Neurodevelopmental Programming via GLP-1 and Insulin Signalling: Effects of Maternal Obesity

This project focuses on maternal obesity and its impact on offspring mental health, studying mechanisms to inform future prevention and treatment.

Project Summary

Obesity is a global epidemic, affecting 18.5% of women. In the UK, 1 in 4 women enter pregnancy having obesity (1, 2). Maternal environments ‘program’ offspring health by inducing plasticity in the structure and function of developing tissues, setting the trajectory for later life (3). Consequently, lifelong health, including non-communicable diseases and mental health, have developmental origins (4). The mechanistic role of maternal obesity on offspring neurodevelopment is not yet fully understood. 

Maternal obesity during pregnancy influences brain white matter development in the offspring (5). A recent study revealed a negative interaction between maternal obesity and tract fibre density in white matter tracts within the limbic system, meaning that obesity-exposed neonates had a slower fibre density growth trajectory compared to infants of normal-weight women (6). White matter is composed of nerve fibres and myelin, a fatty substance wrapping the nerves. Disruption in myelin synthesis alters white matter tract structure, and is a major characteristic of neurodevelopmental disorders. Children of maternal obesity have a higher risk of developing emotional and behavioural disorders such as attention deficit hyperactivity disorder (ADHD) and anxiety (7, 8), depending on their sex (9) but more research is required to understand the mechanisms behind this. 

This project has three main aims: 
1.    Determine the effects of maternal obesity on adult offspring neurobehavioural outcomes in a mouse model of diet-induced obesity (Dio) 
2.    Characterise brain white matter structure with MRI in vivo and oligodendrocyte maturation and myelination ex vivo in Dio offspring 
3.    Investigate the potential causal role of GLP-1 and insulin signalling in myelination processes in the limbic region of the brain 

This project is important in that it focuses not only on the global health challenge of increasing obesity rates, but by focusing on maternal obesity and offspring outcomes, it considers the intergenerational consequences. It directly addresses the priorities of the Grand Challenge of Mental Health & Wellbeing by investigating the developmental origins of mental health and laying the groundwork for potential future early intervention strategies for children exposed to neurodevelopmental risk factors. 
 
References: 
1. Relph S, Coe M, Carroll F, Gurol-Urganci I, Webster K, Jardine J, et al. NHS Maternity Care for Women with a Body Mass Index of 30 kg/m2 or Above: Births between 1 April 2015 and 31 March 2017 in England, Wales and Scotland. RCOG; 2021. 
2. Digital N. Health Survey for England, 2021 part 1. National Statistics London; 2022. 
3. Nijland MJ, Ford SP, Nathanielsz PW. Prenatal origins of adult disease. Current Opinion in Obstetrics and Gynecology. 2008;20(2):132-8. 
4. Doi M, Usui N, Shimada S. Prenatal environment and neurodevelopmental disorders. Frontiers in Endocrinology. 2022;13:860110. 
5. Ou X, Thakali KM, Shankar K, Andres A, Badger TM. Maternal adiposity negatively influences infant brain white matter development. Obesity. 2015;23(5):1047-54. 
6. Sigurdardottir JN, Tournier J-D, Batalle D, Bonthrone AF, Christiaens D, Hutter J, et al. In vivo tractography of human neonatal white-matter pathways underlying hypothalamic and reward functions to study predispositions to neurodevelopmental conditions and obesity. bioRxiv. 2025:2025.02. 28.640038. 
7.Lahti-Pulkkinen M, Räikkönen K, Bhattacharya S, Reynolds RM. Maternal body mass index in pregnancy and mental disorders in adult offspring: a record linkage study in Aberdeen, Scotland. Scientific Reports. 2021;11(1):15132. 
8. Duko B, Mengistu TS, Stacey D, Moran LJ, Tessema G, Pereira G, et al. Associations between maternal preconception and pregnancy adiposity and neuropsychiatric and behavioral outcomes in the offspring: a systematic review and meta-analysis. Psychiatry Research. 2024:116149. 
9. Davis EP, Pfaff D. Sexually dimorphic responses to early adversity: implications for affective problems and autism spectrum disorder. Psychoneuroendocrinology. 2014;49:11-25.