Maternal over-nutrition and offspring health: role of translational programming of insulin action
Lead Research Organisation:
University of Cambridge
Department Name: MRC Toxicology Unit
Abstract
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Technical Summary
The developmental origins of health and disease hypothesis links the intrauterine environment to long term health of offspring. There is evidence from human and animal studies that metabolic health of offspring is adversely affected by maternal obesity and diabetes during pregnancy. Using a mouse model of maternal diet-induced obesity we found that exposure to an obesogenic environment in utero led to the development of insulin resistance in young adult life. This was associated with altered expression of insulin signalling proteins in muscle, liver and adipose tissue. Notably, there was a marked decrease in IRS-1 protein in adipose tissue without any change in IRS-1 mRNA. Using primary cultured pre-adipocytes we showed that this reflects decreased synthesis of IRS-1 protein and that it is paralleled by an increased level of miRNA-126 that targets IRS-1 mRNA. We therefore hypothesise that maternal diet-induced obesity programmes adipose tissue insulin action in offspring through cell autonomous, post-transcriptional mechanisms that influence levels of IRS-1 and other proteins. The overall aim of this project is to elucidate the molecular mechanisms underlying this programming. We will take a global approach to identify miRNAs in adipose tissue that are programmed by maternal over-nutrition and identify targets of these miRNAs using a combination of bioinformatics, RNA-Seq and Ago2 immunoprecipitation. We will then define the role of selected miRNAs, including miR-126, in programming adipose tissue insulin sensitivity and function, by using miR mimics and antagonists. Finally, we will establish whether normalisation of maternal insulin in obese dams can prevent programming of adipocytes.
These studies will advance understanding of developmental programming arising from maternal over-nutrition and how such programming might be ameliorated. Most importantly, our experiments in animal models will inform debate on how to manage the corresponding human condition.
These studies will advance understanding of developmental programming arising from maternal over-nutrition and how such programming might be ameliorated. Most importantly, our experiments in animal models will inform debate on how to manage the corresponding human condition.
Planned Impact
This proposal falls within the BBSRC strategic priority Ageing Research Lifelong Health and Wellbeing and specifically is within the scope of Fundamental research on the biology of ageing and its modulation by diet, physical activity and developmental factors. The proposal addresses two of the key issues identified and seeks to make an impact on both of these:
i) Diet, physical activity and health during ageing, and the need to understand the mechanisms by which diet and physical activity influence health across the lifecourse.
ii) Developmental factors and health during ageing, and the need to encourage research that investigates how early developmental factors may influence health during ageing, including the specific challenges to understand how nutritional exposures are recorded and transmitted through subsequent generations of cells and how this memory is translated into altered function in later life.
Academic impact
Developmental origins of health and disease is an expanding field in which UK research has so far been at the forefront. It cuts across many disciplines, most obviously physiology, nutrition and public health, with an urgent need for greater understanding at the biochemical level. The proposal therefore has potential to make a major academic impact by increasing knowledge of the molecular mechanisms linking maternal diet to metabolic phenotype of offspring. In addition to advancing knowledge, the research will involve development of new databases of miRNAs and their targets that will be broadly applicable in academia. On-going collaborations with other institutions in the UK and Europe will provide potential for extension of findings into other human cohort studies and animal models and in systems biology approaches. The research will provide cross-disciplinary training for the PDRAs, and opportunities for enhancing teaching and learning of undergraduate and postgraduate students through seminars and projects.
Economic and societal impacts
The research aims to define the network of miRNAs and their targets in adipose tissue that are programmed in offspring as a consequence of maternal obesity, predisposing to insulin resistance and metabolic disease in later life. These miRNAs may provide novel targets for therapeutic intervention and patentable discoveries may emerge. Although this application focuses on adipose tissue, we intend in the longer term to establish if miRNAs are also programmed in readily accessible tissues such as white blood cells with potential utility as biomarkers of disease risk that would indicate the need for lifestyle change or other intervention.
The lead researchers are actively engaged with the commercial pharmaceutical sector (including Unilever, Astra Zeneca and Abbott Laboratories) through joint research projects and studentships. The proposed research will inform and benefit this sector through access to new knowledge, technology development and databases. Thus in the longer term we foresee opportunities for commercialization of both diagnostics (identifying individuals at risk of metabolic disease as a consequence of early life nutrition) and therapeutics (targeting specific miRNAs whose programmed expression contributes to adverse metabolic phenotype). Thus the proposed research has potential to enhance the knowledge economy and economic competitiveness of the UK.
