Beta-defensins in the prevention of obesity

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Inflammation Research

Abstract

Obesity has reached epidemic levels in the UK and globally: both in adults and (most worrying in the longer term) in children. Obesity and obesity-related disease (including type 2 diabetes, heart disease, asthma and some forms of cancer) are major contributors to NHS and welfare costs and to reduced quality of life. The incidence of obesity in the UK has trebled over the last 25 years. In 2014, the Scottish Government reported that 64.6% of adults (aged over 16) in Scotland were overweight, including 27.1% who were obese. The UK Parliament Health Select Committee in Nov 2015 released a report on Childhood Obesity demanding Brave and Bold action to counteract this crisis. Treating obesity and its consequences is currently estimated to cost the NHS £5.1bn every year and the wider costs estimated to be around three times this amount. Lifestyle and social environment factors clearly play major roles, but so too do genetic factors: Obesity has been shown to be passed on in families and so understanding what genes are involved is an important research priority to enable the design of appropriate therapies.
Mice can be bred that have loss or gain of particular genes and in this way models of fatness or leanness can be made. These weight increase or reduction models can then be used to identify what pathways are accelerated or slowed down in mice that are fat or thin and this can lead to designing good drugs to stop obesity and promote being lean.
We have removed a cluster genes from the mouse and find that complete loss of these genes results in animals that are fat. Conversely, if we put a human version of one of these genes into mice then these mice are lean.
Together, these data strongly imply that these particular genes (beta-defensins) have a role in controlling body weight and have potential as drugs for obesity in humans. We seek her to understand what is going on in these mice so we can design good drugs for people who are fat.

Technical Summary

Obesity (excess adiposity) has reached epidemic levels in the UK and globally: in both adults and (most worrying in the longer term) in children. Obesity and obesity-related disease (including type 2 diabetes, hypertension, dyslipidaemia, asthma and some forms of cancer) are major contributors to NHS and welfare costs and to reduced quality of life. Lifestyle and sociodemographic factors clearly play major roles, but so do genetic factors. Obesity is highly heritable, estimated to be between 50% and 70%.
Understanding the phenotypes in genetically mutant rodents is a valuable path towards understanding both factors contributing to obesity and those that may help prevent it.
We have deleted a cluster of antimicrobial and immunomodulatory (beta-defensin) genes from the mouse and find that homozygous mutant animals of both sexes are obese (25% heavier) in adulthood. Conversely, transgenic expression of a human beta-defensin leads to reduced weight.
Together, these data strongly imply that beta-defensins have a role in bodyweight regulation and have therapeutic potential.
We seek here to characterise the phenotypes we observe in the defensin deletion and transgenic mice to understand the mechanism by which deletion causes obesity and yet over expression leads to a lean phenotype. We wish to clarify whether the lean phenotype requires neuronal expression or whether systemic delivery will allow the lean phenotype to be evident. This proposal outlines work essential for considering rationally designed novel, defensin-based therapeutic approaches for obesity reduction in humans.

Planned Impact

Defensins are a vast gene family and their precise function remains ill-defined, although they have the ability to kill pathogens and modulate the immune system. This work will expand the knowledge of the academic world as to the function(s) of defensin genes and specifically the influence these genes have on weight regulation.

Obesity can reduce the length and overall quality of life. It puts a significant cost on the NHS by increasing the incidence of other diseases such as type 2 diabetes, hypertension, hyperlipidaemia, (all major risk factors for cardiovascular disease), some cancers and asthma. The incidence of obesity is rising dramatically worldwide and in the UK the number of obese individuals has trebled over the last 25 years.
This work will contribute to the understanding of the relationship between defensins and obesity and increased understanding will lead to novel therapeutic avenues to be followed. This will be of interest to pharmaceutical companies with a research focus in this area.
Overweight individuals both in the UK and internationally will appreciate research funds being spent on this work and should the work lead to advances in therapeutic treatment then the benefit to the nation in terms of reduced health costs; reduction in type II diabetes; indirect costs to NHS and general increase in well-being will be significant.

Publications

10 25 50
 
Description Communicating Immunology
Amount £995 (GBP)
Funding ID 195cir r45162 3138 
Organisation British Society For Immunology 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2017 
End 11/2017
 
Description NM obesity 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration with Prof. Nik Morton at University of Edinburgh BHF Cardiovascular Sciences. Expert in obesity and mouse models. He was co-applicant on this grant application that I initiated and am leading. Nik supplies expertise in cellular metabolism and enables us to use his Seahorse instrument and we supply immunology and additional obesity knowledge.
Collaborator Contribution Source of information on mouse models of obesity. Assisting in training of my staff in procedures and we now have joint lab meetings and access to essential equipment.
Impact success in grantfunding (this one). Manuscript in preparation
Start Year 2016
 
Description defensin mouse obesity 
Organisation University of Edinburgh
Department British Heart Foundation Centre for Cardiovascular Science
Country United Kingdom 
Sector Academic/University 
PI Contribution this collaboration has allowed submission of a grant that is currently being considered at PSMB final discussions for funding.
Collaborator Contribution BHF/CVS are experts in obesity in mouse models Uof L Genetics expert in cnv of defensin
Impact obesity expertise. ability to successfully write grant to MRC with partners experience a major factor.
Start Year 2015
 
Description defensin mouse obesity 
Organisation University of Leicester
Department Department of Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution this collaboration has allowed submission of a grant that is currently being considered at PSMB final discussions for funding.
Collaborator Contribution BHF/CVS are experts in obesity in mouse models Uof L Genetics expert in cnv of defensin
Impact obesity expertise. ability to successfully write grant to MRC with partners experience a major factor.
Start Year 2015
 
Description Denny and the T team 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact attended local primary school science club to present Denny and the T team describing ability of immune system to detect and deal with cancer.
Year(s) Of Engagement Activity 2017