Head of Molecular & Clinical Medicine Division/Professor of Neuroscience
Understanding energy homeostasis in metabolic disease
Division of Molecular & Clinical Medicine
Level 5, Mailbox 12
School of Medicine, University of Dundee
Ninewells Hospital and Medical School
+(44) 01382 383095
Chronic obesity is currently at epidemic levels in the UK and many other countries worldwide and is having a major adverse impact on our society. It is estimated that more 25% of the adult population are obese and around two thirds are either overweight or obese. Worryingly over the last 20 years there has been a ~3 fold increase in the number of children and adolescents who are obese or overweight. This trend is alarming, as chronic obesity is associated with increased risk of cardiovascular and liver disease and some cancers. Most notably however, obesity is a primary driver for induction of peripheral insulin resistance, which when coupled with pancreatic beta cell functional insufficiency, leads to diabetes. Recent work also indicates that the risk of Alzheimer’s disease is higher in patients with diabetes and obesity. Therefore it is clear that our society is on a trajectory that will see significant increases in the proportion of individuals entering or in old age with severe chronic health issues. This places an enormous burden on the NHS and society generally, which is likely to worsen over the next 10-20 years if effective actions are not taken soon.
The aim of our work is to understand, at a molecular level, why and how these diseases are linked, in order to find new ways to prevent their long-term harmful consequences. We currently use a number of different systems to study the interactions between the hormones, leptin and insulin, and glucose and fat metabolism. Our current research projects are addressing: (i) how the enzyme beta secretase (BACE1) influences nutrient metabolism and leptin and insulin sensitivity; (ii) the role of the transcription factor, Nrf2, on glucose and lipid metabolism; (iii) how different cellular stresses influence cell metabolism and function; and (iv) how hypothalamic neurons and pancreatic beta cells sense changes in glucose levels.
- Meakin PJ, Harper AJ, Hamilton DL, Gallagher J, McNeilly AD, Burgess LA, Vaanholt LM, Bannon KA, Latcham J, Hussain I, Speakman JR, Howlett DR and Ashford ML (2012). Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice. Biochem J 441:285-296
- Claret M, Smith MA, Knauf C, Al-Qassab H, Woods A, Heslegrave A, Piipari K, Emmanuel JJ, Colom A, Valet P, Cani PD, Begum G, White A, Mucket P, Peters M, Mizuno K, Batterham RL, Giese KP, Ashworth A, Burcelin R, Ashford ML, Carling D, Withers DJ. (2011) Deletion of LKB1 in Pro-Opiomelanocortin neurons impairs peripheral glucose homeostasis in mice. Diabetes 60:735-745
- Deldicque L, Cani PD, Philp A, Raymackers J-M, Meakin PJ, Ashford MLJ, Delzenne NM, Francaux M, Baar K. (2010) The unfolded protein response is activated in skeletal muscle by high-fat feeding: potential role in the down-regulation of protein synthesis. Am J Physiol Endocrinol Metab 299:E695-705
- Beall C, Piipari K, Al-Quassab H, Smith MA, Parker N, Carling D, Viollet B, Withers DJ, Ashford MLJ. (2010) Loss of AMP-activated protein kinase 2 subunit in mouse ß-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia. Biochem J 429:323-333.
- Chowdhry S, Nazmy MH, Meakin PJ, Dinkova-Kostova AT, Walsh SV, Tsujita T, Dillon JF, Ashford MLJ, Hayes JD. (2010) Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic Biol Med 48:357-371.
- Al-Qassab H, Smith MA, Irvine EE, Guillermet-Guibert J, Claret M, Choudhury AI, Selman C, Piipari K, Clements M, Lingard S, Chandarana K, Bell JD, Barsh GS, Smith AJH, Batterham RL, Ashford MLJ, Vanhaesebroeck B, Withers DJ. (2009) Dominant role of the p110 isoform of PI3K over p110 in energy homeostasis regulation by POMC and AgRP neurons. Cell Metabolism 10:343-354.
- Ning K, Miller LC, Laidlaw HA, Watterson KR, Gallagher J, Sutherland C, Ashford MLJ. (2009) Leptin dependent phosphorylation of PTEN mediates actin restructuring and activation of ATP-sensitive K+ channels. J Biol Chem 284:9331-9340
- Hisadome K, Smith MA, Choudhury AI, Claret M, Withers DJ, Ashford MLJ. (2009) 5-HT inhibition of rat insulin 2 promoter Cre recombinase transgene and proopiomelanocortin neuron excitability in the mouse arcuate nucleus. Neuroscience. 159(1):83-93
- Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LGD, Clements M, Al-Qassab H, Heffron H, Xu AW, Speakman JR, Barsh GS, Viollet B, Vaulont S, Ashford MLJ, Carling D, Withers DJ (2007) AMP kinase is essential for energy homeostasis regulation and glucose-sensing by POMC and AgRP neurons. J Clin Invest 117:2325-2336
- Smith MA, Hisadome K, Al-Qassab H, Heffron H, Withers DJ, Ashford MLJ (2007) Melanocortins and agouti-related protein modulate the excitability of two arcuate nucleus neuron populations by alteration of resting potassium conductances. J Physiol 578, 425-438