis. Brown adipocyte-like cells (beige adipocytes) are interspersed within WAT, and alter systemic energy balance with anti-obesity effects. Recent studies suggest brown/beige adipocytes influence systemic metabolism through endocrine/paracrine signals in the adipocyte secretome. We identified a bioactive lipid (lipokine), released from browning adipocytes, with endocrine signalling properties.
We aim to identify Brown AT / beige adipocyte lipokines that regulate systemic energy balance with anti-obesity effects through interorgan action on skeletal muscle, adipose tissue and liver metabolism.
Our objectives are: 1) Characterise the anti-obesity effects of a putative lipokine on WAT, muscle, liver and systemic metabolism. Identify the adipocyte mechanism of lipokine 2) synthesis and 3) secretion. 4) Determine the lipokine-mediated mechanisms regulating target tissue metabolism. 5) Define the relationship of the lipokine to human obesity.
An interdisciplinary approach will combine molecular biology, physiology, imaging and lipidomics. The lipokine's effect on systemic and tissue-specific metabolism will be defined with state-of-the-art metabolic profiling of mouse obesity models (metabolic cages, high-resolution respirometry, mass spectrometry). Lipokine synthesis and secretion mechanisms and their pathophysiological relevance will be determined using tissue-specific transgenic mice. The lipokine's mechanism of action and relevance to human obesity will be defined with human primary cells and tissues.
Lipokine-mediated interorgan signalling will be established as a therapeutic target for obesity
