November 12th, 2015
Glucagon-like peptide 1 (GLP-1) is an hormone secreted from intestinal endocrine L cells and also from pancreatic α-cells that cause an increase in the amount of insulin released from the beta cells. Its ability to stimulate insulin secretion and regulate blood glucose has been used as a treatment for type 2 diabetes. Importantly, GLP-1 and its long-lasting analogs reduce food intake and body weight. These effects have been regarded as of potential clinical relevance for successful treatment of obesity. There is limited knowledge regarding the mechanisms behind the anorexic effect of GLP-1, but it is likely exerted at the level of the central nervous system.
A number of findings suggest a potential link between GLP-1 and cytokine signaling outside of the central nervous system. Indeed, elevated interleukin-6 (IL-6) levels in the blood, particularly the IL-6 secreted by the skeletal muscle, increase both secretion and production of GLP-1 from intestinal L-cells and pancreatic α-cells. Moreover, peripheral GLP-1 may mediate beneficial effects of IL-6 on blood glucose and the capacity of β-cells to secrete insulin. GLP-1 may also interact with interleukin-1β (IL-1β). However, until recently, there was no studies on possible interactions between GLP-1 and IL-6 and IL-1β at the level of the brain. IL-1 and IL-6 are key regulators of the inflammatory response (13, 14), influencing metabolism and behavior during illness, including the induction of fever and loss of appetite and mobility. When both IL-1β and IL-6 are lacking, mice develop obesity and hyperphagia.
A recent study published in the Proceedings of the National Academy of Science of the United States of America (PNAS) aimed to investigate whether GLP-1, IL-6, and IL-1 interact at the level of the central nervous system in regulation of feeding and body weight. Rats have been use for this study, as well as the clinically relevant GLP-1 analog [exendin-4 (EX4)] to stimulate GLP-1 receptors.
Results shown an enhanced attenuation of the GLP-1 receptor–mediated inhibition of feeding with a simultaneous IL-1 and IL-6 blockade. Furthermore, GLP-1 receptor stimulation with EX4 led to a striking elevation of IL-6 gene expression in two key brain energy balance controlling areas—the hypothalamus and the hindbrain—and to increased IL-1β expression in the hypothalamus.
Clinically used GLP-1 analogs may provide beneficial effects on food intake and body weight reduction that are likely exerted at the level of the central nervous system, but the knowledge about how this effect is exerted is limited. This study report evidence that, surprisingly, two cytokines, IL-6 and IL-1, mediate the suppression of food intake and body weight induced by GLP-1 receptor stimulation. Although this finding is unexpected, it is in line with earlier reports that both IL-6 and IL-1 exert a tonic suppression of body weight in the absence of illness at the level of the central nervous system/hypothalamus. The current findings increase our knowledge of a widely used group of therapeutics and may result in a more refined treatment of obesity.
Photo: Flickr, didbygraham
Shirazi R, Palsdottir V, Collander J, Anesten F, Vogel H, Langlet F, Jaschke A, Schürmann A, Prévot V, Shao R, Jansson JO, & Skibicka KP (2013). Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6. Proceedings of the National Academy of Sciences of the United States of America PMID: 24048027