ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 P131

Interactions between glucagon and GLP-1 in neuronal pathways affecting food intake

Jennifer Parker, Katherine Simpson, James Minnion, Ben Field, Mohammad Ghatei & Steve Bloom

Imperial College, London, UK.

Glucagon is released from α-cells in the pancreatic islets and is best known for its role in glucose homeostasis. Glucagon/GLP-1 receptor co-agonists have recently been shown to improve glucose homeostasis and reduce body weight in diet-induced obese mice. Glucagon receptor agonism increases energy expenditure while the GLP-1 receptor agonism prevents glucagon-induced hyperglycemia. Peripherally administered glucagon is also capable of reducing food intake, and glucagon neutralising antibodies increase food intake. The neuronal pathways involved in this effect have not been identified.

We have used c-fos immunohistochemistry to examine the effect of peripherally administered glucagon on neuronal activity in the brain. Anorectic doses of glucagon increased c-fos levels in the nucleus tractus solitarius (NTS), area postrema (AP) and central nucleus of the amygdala (CeA). These effects appeared to be dose dependent and restricted to doses capable of inhibiting food intake. The same nuclei were also activated in a dose responsive manner by the related hormone GLP-1.

In addition, we have studied the effect of combined administration of glucagon and GLP-1 on food intake in fasted mice. Doses of each hormone that were individually too small to significantly affect food intake were shown, when administered together, to reduce food intake significantly. In parallel studies, c-fos expression in the AP, NTS, and CeA also appeared greater when the two hormones were administered in combination.

Our studies show that glucagon and GLP-1 have an effect on food intake that is, at minimum, additive. This effect appears to involve the same neuronal pathways activated by either hormone individually. This suggests it may be possible to achieve the same maximal effect produced by a high dose of a GLP-1 by combining a low dose of GLP-1 with glucagon. This approach may be valuable in developing novel treatments for diabetes and obesity.

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