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Metabolic Signalling

Dominic Withers

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Medical Research Council (MRC)
Obesity is one of the greatest public health challenges of the 21st century. In the UK currently over 60% of the adult population is overweight with 1 in 4 adults being obese (BMI >30). Obesity is a major risk factor for a range of common morbid conditions including type 2 diabetes, cardiovascular disease, and cancer as well as having significant psychological and social impact. Body weight is regulated by a complex physiological system that controls food intake, nutrient storage and energy expenditure. The central nervous system plays a pivotal role in this regulatory mechanism. The hypothalamus and caudal brainstem have been implicated in the homeostatic regulation of body weight responding to a number of hormonal and neural systems that inform the brain about nutrient status. More recently it has become clear that other brain regions including the cerebral cortex, basal ganglia and limbic system potentially play roles in the regulation of metabolism. Recent genome wide association studies in humans have also strongly implicated neuronal genes as risk alleles for obesity. The overall aim of future work will be to further understand the CNS regulation of energy homeostasis. We will analyse the role of the hypothalamic signalling mechanisms we have implicated in the regulation of food intake and body weight extending studies to new brain regions and neuronal circuits. The work is divided into 4 programmes: Analysis of signalling pathways downstream of IRS proteins in the hypothalamic regulation of energy homeostasis. Analysis of AMPK cascade signalling components in the hypothalamic regulation of energy homeostasis. Studies on the midbrain dopaminergic system in the regulation of energy homeostasis and reward. Analysis of the function of defined neuronal circuits in the regulation of feeding behaviour using optogenetics. The first programme will identify signals downstream of Irs2 that regulate feeding and body weight. We have previously shown that deletion of Irs2 in the brain causes marked obesity. The second programme builds on our published and unpublished work demonstrating a key role for the AMPK cascade in the hypothalamus. The third programme will explore the role of non-homeostatic dopaminergic circuits that are thought be regulate the rewarding aspects of food. The final programme will start to exploit available technologies using light-modulated conductances that increase or suppress neuronal firing, to explore the function of appetite circuits in vivo.

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