The role of galanin-like peptide in energy balance and the involvement of inflammatory mediators: an in vivo physiological investigation

Severe weight gain (obesity) or loss (cachexia, anorexia) present massive world-wide medical and social problems. Understanding the events that control body weight will help to develop treatments for these conditions. Changes in body weight result from alterations in appetite and/or the rate of the body's metabolism. These processes are controlled by the brain through complex interactions between hormonal and nervous systems. However, it is now believed that the immune system may also play a role in the regulation of body weight through actions of inflammatory molecules such as cytokines. Leptin, a cytokine-like hormone is produced by fat cells and regulates body weight by acting in the brain. Recently it has been shown that the effects of leptin on appetite and body weight in rodents are due to changes in the cytokine interleukin-1 (IL-1). However, the way in which leptin regulates the production of IL-1 and the key messengers involved are largely unknown. Galanin-like peptide (GALP) is a small molecule that was identified recently in the brain. Injection of GALP into the brain of rodents causes a reduction in appetite and body weight, and leptin increases the production of GALP very much like IL-1. I have preliminary results to show that GALP may affect the release of IL-1 in rodents. This proposal will test whether GALP affects appetite and body weight through the production of IL-1. Part of my studies will use mice that do not have IL-1 to see if they can respond to GALP. I will also investigate where in the brain GALP is acting, and how it stimulates the release of IL-1. This work will, therefore, establish if GALP affects body weight by producing inflammatory molecules, and may also identify new ways of treating disorders of body weight regulation.

Maintenance of energy homeostasis is fundamental to life. This process is regulated by the brain and therefore understanding the mechanisms involved in the regulation of appetite and body weight is a key aim in neuroscience. Recent evidence now implicates inflammatory mediators (e.g. cytokines) in the physiological regulation of energy balance as well as disorders of energy homeostasis, such as cachexia and anorexia, and obesity. Galanin-like peptide (GALP) is a neuropeptide that has dichotomous effects on appetite and body weight, producing orexigenic effects in the short-term, but anorexigenic effects over the longer-term. The downstream mediators and mechanisms involved in these actions of GALP are currently unknown but may be due to interaction with a novel GALP-specific receptor. My preliminary data show that central administration of GALP induces expression of the pro-inflammatory cytokine interleukin-1 (IL-1) in the brain, and IL-1 may be responsible for GALP-induced anorexia. This project will use a combination of in vivo and brain cell culture studies to establish the site and mode of action of GALP in the brain and establish if IL-1 mediates its effects.