Till startsida
Webbkarta
Till innehåll Läs mer om hur kakor används på gu.se

Current research themes


Current research themes are:

  1. Gut-brain hormones control ingestive behavior and food reward: understanding the neurocircuitry involved
     
  2. Sex differences in regulation of appetite and food reinforcement and interaction of gut-brain hormones with sex steroids
     
  3. Gut-brain hormones engage immune system signals to reduce body weight
     
  4. Gut-brain hormones regulate a wide range of behaviors: impulsivity, novelty seeking, anxiety and depression-like behavior

Gut-brain hormones control ingestive behavior and food reward: understanding the neurocircuitry involved

Figure legend: Neurons in the nucleus of the solitary tract in the hindbrain that produce glucagon like peptide are visualized under a confocal microscope in green.  These neurons were engineered by Frank Reimann and Fiona Gribble (Cambridge University) to produce yellow fluorescent protein in a mouse. Image credits: Richard/Skibicka.

Neurons in the nucleus of the solitary tract in the hindbrain that produce glucagon like peptide are visualized under a confocal microscope in green. These neurons were engineered by Frank Reimann and Fiona Gribble (Cambridge University) to produce yellow fluorescent protein in a mouse.  Image credits: Richard/Skibicka

Glucagon like peptide 1 (GLP-1) is a key satiety hormone produced in the intestine and in the hindbrain in response to food. GLP-1 analogues are now used in the clinic to regulate blood glucose in Type 2 Diabetes patients. Despite the widespread clinical use of GLP-1 analogues, combined with the fact that they cross the blood brain barrier to reach the brain, much remains to be discovered about the impact of GLP-1 on the brain. Our group found that GLP-1 reduces food reward behavior and does so by stimulating GLP-1 receptors directly on neurons in the mesolimbic reward circuitry. This discovery challenged the view that GLP-1 is simply a glucoregulatory and homeostatic hormone, and opened up new therapeutic applications for the GLP-1 analogues.

Since a considerable overlap has been suggested for circuitry controlling reward behavior derived from food and alcohol we are also interested in the ability of GLP-1 to regulate alcohol intake and alcohol reward. We already showed that GLP-1 leads to reduced alcohol intake and attenuated alcohol reward, responses driven by selective activation of GLP-1 receptors in the mesolimbic system.
 

Figure legend: Effect of GLP-1 on food intake and many associated behaviors is neuroanatomicaly distributed (Skibicka 2013, Frontiers in Neuroscience). This image represents a neuroanatomical map of physiological and behavioral responses obtained by stimulation of GLP-1 receptors in different nuclei of the central nervous system.

Effect of GLP-1 on food intake and many associated behaviors is neuroanatomicaly distributed This image represents a neuroanatomical map of physiological and behavioral responses obtained by stimulation of GLP-1 receptors in different nuclei of the central nervous system.

(Skibicka 2013, Frontiers in Neuroscience). 

In a series of studies that followed our initial discovery we outline mechanisms via which GLP-1 reduces food intake and food reward behavior. We show that GLP-1 engages the dopamine system, but that unexpectedly the dopaminergic target nucleus is the amygdala, and not nucleus accumbens.  

Gut-Brain Pathway that Controls Food Intake

We also found two new target nuclei for GLP-1’s impact on food reward - the nucleus of the solitary tract and the parabrachial nucleus. In the parabrachial nucleus our molecular, anatomical, electrophysiological, pharmacological and behavioral data provide evidence for a necessary and sufficient role of GLP-1 in food intake control. We also find a link between GLP-1, and an appetite reducing neuropeptide, CGRP, specifically in the parabrachial nucleus. These studies represent a significant step forward in understanding how gut hormones can affect the brain.

Figure legend: Our data reveal the lateral parabrachial nucleus (PBN) as a neural substrate for the feeding and body weight suppression effect of GLP-1 and identify the mechanisms involved. Elements of this new energy balance relevant circuit identified in our study are indicated in red. (from Richard et al, Endocrinology 2014).

Our data reveal the lateral parabrachial nucleus (PBN) as a neural substrate for the feeding and body weight suppression effect of GLP-1 and identify the mechanisms involved. Elements of this new energy balance relevant circuit identified in our study are indicated in red. (from Richard et al, Endocrinology 2014).

