Metabolic Signalling

Lead Research Organisation: MRC Clinical Sciences Centre

Abstract

Obesity is a major health problem and significantly increases the risk for a number of common diseases such as diabetes and cancer. Obesity occurs when there is a mismatch between the amount of energy consumed and the amount to energy used: excess energy is stored as fat. Studies have shown that the brain acts as the major part of the body that regulates food intake and energy use. One key role of the brain is to respond to the hormonal and nutrient signals that tell the body what has been eaten and what its current energy stores are. Previously we have identified some of the signals that the brain uses and have shown that when these signals stop working this results in obesity. We now aim to further define the signalling mechanisms in the subconscious part of the brain that regulates energy balance aiming to understand what goes wrong when obesity develops. We also wish to study the signalling pathways in the parts of the brain that regulate the pleasurable and rewarding aspects of eating. Finally we wish to test out whether changing activity in these different brain regions can be used to alter feeding behaviour and ultimately treat obesity.

Technical Summary

Obesity is one of the greatest public health challenges of the 21st century. In the UK currently over 60% of the adult population is overweight with 1 in 4 adults being obese (BMI >30). Obesity is a major risk factor for a range of common morbid conditions including type 2 diabetes, cardiovascular disease, and cancer as well as having significant psychological and social impact. Body weight is regulated by a complex physiological system that controls food intake, nutrient storage and energy expenditure. The central nervous system plays a pivotal role in this regulatory mechanism. The hypothalamus and caudal brainstem have been implicated in the homeostatic regulation of body weight responding to a number of hormonal and neural systems that inform the brain about nutrient status. More recently it has become clear that other brain regions including the cerebral cortex, basal ganglia and limbic system potentially play roles in the regulation of metabolism. Recent genome wide association studies in humans have also strongly implicated neuronal genes as risk alleles for obesity. The overall aim of future work will be to further understand the CNS regulation of energy homeostasis. We will analyse the role of the hypothalamic signalling mechanisms we have implicated in the regulation of food intake and body weight extending studies to new brain regions and neuronal circuits. The work is divided into 4 programmes: Analysis of signalling pathways downstream of IRS proteins in the hypothalamic regulation of energy homeostasis. Analysis of AMPK cascade signalling components in the hypothalamic regulation of energy homeostasis. Studies on the midbrain dopaminergic system in the regulation of energy homeostasis and reward. Analysis of the function of defined neuronal circuits in the regulation of feeding behaviour using optogenetics. The first programme will identify signals downstream of Irs2 that regulate feeding and body weight. We have previously shown that deletion of Irs2 in the brain causes marked obesity. The second programme builds on our published and unpublished work demonstrating a key role for the AMPK cascade in the hypothalamus. The third programme will explore the role of non-homeostatic dopaminergic circuits that are thought be regulate the rewarding aspects of food. The final programme will start to exploit available technologies using light-modulated conductances that increase or suppress neuronal firing, to explore the function of appetite circuits in vivo.

Publications


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Cantley J (2010) The hypoxia response pathway and ß-cell function. in Diabetes, obesity & metabolism
 
Description Wellcome Trust Strategic Award
Amount £1,800,000 (GBP)
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2013 
End 02/2017
 
Title Irs knock-in mutants 
Description Series of mouse mutants modelling insluin resistance and diabetes 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact New data generation in progress 
 
Title Lkb 
Description Mice with deletion of Lkb in POMC neurons which develop diabetes 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2010 
Provided To Others? Yes  
Impact Insights into how brain controls metabolism. Lkb AMPK pathway id target for drugs used to treat diabetes. 
 
Title Optogenetic reagents 
Description Series of optogenetic and DREADD reagents 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2012 
Provided To Others? Yes  
Impact Development of new research programme at MRC Clinical Sciences Centre 
 
Title S6K1 conditional mice 
Description Mice with conditional allele of S6K1 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2012 
Provided To Others? Yes  
Impact Further grant award 
 
Description Batterham 
Organisation University College London (UCL)
Department UCL Biosciences
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Joint studies on human appetite regulation
Collaborator Contribution Moecular and physiological studies
Impact Multidisciplinary
Start Year 2011
 
Description Carling 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution Contribution to publication
Collaborator Contribution Publication
Impact Publication
 
Description GM 
Organisation University of Glasgow
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Collaborations on reagents and techniques resulting in papers
Collaborator Contribution Collaborations on reagents and techniques resulting in papers
Impact Papers published: see publication list
Start Year 2012
 
Description JG 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution Collaborative work on senescence in vivo with joint PhD studentship
Collaborator Contribution Collaborative work on senescence in vivo with joint PhD studentship
Impact Paper reported
Start Year 2010
 
Description Partridge 
Organisation University College London (UCL)
Department Department of Genetics, Evolution and Environment
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Collaborative work on ageing on model organisms
Collaborator Contribution Contributions ot papers and succesful grant applications.
Impact Large number of published papers and succesful grant applications including a £5m Wellcome Strategic Award
 
Description Newspaper coverage and online media coverage of our work 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Major press coverage for a manuscript that we published

Almetrics score for article is one of the highest seen for the journal.
Year(s) Of Engagement Activity 2013,2016
 
Description Press coverage of News and Views Article in Nature 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press coverage of News and Views Article in Nature
Year(s) Of Engagement Activity 2016