Disordered nutrient homeostasis: links to disease

Obesity is a major problem in many industrialised countries, where it has serious and significant socio-economic implications. It is a major risk factor in the development of non-insulin dependent (Type 2) diabetes mellitus (T2DM), cardiovascular disease and several cancers. Furthermore, people with diabetes have a higher risk of developing Alzheimer’s disease, and patients with dementia, an increased risk of T2DM. Diet and lack of exercise are clearly important contributors but there is also evidence that hormone and nutrient sensing mechanisms in the brain and peripheral tissues play key roles in the aetiology of the obese/diabetic state. Studies on rodent models of obesity have highlighted the importance of the hormones leptin and insulin for long-term regulation of food intake and energy homeostasis. Both hormones act in the brain, predominantly at the level of the hypothalamus, and recent studies have uncovered links between hypothalamic signalling and peripheral blood glucose levels. It is also becoming clear that aberrant glucose metabolism and insulin sensing are significant contributing factors to Alzheimer’s pathophysiology. Our current research programmes are:

1. Nutrient sensing mechanisms in hypothalamic neurons and pancreatic beta cells. Pancreatic beta cells and certain hypothalamic neurons utilize similar molecular mechanisms to sense changes in local glucose levels, which are transduced into altered electrical activity and release of peptides. Both cell types require activity of the protein kinase AMPK to perform this role. In addition, obesity/high fat diet engenders impaired glucose signalling and altered function, resulting in loss of glucose homeostasis, which may in turn lead to T2DM. Consequently, we are investigating how AMPK activity contributes to glucose sensing in these cells and how exposure to various fatty acids alters these outputs.  Identifying the underlying mechanism(s) may result in new potential targets for therapeutic intervention to treat the diabetic and obese states.
2. Determining the molecular links between amyloid processing and nutrient homeostasis. A feature common to Alzheimer’s disease and T2DM is disturbed glucose homeostasis and insulin resistance.  Consequently, we are investigating the relationship between alterations in proteolytic processing of the amyloid precursor protein (APP) and whole body energy metabolism. Our studies indicate a close link between amyloid metabolism and body weight, insulin sensitivity and peripheral glucose levels. We are also examining the effects of high fat diet/obesity on the levels and activity of the amyloid processing proteins. This work should impact significantly on current understanding of the connection between diabetes, obesity and Alzheimer’s disease.
3. Leptin signalling mechanisms: relation to obesity and diabetes. Most obese humans and animals have a surfeit of circulating leptin (and insulin) and this is deemed indicative of leptin resistance, a significant component in the pathogenesis of obesity. Indeed, in many instances leptin and insulin resistance co-exist, both peripherally and centrally. Thus, determination of the underlying molecular changes associated with leptin resistance should allow the generation of molecular strategies to counteract these. We are currently examining the signalling mechanisms employed by leptin and insulin in hypothalamic neurons, and their role(s) in modulating electrical excitability. In addition, agents that mimic some of the signalling actions of leptin are being investigated for future therapeutic potential.

1. 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
2. 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
3. K. Ning, LC Miller, HA Laidlaw, LA Burgess, NM Perera, CP Downes, NR Leslie, MLJ Ashford (2006) A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic beta-cells. EMBO J 25:2377-2387
4. Choudhury AI, Heffron H, Smith MA, Al-Qassab H, Xu AW, Selman C, Simmgen M, Clements M, Claret M, MacColl G, Bedford DC, Hisadome K, Diakonov I, Moosajee V, Bell JD, Speakman JR, Batterham RL, Barsh GS, Ashford MLJ, Withers DJ (2005) The role of insulin receptor substrate 2 in hypothalamic and b cell function. J. Clin. Invest. 115:940-950
5. Mirshamsi S Laidlaw HA, Ning K, Anderson E, Burgess LA, Gray A, Sutherland C, Ashford MLJ (2004) Stimulation of PI3K by leptin and insulin leads to actin reorganization and KATP activation in arcuate nucleus neurones. BMC Neuroscience 5, 54
6. Spanswick, D, Smith, M.A., Mirshamsi, S., Routh, V.H. & Ashford, M.L.J. (2000) Insulin activates ATP-sensitive K+ channels in hypothalamic neurones of lean, but not obese rats. Nature Neuroscience 3, 757 – 758.