“Our research focuses on the roles of hormone and nutrient-regulated signalling pathways in type II diabetes, obesity and age-related diseases”

Our work investigates the signalling processes in the central nervous system that regulate energy homeostasis and their contribution to diseases such as obesity and type II diabetes. For example, we have identified key roles for insulin receptor substrate (IRS) proteins and AMP-activated protein kinase (AMPK) in the regulation of food intake and body-weight. We have also shown that such signalling pathways regulate mammalian longevity and resistance to the diseases of ageing. Our work will continue to identify the cellular and physiological mechanisms that control energy balance and explore the mechanisms by which mammalian longevity is regulated with regards to the pathogenesis of metabolic and age-related disease.

Metabolic Signalling

A coronal section through the arcuate nucleus of the hypothalamus showing pro-opiomelanocortin (POMC) neurons expressing green fluorescent protein transduced with an adenovirus expressing channelrhodopsin and mCherry (red). POMC neurons co-expressing the virus appear yellow.

Selected Publications

Claret, M., Smith, M. A., Knauf, C., Al-Qassab, H., Woods, A., Heslegrave, A., Piipari, K., Emmanuel, J. J., Colom, A., Valet, P., Cani, P. D., Begum, G., White, A., Mucket, P., Peters, M., Mizuno, K., Batterham, R. L., Giese, K. P., Ashworth, A., Burcelin, R., Ashford, M. L., Carling, D., & Withers, D. J. (2011). Deletion of lkb1 in pro-opiomelanocortin neurons impairs peripheral glucose homeostasis in mice. Diabetes, 60(3), 735–745.

Selman, C., Tullet, J. M., Wieser, D., Irvine, E., Lingard, S. J., Choudhury, A. I., Claret, M., Al-Qassab, H., Carmignac, D., Ramadani, F., Woods, A., Robinson, I. C., Schuster, E., Batterham, R. L., Kozma, S. C., Thomas, G., Carling, D., Okkenhaug, K., Thornton, J. M., Partridge, L., Gems, D., & Withers, D. J. (2009). Ribosomal protein s6 kinase 1 signaling regulates mammalian life span. Science,
326(5949), 140–144.

Al-Qassab, H., Smith, M. A., Irvine, E. E., Guillermet-Guibert, J., Claret, M., Choudhury, A. I., Selman, C., Piipari, K., Clements, M., Lingard, S., Chandarana, K., Bell, J. D., Barsh, G. S., Smith, A. J., Batterham, R. L., Ashford, M. L., Vanhaesebroeck, B., & Withers, D. J. (2009). Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metabolism, 10(5), 343–354.

Selman, C., Lingard, S., Choudhury, A. I., Batterham, R. L., Claret, M., Clements, M., Ramadani, F., Okkenhaug, K., Schuster, E., Blanc, E., Piper, M. D., Al-Qassab, H., Speakman, J. R., Carmignac, D., Robinson, I. C. A., Thornton, J. M., Gems, D., Partridge, L., & Withers, D. J. (2008). Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. The FASEB Journal, 22(3), 807–818.

Claret, M., Smith, M. A., Batterham, R. L., Selman, C., Choudhury, A. I., Fryer, L. G., Clements, M., Al-Qassab, H., Heffron, H., Xu, A. W., Speakman, J. R., Barsh, G. S., Viollet, B., Vaulont, S., Ashford, M. L., Carling, D., & Withers, D. J. (2007). AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. The Journal of Clinical Investigation, 117(8), 2325–2336.

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