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Obesity mechanism investigated

6 August 2007

Research into the control of bodyweight and blood glucose led by Professor Dominic Withers, UCL Medicine, is published this week in the 'Journal of Clinical Investigation'.

Obesity and type-2 diabetes are two of the greatest challenges facing modern medicine. Research over the last 10 years has revealed that a key region in the brain, called the hypothalamus, is responsible for regulating both body weight and glucose levels. Recent studies have implicated the "fuel-gauge" enzyme AMP-activated protein kinase (AMPK) as a key sensing mechanism for hormones and nutrients. However, the exact components within this brain area responsible for controlling energy balance and blood glucose remain to be determined. A better understanding of the role of AMPK in the hypothalamus is of great importance in order to develop new strategies for the treatment of type-2 diabetes and obesity.

New research from Professor Withers' lab within UCL Medicine gives key insights into the role of AMPK in the hypothalamus. His research team generated mice that lacked AMPK in specific subpopulations of neurons (AgRP and POMC) within the hypothalamus and investigated the effects of lacking this energy sensor on body weight and glucose metabolism. Professor Withers said: "AMPK is a promising drug-target for type 2 diabetes and obesity and this is the reason why we conducted this research. AMPK can be regarded as the fuel gauge of the body. In conditions where you are energy deficient, it is turned on. It is a cell defence mechanism that protects the cell from energy deprivation. However, as a mechanism, it is complex and not fully understojod".

The mice generated showed alterations in systems that keep body weight stable and within a healthy range. Professor Withers said: "The lack of AMPK in POMC and AgRP neurons led to obese and thin mice, respectively. This data strongly suggested that AMPK in these neurons is an essential component of the mechanism involved in body weight regulation". Since POMC and AgRP neurons play a role in sensing nutrients and certain types of hormones, the next step was to check their responses to such signals.

The absence of AMPK in these neuronal populations did not alter the responses to the body-weight regulating hormones leptin and insulin but led to dramatic defects in the ability of the neurons to sense changes in glucose levels. Professor Withers said: "These results show that AMPK is essential for glucose-sensing signalling mechanisms but not for sensing hormones such as insulin and leptin.

This is an important finding that suggests that glucose-sensing mechanisms in these neurons are distinct from those pathways used by certain hormones. Although AMPK plays a key role in the hypothalamus, it does not act as a general sensor and integrator of energy homeostasis in the brain as was suggested previously. It was thought that leptin and insulin both need AMPK to affect the neurons - we have shown that this is not the case and that the situation is actually much more complicated than was previously thought. This is likely to be important when considering AMPK as a drug target for obesity."

Researchers throughout UCL are studying aspects of the obesity crisis, including research at the UCL Institute of Child Health into childhood obesity, population studies at UCL Epidemiology & Public Health, and transport studies at the UCL Bartlett. For a few recent examples of UCL news on obesity, use the links at the top of the article.