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Role of clock genes in a mouse model for developmental origins of the metabolic syndrome

Reference	BB/G01812X/1
Principal Investigator / Supervisor	Dr Felino Cagampang
Co-Investigators / Co-Supervisors	Professor Graham Burdge, Professor Christopher Byrne, Professor Mark Hanson, Professor Karen Lillycrop
Institution	University of Southampton
Department	Development Origin of Health and Disease
Funding type	Research
Value (£)	297,008
Status	Completed
Type	Research Grant
Start date	01/08/2009
End date	31/07/2012
Duration	36 months

Abstract

This proposal aims to identify key molecular clock and clock-controlled mechanisms underlying prenatal induction of phenotypic susceptibility to the metabolic syndrome. We will use a mouse model, where offspring prenatally exposed to a high fat nutritional environment develop the metabolic syndrome phenotype in adulthood following post-weaning high-fat feeding. We are suggesting that a maternal diet during pregnancy that is high in fat can adversely affect the development of the offspring's circadian clock system in the hypothalamic suprachiasmatic nucleus (SCN) and in peripheral tissues, resulting in altered rhythmic expression and function of clock and clock-controlled genes involved in the regulation of adipogenesis, metabolism and cardiovascular function. If these offspring are subsequently fed the same high fat diet, their physiology will be unable to respond appropriately making them particularly susceptible to developing metabolic To address our aim we will look at circadian metabolic, hormonal and activity patterns in mouse offspring from high fat fed dams and examine the effects of a post-weaning high fat feeding. We will then measure the 24h mRNA expression pattern of clock and clock-controlled genes, and other 'candidate' genes linked to both circadian and metabolic/cardiovascular/adipocyte function in neonate and adult offspring SCN and peripheral tissues which are key organelles to the pathogenesis of the metabolic syndrome. We will also examine whether an epigenetic mechanism, i.e. modification of rhythmic histone acetylation of clock-associated genes and RNA polymerase binding, is involved in the aberration and phase-shift in the circadian timing system and maladapted responses to a post-weaning high fat diet. Our proposed study will provide the scientific basis for understanding how an unhealthy diet in early life contributes to metabolic syndrome later in life. Results from this study will have direct relevance to humans.

Summary

Daily, or circadian, rhythms are important in all organisms, including humans. Circadian rhythms influence nearly all aspects of physiology and behaviour, including our sleep-wake cycles, activity, feeding behaviour, cardiovascular function, body temperature and metabolism. These rhythms are generated within the body and the mechanisms that control them takes form while the baby is still in the mother's womb. Studies have shown that the diet of the mother during pregnancy is important in maintaining the health of her offspring and may also influence their susceptibility to developing obesity, diabetes and heart disease later in life. If the mother eats a healthy diet during pregnancy, one would expect the development of normal circadian rhythms of the baby's body function and metabolism, enabling the baby to cope with a healthy diet in childhood and adulthood. The risk of the person developing obesity, diabetes and heart disease later in life is very low. However, if the mother eats an unhealthy diet during pregnancy it might result in the abnormal development of circadian rhythms of body function and metabolism. This leads to disruption in sleep and activity patterns and inefficient processing of the food the baby eats. The baby is at risk of becoming heavier and fatter and will have high blood pressure in adulthood. If the baby is not brought up after birth and throughout childhood to eat a healthy diet, but eats instead a diet rich in fat, the baby's already disrupted circadian rhythms of metabolism is now not able to cope with this diet. This person is likely to become obese and risk of adult diabetes and heart disease later in life increases considerably. It is our intention of undertaking this study using a rodent model. Only by choosing an animal model is it possible to study this phenomenon, because it is necessary to change both the pre- and post natal diets and it would be unethical to undertake these changes in pregnant mothers and their babies.

Committee	Closed Committee - Agri-food (AF)
Research Topics	Diet and Health, Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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