Developmental programming of the cell stress response and metabolic inflammation in liver and adipose tissue in an ovine model

Saroha, Vivek (2017) Developmental programming of the cell stress response and metabolic inflammation in liver and adipose tissue in an ovine model. PhD thesis, University of Nottingham.

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A state of chronic metabolic inflammation and activation of the cell stress response in organs such as liver and adipose tissue are important pathogenic adaptations with the onset of obesity and the metabolic syndrome. The extent to which these processes are modulated by the early life nutritional experience is not well established, especially in large animal models. The overall aim of this thesis was to identify whether nutritional programming during prenatal and postnatal development enhances metabolic inflammation and cell stress response of obesity. A nutritional model of fetal growth restriction achieved by maternal nutrient restriction (NR) to 60% of requirements during late gestation (110 days to term at 147 days) in twin bearing sheep was used. Combination of prenatal and postnatal nutritional interventions were studied with the following three study protocols:

1. Offspring of twin bearing sheep born to mothers nutrient restricted or fed to appetite were separated after weaning at 3 months of age and then exposed to either restricted physical activity leading to obesity or to unrestricted activity and remained lean.

2. Following maternal NR, both twins or only one twin were reared on their mother’s milk during suckling period in order to achieve a relatively faster growth rate in the latter.

3. Twin offspring of sheep randomised to NR or feeding to requirement during late gestation were separated after birth and randomised to either formula feeding or being fed by the mother until weaning followed by obesogenic rearing.

Total body weight of sheep in the obese group was raised by ~30% and was unaffected by any intervention. Obesity led to an increased insulin response to the glucose tolerance test, together with hepatic triglyceride deposition, and adipocyte hypertrophy with macrophage infiltration in omental adipose tissue. NR exacerbated obesity associated hepatic triglyceride deposition and upregulated gene expression of hepatic autophagy and omental unfolded protein response. Formula feeding of sheep offspring following NR was associated with slower weight gain and decreased gene expression for MTOR. Sheep offspring fed by mother as singleton gained weight at faster rate during suckling period as compared to offspring fed by their mothers as twins. Neither postnatal interventions exacerbated the state of obesity associated metabolic inflammation and cell stress response. It is possible that the increased hepatic autophagic gene expression is a reflection of defective autophagy and future work should include study of markers of autophagic function. Possible mechanisms of upregulated omental adipose UPR in offspring of sheep undergoing NR could include a programmed decrease in adipocyte number or selective survival of preadipocytes with effective ER stress response. Such adaptations followed by obesity would predispose the adipocytes to initiate inflammation and cell death pathways.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Budge, H.
Symonds, M.E.
Keywords: Developmenta programming, Perinatal nutrition, Cell stress, ER stress, UPR, Autophagy, Cell death, Crown like strictures, Adipose, Liver, Omentum, Ovine, Sheep, Hepatic, DOHAD, Metabolic inflammation, Inflammation, IUGR, SGA, Formula feeding, Postnatal growth, Gestational nutrition, Obesity, Metabolic syndrome, Insulin resistance
Subjects: QS-QZ Preclinical sciences (NLM Classification) > QU Biochemistry
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 47527
Depositing User: Saroha, Vivek
Date Deposited: 15 Dec 2017 04:40
Last Modified: 16 Dec 2017 02:10

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