Dr Tim Wells
The focus of my laboratory is on the endocrine and neuroendocrine actions of ghrelin. A variety of contemporary technologies are employed to investigate the way in which ghrelin interacts with the brain and peripheral tissues to regulate adiposity and the secretion of pituitary hormones. This research falls into the following areas:
1. Ghrelin and Obesity
Ghrelin stimulates fat deposition. Following our landmark publication showing that ghrelin has a direct adipogenic (increases the number of fat cells) action in bone marrow (Figure 1)[i], we have established the mechanisms by which ghrelin induces an increase in abdominal adiposity. Using MRI we have shown that this effect of ghrelin increases the volume of adipose tissue locations associated with the development of the metabolic syndrome (Figure 2)[ii].
We have shown that this effect is:
- Due to an increase in adipocyte size (Figure 3)
- Probably due to a reduction in lipid export.
- Dependent upon expression of the recognized receptor for ghrelin, GHS-R1a.
- Also seen in liver2.
We have used microarray analysis to investigate why specific adipose tissue depots respond differently to ghrelin exposure. This analysis suggests that depot-specificity arises from differences in signal transduction and lipid handling2. A complete dataset from this microarray analysis is available here.
Coupled with evidence that circulating ghrelin is suppressed by feeding and that ghrelin stimulates food intake (especially the ingestion fat), our data indicates that:
- Ghrelin may restrict lipid loss during food deprivation.
- Interrupting ghrelin signalling may be an essential component of any programme of sustained fat loss.
2. Ghrelin and Growth Hormone Secretion
Ghrelin was first identified as a hormone that stimulates GH secretion and might therefore be useful in accelerating skeletal growth in a particular group of GH-deficient children. We used the Tgr rat, a model of hypothalamic GH deficiency, to demonstrate that the growth promoting potential of ghrelin is also dependent upon the pattern of treatment[iii]. We are currently investigating the effect of continuous exposure to ghrelin and unacylated ghrelin (UAG) on spontaneous GH secretion. Interestingly, although GH-deficiency is usually associated with obesity, the profoundly GH-deficient dw/dw rat is surprisingly lean[iv].
3. Ghrelin and Reproduction
Ghrelin is now thought to provide a metabolic signal to delay the development of reproductive function. In this context we have shown that:
- Ghrelin (and UAG) suppresses gonadotrophin secretion[v] even in the hypergonadotrophic Tgr rat[vi].
- Circulating ghrelin is not increased consistently during pregnancy and is not responsible for the elevation in baseline GH secretion. Pregnancy is accompanied by a marked polarisation of GH secretory granules towards the vasculature (Figure 4)[vii].
4. Interactions Between Adiposity Status and the Growing Skeleton
Given the interactions of ghrelin, GH and adiposity we are also investigating the influence of these variables on bone formation. We have now used in vitro strength testing and µ-computer tomography (µ-CT) to demonstrate that:
- The impairment of bone strength in the Tgr model of moderate GH-deficiency[viii] is more profound than in the severely deficient dw/dw rat[ix].
- The impairment of bone strength and microarchitecture in these models of GH-deficiency is not related to the accompanying adiposity status, or the secretion of leptin[x].
The Ipsen Fund
The Wellcome Trust
Prof David Carter, School of Biosciences, Cardiff University.
Dr Helen Christian, Oxford University.
Dr Karen Coschigano, Ohio University, Ohio, USA.
Dr Jeffrey Davies, University of Swansea.
Dr Bronwen Evans, school of Medicine, Cardiff University.
Dr Sam Evans, School of Engineering, Cardiff University.
Dr Evelien Gevers, National Institute of Medical Research, London.
Prof John Kopchick, Ohio University, Ohio, USA.
Prof Agneta Mode, Karolinska Institute, Stockholm, Sweden.
Prof Iain Robinson, National Institute of Medical Research, London.
Dr Manuel Tena-Sempere, University of Cordoba, Spain.
Dr Jeffrey Zigman, University of Texas Southwestern Medical Center at Dallas, USA.
[i] Thompson NM et al, (2004) Endocrinology 145:234-242.
[ii] Davies JS et al, (2008) submitted.
[iii] Thompson NM et al (2003) Endocrinology 144:4859-4867.
[iv] Davies JS et al, (2007) Am J Physiol Endocrinol Metab 292:E1483-E1494.
[v] Martini AC et al, (2006) Endocrinology 147:2374-2382.
[vi] Davies JS et al, (2006) J Neuroendocrinol 18:719-731.
[vii] El-Kasti MM et al, (2008) J Neuroendocrinol 20:309-322.
[viii] Evans BAJ et al, (2003) J Bone Miner Res 18:1308-1316.
[ix] Stevenson AE et al, (2008) Submitted.
[x] Evans BAJ et al, (2008) Submitted.