Ageing and obesogenic diets are two prominent problems in the developed world, as both lead to an increase in body mass and insulin resistance, which can then result in further pathophysiologies, such as type 2 diabetes, cancer and cardiovascular disease. Protein tyrosine phosphatase 1B (PTP1B) contributes to development of body weight gain and insulin resistance through negatively regulating leptin and insulin signalling, respectively. Liver-specific ptp1b deletion from birth improves insulin sensitivity, lipid metabolism and decreases endoplasmic reticulum (ER) stress. However, as a therapy in humans, PTP1B inhibition would target pre-diabetic and diabetic adults; therefore, we investigated the effects of liver-specific inhibition of PTP1B in adult, insulin resistant, obese mice. Restricting the amount of the essential amino acid, methionine, five-fold in the diet, decreases body weight, adiposity and improves insulin sensitivity in young mice. In order to delineate if this would be a feasible treatment in adulthood, we administered the diet to 12-month-old mice with age-induced obesity and insulin resistance and compared its effects to those in 2-month-old mice. As hepatic ptp1b deletion and methionine restriction (MR) both improve hepatic insulin signalling, we investigated if the combined treatment could have additive effects compared to MR alone on whole-body glucose homeostasis. To examine if the effects of MR are methionine-specific or if they would occur with restriction of other EAAs, we compared leucine restriction (LR) to MR in adult mice. Overall, hepatic PTP1B inhibition in adult mice reversed high-fat diet (HFD) -induced glucose intolerance, hepatic lipid accumulation and ER stress. MR administered to 12-month-old adult mice reversed the metabolic effects of ageing back to levels measured in healthy, young, 2-month-old mice. The combination of MR and hepatic ptp1b deletion from birth had no further beneficial effect in male mice, but possibly an additional effect in female mice. MR produced stronger beneficial metabolic effects than LR in mice, suggesting methionine-specific mechanisms may play a role.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:683454 |
| Date | January 2015 |
| Creators | Lees, Emma Katherine |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=229428 |
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