Body and mind

The brain’s fear centre also controls hunger

The amygdala is the area of our brain that plays a key role in processing emotions, including fear. New research shows that it also regulates our appetite through interaction between a vital signalling substance in the immune system and one of the most important metabolic hormones. Mice without this immune substance become obese. In addition to contributing to knowledge about the interaction between the brain and the gut, this new knowledge is especially important in treating people with autoimmune diseases.

Few people question the role of the brain in making us feel hungry. Nevertheless, recent research has focused on the opposite: namely, whether signals from our intestinal system may control hunger. Interaction between brain signals, gut hormones and especially the gut bacteria may be key to understanding the worldwide obesity epidemic. Researchers have now revealed that an intestinal hormone, interacting with a signalling substance in the immune system, affects the tiny fear centre in the brain called the amygdala and that this interaction can influence whether we become overweight or not.

”Mice that lack interleukin-6 (IL-6) become obese, but if you inject it into their brain, they return to their normal weight again. Our experiments show that the amygdala significantly regulates this process through interaction between glucagon-like peptide-1 (GLP-1) and IL-6, a key signalling substance in the immune system. This is especially important knowledge in treating people with autoimmune diseases to avoid excessively suppressing the IL-6 signal so that the people become overweight,” explains John-Olov Jansson, Professor, Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Sweden.

Close interaction

This discovery can be traced back to 2002, when the Swedish researchers published a remarkable study in Nature Medicine. While investigating what happens to mice lacking cytokines, essential signalling substances in the immune system, they noticed that mice lacking IL-6 became obese.

”When we injected IL-6 into the mice lacking the protein, nothing happened immediately – until we injected it into the brain. This helped the mice to return to their normal weight. Since then, we have tried to understand why IL-6 is associated with obesity if it is secreted from fat tissue into the blood, whereas injecting it into the brain inside the blood–brain barrier helps to prevent obesity. Our new results show that the amygdala is responsible for some of this effect.”

The facts that the amygdala regulates hunger and that GLP-1 also plays a role are well known. The researchers therefore wanted to determine whether GLP-1 and IL-6 interact, and the results showed that they interact very closely.

”These proteins bind to the same neurons, so they obviously influence each other. We do not yet know exactly how, but IL-6 seems to be unable to cross the blood–brain barrier. Conversely, GLP-1 can do this, and GLP-1 seems to induce an IL-6 signal, but it is too early to conclude anything about this complementary signalling. Clearly, however, the interaction between GLP-1 and IL-6 in the amygdala affects appetite and metabolism,” says Fredrik Anesten, Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Sweden.

Autoimmunity and obesity

Although more studies are needed before researchers can elucidate how GLP-1 and IL-6 interact in the amygdala and thus help control our desire for food, the new findings already have obvious uses: treating people with autoimmune diseases.

”Today, people with autoimmune diseases are treated with various types of medicine that suppress their symptoms. However, our study shows that we may need to avoid excessively suppressing the IL-6 signal, since this can strongly affect the metabolism and health of these people,” explains Fredrik Anesten.

Using IL-6 as a general remedy against obesity is probably not an option for now. It actually affects the brain very differently from the rest of the body. Thus, although IL-6 in the brain can suppress hunger and lead to weight loss, this is less obvious elsewhere in the body.

”IL-6 is often present in fatty tissue together with other inflammatory signalling substances in the immune system such as tumour necrosis factor-alpha. Together these have a devastating effect on our metabolism, in stark contrast to the effect of IL-6 interaction with GLP-1. We therefore need to understand IL-6 and its interactions better before we can use it for treatment,” says John-Olov Jansson.

Interleukin-6 (IL-6) in the central amygdala is bioactive and co-localized with glucagon-like peptide-1 (GLP-1) receptor” has been published in the Journal of Neuroendocrinology. In 2013, the Novo Nordisk Foundation awarded a grant to co-author Karolina P. Skibicka for the project Can GLP-1 Modify Reward Behaviour and Circuitry to Reduce Reward Cravings? Answers from Rodents and Men in Health and Disease.

Karolica Skibicka
Associate professor
Appetite and body weight are under the tight control of the central nervous system. The goal of our research is to understand the brain mechanisms that govern feeding behavior and energy expenditure. Knowledge about these mechanisms may be utilized to find more effective anti-obesity drug targets. Our current research themes are: Gut-brain hormones control ingestive behavior and food reward: understanding the neurocircuitry involved Sex differences in regulation of appetite and food reinforcement and interaction of gut-brain hormones with sex steroids Gut-brain hormones engage immune system signals to reduce body weight Gut-brain hormones regulate a wide range of behaviors: impulsivity, novelty seeking, anxiety and depression-like behavior