- Circadian and photoperiod timing, Prof. David Hazlerigg
- Energetics, Prof. John Speakman
- Ageing, Dr. Colin Selman
- Insulin action & glucose homeostasis, Dr. Mirela Delibegovic, Dr. Nimesh Mody
Circadian and photoperiodic timing in mammals
Siberian Hamsters raised under short photoperiods and long photoperiods. Under short photoperiods the animals change their fur to white.
Internal clocks are important regulators of our physiological function, coordinating daily rhythms in physiology (e.g core temperature) and behaviour (e.g. sleep). They also control seasonal rhythms such as breeding and moulting cycles by responding to changes in day length (photoperiod). For a long time it was thought that a central clock in the brain regulated these processs, but we now believe that tissues throughout the body have clock-like properties, and the brain acts as a pacemaker to keep them synchronised.
In situ hybridisation images of day / night changes in gene Expression in the sheep pituitary
Animal Energetics
Animal energy expenditure is a key element at the heart of several important processes – including the regulation of body weight/adiposity, and the process of ageing. This group is interested in the details of these relationships, in particular focusing on the factors that cause individual variations in energy metabolism and what the consequences of such variations are at the whole animal level. They are also using gene expression microarraying to profile the expression patterns of different tissues from mice with high and low metabolic rates.
We have shown recently that contrary to popular belief having a high rate of metabolism is positively linked to lifespan. These differences are associated with activity differences of many genes in brown adipose tissue:
Gene expression profile for 4 mice with high Resting Metabolic Rate (RMR) and 4 with low RMR. Blue is down regulation and red/yellow is upregulation.
Gene expression array
Mechanisms underlying the ageing process in mammals
Calorie (dietary) restriction (CR) has been shown to extend both mean and maximum life span and retard various age-associated pathologies in a range of vertebrate and invertebrate species. In addition, single gene mutations, particularly in the insulin/insulin-like growth factor-1 (IIS) pathway, can also extend lifespan in a range of animals. The use of such experimental paradigms may help unravel the mechanistic processes underlying the ageing process, and thus may help identify interventions which may ultimately extend healthy-lifespan in humans.
We, and others, have shown that many transcriptional changes observed during acute CR (days/weeks) overlap with longer-term CR, suggesting that beneficial effects of CR may require only a short-term reduction in energy intake.
Comparative tissue response to acute CR (30% CR for 48hrs). The number of shared genes up-regulated (RED) and down-regulated (DOWN) across tissues. P<0.001 denoted by dotted line and P<0.0001 denoted by solid line.
Clear transcriptional response across multiple tissues during acute CR, with congruent plasma metabolite changes (detected by 1H-NMR spectroscopy).
We have also shown recently that CR is not associated with decreased metabolic rate.
Daily energy expenditure of CR rats is HIGHER than predicted from their altered body composition relative to controls.
Insulin action & glucose homeostasis in mouse models of obesity and insulin resistance.
Protein tyrosine phosphorylation (by tyrosine kinases) and dephosphorylation by protein-tyrosine phosphatases (PTPs) are key regulatory processes of cell signaling by insulin and leptin. Deregulation of these pathways leads to the development of diseases such as type 2 diabetes and obesity. Understanding the role of these key regulatory proteins and the metabolic pathways that they regulate is of critical importance partly because type 2 diabetes and obesity are reaching epidemic proportions. Protein tyrosine phosphatase 1B (PTP1B) has been identified as an important potential anti-diabetic, anti-obesity drug target and understanding its role and mechanism of action in control of insulin action, glucose homeostasis and body mass regulation is essential for future therapeutics. Through the combined use of biochemical, cellular and gene knockout mouse models, my research focuses on the function of PTP1B in regulating insulin and leptin signaling pathways and whole body metabolism.
Physiology and molecular link between obesity and insulin in mouse models
I aim to study the interplay between genetic background and environmental challenges that lead to the development of obesity and type 2 diabetes. Mice fed high-fat diet rapidly undergo many molecular and physiological changes such as gain adipose (fat) mass and become insulin resistant. Prolonged exposure to a high-fat diet leads to full blown obesity, severe insulin resistance and diabetes.
My research aims to provide further insight into the mechanism of diet-induced obesity and insulin resistance and identify novel molecular target(s) for the development of new, more potent therapies to treat obesity and prevent diabetes.