The research also has high relevance to the public sector, with potential to inform policy making with regard to advice on nutrition and healthy ageing, by strengthening the evidence base concerning relationships between nutrition during pregnancy and long-term health of offspring. The research is also readily accessible to the general public, because of its immediate relevance to improving health and well being and enhancing quality of life. The research therefore provides an excellent vehicle for increasing public engagement and understanding.
i) Diet, physical activity and health during ageing, and the need to understand the mechanisms by which diet and physical activity influence health across the lifecourse.
ii) Developmental factors and health during ageing, and the need to encourage research that investigates how early developmental factors may influence health during ageing, including the specific challenges to understand how nutritional exposures are recorded and transmitted through subsequent generations of cells and how this memory is translated into altered function in later life.
Academic impact
Developmental origins of health and disease is an expanding field in which UK research has so far been at the forefront. It cuts across many disciplines, most obviously physiology, nutrition and public health, with an urgent need for greater understanding at the biochemical level. The proposal therefore has potential to make a major academic impact by increasing knowledge of the molecular mechanisms linking maternal diet to metabolic phenotype of offspring. In addition to advancing knowledge, the research will involve development of new databases of miRNAs and their targets that will be broadly applicable in academia. On-going collaborations with other institutions in the UK and Europe will provide potential for extension of findings into other human cohort studies and animal models and in systems biology approaches. The research will provide cross-disciplinary training for the PDRAs, and opportunities for enhancing teaching and learning of undergraduate and postgraduate students through seminars and projects.
Economic and societal impacts
The research aims to define the network of miRNAs and their targets in adipose tissue that are programmed in offspring as a consequence of maternal obesity, predisposing to insulin resistance and metabolic disease in later life. These miRNAs may provide novel targets for therapeutic intervention and patentable discoveries may emerge. Although this application focuses on adipose tissue, we intend in the longer term to establish if miRNAs are also programmed in readily accessible tissues such as white blood cells with potential utility as biomarkers of disease risk that would indicate the need for lifestyle change or other intervention.
The lead researchers are actively engaged with the commercial pharmaceutical sector (including Unilever, Astra Zeneca and Abbott Laboratories) through joint research projects and studentships. The proposed research will inform and benefit this sector through access to new knowledge, technology development and databases. Thus in the longer term we foresee opportunities for commercialization of both diagnostics (identifying individuals at risk of metabolic disease as a consequence of early life nutrition) and therapeutics (targeting specific miRNAs whose programmed expression contributes to adverse metabolic phenotype). Thus the proposed research has potential to enhance the knowledge economy and economic competitiveness of the UK.
The research also has high relevance to the public sector, with potential to inform policy making with regard to advice on nutrition and healthy ageing, by strengthening the evidence base concerning relationships between nutrition during pregnancy and long-term health of offspring. The research is also readily accessible to the general public, because of its immediate relevance to improving health and well being and enhancing quality of life. The research therefore provides an excellent vehicle for increasing public engagement and understanding.
People |
ORCID iD |
Martin Bushell (Principal Investigator) |
Publications
Alfaradhi MZ
(2016)
Maternal Obesity in Pregnancy Developmentally Programs Adipose Tissue Inflammation in Young, Lean Male Mice Offspring.
in Endocrinology
De Almeida-Faria J
(2021)
Maternal obesity during pregnancy leads to adipose tissue ER stress in mice via miR-126-mediated reduction in Lunapark.
in Diabetologia
Fletcher CE
(2017)
A novel role for GSK3ß as a modulator of Drosha microprocessor activity and MicroRNA biogenesis.
in Nucleic acids research
Gillen S
(2021)
Differential regulation of mRNA fate by the human Ccr4-Not complex is driven by coding sequence composition and mRNA localization
in Genome Biology
Hawley BR
(2017)
The emerging role of RNAs in DNA damage repair.
