| John Speakman | |||||
| 2019-03-07 | | 【Print】 | |||||
My research concerns the causes and consequences of variation in energy balance. In particular the implications of dysfunction in energy balance for body weight regulation (obesity). I am an internationally recognised expert in the study of energy demands using the doubly-labelled water method, which I first started to use over 25 years ago and for which I wrote the definitive guide in 1997. Historically my work has also focussed on variation in energy demands in free-living animals (see selected publications) and the implications of energy regulation for ageing. In Beijing my work will focus on two main areas. 1) Regulation of food intake and energy balance in the mouse. The mouse is an ideal model for the study of energy regulation. Modern technology allows us to follow in close detail minute by minute changes in energy demands, physical activity, body temperature and feeding behaviour of mice. While molecular biology techniques allow us to probe the changes in gene expression of critical areas of the brain that are involved in regulation of food intake. The availability of knock-out and transgenic mouse models allows experimental analysis of the effects of specific genes on feeding behaviour and energy balance. My work will include next generation sequencing technology of specific brain regions and peripheral tissues combined with metabolomics analysis to build an integrated physiological model for the regulation of energy balance in the mouse. I am particularly interested to interact with mathematical biologists to develop such a model. An example of co-ordinated changes in gene expression relating to the fatty acid metabolism in brown adipose tissue revealed by RNA-seq performed by my group is shown in figure 1. Down-regulated genes are shown in green and up-regulated genes shown in red. In this experimental manipulation there is a broad-scale down-regulation in the entire pathway reflecting shutdown of the BAT. Discovering the metabolic factors that cause such co-ordinated changes is a key goal of this research program.
Figure 1: Fatty acid metabolism pathway gene expression changes revealed by RNA-seq in brown adipose tissue. In this manipulation there was a broad reduction in gene expression reflecting a reduction in BAT function following the manipulation. Pathway analysis by Ingenuity Pathway analysis. 2) Factors influencing susceptibility and resistance to obesity in the Chinese urban population. Obesity is one of the greatest health threats in modern society. It is widely assumed that the major cause of obesity is a gene-environment interaction. Some individuals have a genetic propensity to put on weight which is expressed in the modern environment. Elevated levels of food consumption and decreased levels of energy expenditure are widely cited as the major factors in urban society that promote obesity risk. Yet the evidence for both of these ideas is at best weak. Studies of food intake suggest little change over time, but these studies are marred by the difficulty of accurately measuring food intake. In contrast for energy expenditure we have shown no evidence for a decrease in energy expenditure over the time course of the epidemic (Westerterp and Speakman 2008 International Journal of Obesity) (see figure 2). My work will address the factors that may predispose to obesity in the Chinese urban population including genetic and environmental influences.
Figure 2: Energy expenditure on physical activity (PAL) in relation to date of measurement for a population in western Europe. There has been no decline in energy expenditure over the time course of the obesity epidemic (from Westerterp and Speakman, 2008)
1. Wang, G.L. and Speakman J.R.* Analysis of Positive Selection at Single Nucleotide Polymorphisms Associated with Body Mass Index Dose Not Support the "Thrifty Gene" Hypothesis. Cell Metabolism, in press 2016 2. Zhao, Z.-J.*, Li, L., Yang, D.-B., Chi, Q.-S., Hambly, C. and Speakman, J. R.* Limits to sustained energy intake XXV: milk energy output and thermogenesis in Swiss mice lactating at thermoneutrality. Scientific Reports, 6(31626). 2016 3. Vaanholt, L. M., Milne, A., Zheng, Y., Hambly, C., Mitchell, S. E., Valencak, T. G., Allison, D. B. and Speakman, J. R.* Oxidative costs of reproduction: Oxidative stress in mice fed standard and low antioxidant diets. Physiol Behav, 154(1-7). 2016 4.Speakman, J. R.*, Mitchell, S. E. and Mazidi, M. Calories or protein? The effect of dietary restriction on lifespan in rodents is explained by calories alone. Experimental Gerontology, 2016 5. Speakman, J. R.* and Heidari-Bakavoli, S. Type 2 diabetes, but not obesity, prevalence is positively associated with ambient temperature. Sci Rep, 6(30409). 2016 6. Sadowska, E. T., Krol, E., Chrzascik, K. M., Rudolf, A. M., Speakman, J. R. and Koteja, P. Limits to sustained energy intake. XXIII. Does heat dissipation capacity limit the energy budget of lactating bank voles? Journal of Experimental Biology, 219(6):805-815. 2016 7.Mitchell, S. E., Delville, C., Konstantopedos, P., Derous, D., Green, C. L., Wang, Y. C., Han, J. D. J., Promislow, D. E. L., Douglas, A., Chen, L. N., Lusseau, D. andSpeakman, J. R.*The effects of graded levels of calorie restriction: V. Impact of short term calorie and protein restriction on physical activity in the C57BL/6 mouse. Oncotarget, 7(15):19147-19170. 2016 8. Lipina, C., Vaanholt, L. M., Davidova, A., Mitchell, S. E., Storey-Gordon, E., Hambly, C., Irving, A. J., Speakman, J. R. and Hundal, H. S. CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction. Aging Cell, 15(2):325-335. 2016 9. Joly-Amado, A., Serraneau, K. S., Brownlow, M., Marín de Evsikova, C., Speakman, J. R., Gordon, M. N. and Morgan, D. Metabolic changes over the course of aging in a mouse model of tau deposition. Neurobiology of Aging, 44(62-73). 2016 10.Gamo, Y., Bernard, A., Troup, C., Munro, F., Derrer, K., Jeannesson, N., Campbell, A., Gray, H., Miller, J., Dixon, J., Mitchell, S. E., Hambly, C., Vaanholt, L. M. and Speakman, J. R.* Limits to sustained energy intake XXIV: impact of suckling behaviour on the body temperatures of lactating female mice. Scientific Reports, 6(25665). 2016 11. Davina Derous, Sharon E. Mitchell, Cara L. Green, Luonan Chen, Jing-Dong J. Han, Yingchun Wang, Daniel E.L. Promislow, David Lusseau, John R. Speakman*and Douglas*, A. The effects of graded levels of calorie restriction: VI. Impact of short-term graded calorie restriction on transcriptomic responses of the hypothalamichunger and circadian signaling pathways. Aging-US, 2016 12. Burke, L. K., Doslikova, B., D’Agostino, G., Greenwald-Yarnell, M., Georgescu, T., Chianese, R., de Morentin, P. B. M., Ogunnowo-Bada, E., Cansell, C., Valencia-Torres, L., Garfield, A. S., Apergis-Schoute, J., Lam, D. D., Speakman, J. R., Rubinstein, M., Low, M. J., Rochford, J. J., Myers, M. G., Evans, M. L.and Heisler, L. K. Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons. Molecular Metabolism, 5(3):245-252. 2016
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