Our research focuses on identifying the neuronal mechanisms involved in sensing, integrating and adjusting whole body metabolic state.
Specialized brain structures, including the hypothalamus, sense the body's energy status, integrate this information and elicit an appropriate response to the rest of the body. Recent research has begun to unravel some of the neuronal pathways regulating body weight, but the exact mechanisms by which metabolic signals are sensed by the CNS and translated into a coordinated response are still unclear.
Genome wide association scans in patient populations are identifying more and more novel genes associated with the dysregulation of body weight, food intake and glucose homeostasis, but often the physiological function and how these genes might fit into the pathways leading to disease remain unclear. Using genetic modification techniques, we investigate the cellular and physiological contribution of these genes in subsets of neurons to the control of metabolic balance. Ultimately this research enables us to better understand the mechanisms involved in maintaining metabolic balance.
Although we know that the hypothalamus is one of the key CNS areas sensing and integrating information on body nutrient state, the molecular mechanisms translating hypothalamic nutrient-sensing into changes in gene expression and ultimately adjustment of neuronal function remain poorly defined. Furthermore, the specific physiological functions encoded by these dynamically modulated transcriptional programs (transcriptomes) are unclear. We have recently identified a novel transcriptional co-activator, CRTC2, as an important link between neuronal glucose-sensing and the dynamic regulation of a specific transcriptome (Lerner et. al., 2009, EMBO Reports) and are currently investigating the physiological functions of the CRTC2-mediated transcriptome.
Homing in on neurons themselves, a fascinating aspect of brain performance is how the intra-cellular energy state affects neuronal function, health and longevity. Decline in memory performance is closely related to, for example, age-mediated structural and functional changes of neurons leading to loss of synaptic function (and thus neuron-to-neuron communication). Synaptic performance is critically dependent on robust supply of energy in the form of ATP for neurons’ metabolically very expensive processes. We are currently investigating how CNS genes affected by whole body metabolic state might integrate this information with adjustment of neuronal health and synaptic function (Weir et al., 2012, PLOSOne).
Recent research has demonstrated that agents increasing or decreasing food intake have associated effects on the cardiovascular system; a highly undesirable effect in the design of future body weight reducing therapies. Using genetic modification techniques in combination with radio-telemetry to measure cardiovascular function, we investigate how CNS genes important in the regulation of food intake also affect the cardiovascular system (Sohn et al, 2013, Cell).
A wealth of studies have demonstrated that early life environment significantly influences adult metabolic balance with offspring of obese mothers programmed to become overweight and diabetic. We are currently investigating how maternal diet affects offspring hypothalamic transcriptomic mechanisms and thereby offsring risk of metabolic disease.
01. 2007-present Research Councils UK Academic Research Fellow, University of Bristol, School of Physiology and Pharmacology, UK
11. 2006 - 10. 2010 British Heart Foundation Intermediate Basic Research Fellow, University of Bristol, Department of Physiology and Pharmacology, UK
01.-06. 2006 Research Fellow, University of Bristol, Department of Biochemistry, UK
02.-12. 2005 Instructor in Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
11. 2000 - 02.2005 Postdoctoral Research Fellowship, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
04. 2001 Ph.D. awarded by University College London, UK
1997 - 2000 Ph.D. studentship, National Institute for Medical Research, London, UK
1992 - 1997 Biochemie Diplom (biochemistry degree course), class 1, Ruhr-Universität Bochum, Germany and Imperial College of Science, Technology and Medicine, London, UK
View complete publications list in the University of Bristol publications system
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