in Cell death and differentiation
Description | During the duration of this award we have had a number of seminal publications detailing our key finding, see details below. In these publication we show how maternal obesity during pregnancy impacts on the long-term health of the off-spring. Importantly, we show that mild exercise during pregnancy can reverse reverse the majority of these effects. A number of other publications are in the process of being finalised in which these results are documented. Maternal Obesity in Pregnancy Developmentally Programs Adipose Tissue Inflammation in Young, Lean Male Mice Offspring. Alfaradhi MZ, Kusinski LC, Fernandez-Twinn DS, Pantaleão LC, Carr SK, Ferland-McCollough D, Yeo GS, Bushell M, Ozanne SE. Endocrinology. 2016 Nov;157(11):4246-4256. Epub 2016 Sep 1. A post-weaning obesogenic diet exacerbates the detrimental effects of maternal obesity on offspring insulin signaling in adipose tissue. de Almeida Faria J, Duque-Guimarães D, Carpenter AA, Loche E, Ozanne SE. Sci Rep. 2017 Mar 24;7:44949. doi: 10.1038/srep44949. PMID: 28338072 Free PMC Article Exercise rescues obese mothers' insulin sensitivity, placental hypoxia and male offspring insulin sensitivity. Fernandez-Twinn DS, Gascoin G, Musial B, Carr S, Duque-Guimaraes D, Blackmore HL, Alfaradhi MZ, Loche E, Sferruzzi-Perri AN, Fowden AL, Ozanne SE. Sci Rep. 2017 Mar 14;7:44650. doi: 10.1038/srep44650. |
Exploitation Route | This research may impact on public awareness and may form part of a program for intervention in the further. |
Sectors | Agriculture Food and Drink |
Description | CRT translational control allience |
Amount | £23,000,000 (GBP) |
Organisation | Cancer Research Technology (CRT) |
Sector | Private |
Country | United Kingdom |
Start | 05/2018 |
End | 06/2021 |
Description | CTR Collaboration |
Organisation | Cancer Research Technology (CRT) |
Country | United Kingdom |
Sector | Private |
PI Contribution | Our Lab is actively engaged with CRT within a new alliance to target translational control. |
Collaborator Contribution | Drug discovery efforts |
Impact | This has just begun and no outputs so far |
Start Year | 2017 |
Description | BACR invited talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited talk at a meeting on Non-Coding RNAs in Cancer and Development, at the Royal Society of Medicine, London. |
Year(s) Of Engagement Activity | 2017 |
Description | Bart's RNA and cancer meeting June 2023 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker. I give a talk about our research and people were very positive and said it had changed the way they were thinking about translational control |
Year(s) Of Engagement Activity | 2023 |
Description | Belfast talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | I give a talk about our research and people were very positive and said it had changed the way they were thinking about translational control |
Year(s) Of Engagement Activity | 2023 |
Description | Feb congress Tours France |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I give a talk about our research and people were very positive and said it had changed the way they were thinking about translational control |
Year(s) Of Engagement Activity | 2023 |
URL | https://2023.febscongress.org/program |
Description | Geneve |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited speaker at Univ of Geneva |
Year(s) Of Engagement Activity | 2022 |
Description | Invited speaker CSHL |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker at CSHL translational control meeting |
Year(s) Of Engagement Activity | 2022 |
Description | Invited speaker Dundee |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker at the University of Dundee. Gave a talk on translational control and changed the way they think about this level of gene expression control. |
Year(s) Of Engagement Activity | 2019 |
Description | Invited speaker european society of toxicologist |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | To talk to the European Society of toxicologist. |
Year(s) Of Engagement Activity | 2021 |
Description | Invited talk at the Mellanby Centre for Bone Research |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited talk on miRNA mechanisms |
Year(s) Of Engagement Activity | 2017 |
Description | Royal pathology Society invited speaker |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation was to the Royal Society of pathologist. To update them in emerging technologies round RNA based therapeutic and prognostic approaches. |
Year(s) Of Engagement Activity | 2022 |
Description | School Visit |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | School Visit to engage with 6 former students Oakham School |
Year(s) Of Engagement Activity | 2017 |
Description | Translation UK Keynote address Cambridge July 2023 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I was asked to give the keynote address at the translation UK. I give a talk about our research and people were very positive and said it had changed the way they were thinking about translational control |
Year(s) Of Engagement Activity | 2023 |
Description | UCSF talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker UCSF |
Year(s) Of Engagement Activity | 2022 |
Description | Undergraduate lecture at Nottingham University on further medicines |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Undergraduate students |
Results and Impact | I was invited to give a lecture to undergrad at Nottingham University on Further medicines. They were very excited about the possibilities of using RNA in medicines |
Year(s) Of Engagement Activity | 2016 |