Understanding the neuronal network involved in the regulation of glucose metabolism, feeding behaviour and energy expenditure

Potentially five million people will be morbidly obese in England, Wales, and Scotland by 2035 – more than double the number in 2015. 

Rationale

Obesity causes the development of insulin resistance (inability to respond to changes in insulin levels and control blood sugar levels) that subsequentially triggers Type 2 Diabetes (T2D). Insulin resistance occurs in peripheral organs such as the liver, muscle and fat tissue, and in the brain.

Hormones such as insulin are released into the bloodstream and can reach the brain to control energy homeostasis – how much we eat, how we metabolise sugars and how we burn calories). When the brain becomes insulin resistant, part of its ability to control energy homeostasis is lost.

This project aims to understand how the brain becomes insulin resistant, and will identify which proteins and enzymes are altered in specific brain cell types of diet-induced obese and diabetic rats. These findings can then be used to develop new treatments to counteract obesity and T2D.

The area of the brain that will be the focus of this work is the Dorsal Vagal Complex (DVC) in the brainstem. It can respond to insulin to control food intake and blood sugar levels, and is also important to control thermogenesis (the ability to produce heat in response to cold). The aim is to identify which neuronal cells in the DVC are responsible for controlling these functions and how insulin resistance can affect their activity.

This work looks to understand the physiological impact of the development of insulin resistance in the brain, and there is no possibility of substituting the use of animals with alternative systems. Rodents, especially rats, are the best animals to use to perform metabolic studies as their glucose levels are very stable and, in addition, rodents have a fast and complete recovery after surgery.

Replacement

When possible, we will use cell lines. This means that we set up a model of insulin resistance using cells in a petri dish, that we can use to develop experimental approaches and test molecular markers before performing experiments with animals.. 

Reduction

Tissues from the same animal will be used for different objectives where possible. In addition, each experiment is designed to maximise the amount of information gained, since one experiment often combines different approaches to verify the information. 

Refinement

Over the years, we have refined our surgical procedure in order to improve the recovery of rats. We have modified the post-surgical care in order to improve the welfare of the rats, and we have modified our experimental procedure in order to avoid unnecessary suffering. 

Non-technical summary

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