Sex differences in regulation of appetite and food reinforcement

We initially discovered that GLP-1 interacts with estrogen to reduce food reward behavior when the two substances are co-administered directly into the brain in the form of a conjugate. Since we conducted this study in male rats, we next asked the question whether female rats, that naturally have higher circulating levels of estrogen, are more responsive to reward suppressing effects of GLP-1. Our results confirmed this hypothesis, and additionally indicated that blockade of endogenous central estrogen signaling reduces the reward-suppressing impact of GLP-1.

Interaction of gut-brain hormones with immune system signals to reduce body weight

Recently we revealed an unexpected link between GLP-1 and brain cytokines. We show that GLP-1 can produce a striking upregulation of interleukin 1 and 6 the hypothalamus and brainstem. We go on to show that this upregulation is a crucial step in feeding and body weight reduction effects of GLP-1. So, perhaps surprisingly, the two immune modulating interleukins are acting in the brain of healthy rats and mice to mediate the anti-obesity effect of the clinically used GLP-1 analogue. Overall these results may suggest that immune molecules, like interleukins, may play a beneficial role or a pathophysiological role depending on the physiological context and tissues or cells producing them – an idea we are currently pursuing. 

Gut-brain hormones regulate a wide range of behaviors: impulsivity, novelty seeking, anxiety and depression-like behavior

Impulsivity

Impulsivity, defined as impaired decision making, is associated with many psychiatric and behavioral disorders, such as attention-deficit/hyperactivity disorder as well as eating disorders. Recent data indicate that there is a strong positive correlation between food reward behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Our study, The Stomach-Derived Hormone Ghrelin Increases Impulsive Behavior, provides the first demonstration that the stomach-produced hormone ghrelin increases impulsivity and also indicates that ghrelin can change two major components of impulsivity—motor and choice impulsivity.

Novelty seeking behavior

The personality trait novelty seeking describes the response of a person to novel stimuli or situations in terms of tendency to explore, prefer or react positively to the novelty. Importantly, this trait reliably predicts the tendency to develop drug abuse. A wealth of data suggests that drug seeking and novelty seeking have common neurobiological substrates. Ghrelin, an orexigenic hormone produced in the stomach, enhances food, drug and alcohol reward and does so by regulating the mesolimbic dopamine circuitry. We hypothesized that ghrelin may influence novelty seeking behavior. This may be an adaptive process, since for a hungry animal it could be beneficial to explore new environments in search of food. In this study we provide evidence for a role of ghrelin in novelty seeking behavior in animals and humans, and also find an association between food reward and novelty seeking in rodents. Overall these results indicate that the range of impact of gut hormones on behavior goes beyond feeding behaviors.

 Figure legend: Stomach-produced hormone ghrelin influences a wide range of behaviors. Indicated in red are influences of ghrelin that we have recently discovered

Stomach-produced hormone ghrelin influences a wide range of behaviors. Indicated in red are influences of ghrelin that we have recently discovered.

Anxiety and depression-like behaviors

We show a striking impact of central GLP-1 on emotionality and the amygdala serotonin signaling that is divergent under acute versus chronic GLP-1 activation conditions. While acute administration of GLP-1 and Exendin-4 induces anxiety-like, chronic central administration of Exendin-4 does not alter anxiety-like behavior but significantly reduces depression-like behavior in rats. Importantly, this positive effect of Exendin-4 was not due to significant body weight loss and reduced food intake, since rats pair-fed to Exendin-4 rats did not show altered mood. We also find a novel role for the dorsal raphe GLP-1 receptors in regulation of behavior. These results may have direct relevance to the clinic, and indicate that Exendin-4 may be especially useful for obese patients manifesting with comorbid depression, an idea that ripe for careful clinical investigation.

Likewise, we found that ghrelin changes anxiety-like behavior in rats, by acting directly on the amygdala. Interestingly food availability changes this impact of ghrelin: ghrelin reduces anxiety-like behavior only when food is not available, in the presence of food ghrelin does not alter anxiety. This divergence seems fitting with the idea that hungry rats (those with high levels of ghrelin) exhibit reduced anxiety to be able to satisfy the hunger, on the other hand when hunger is satisfied there is little utility to ghrelin’s anxiolytic effect. Earlier we also showed that ghrelin affects serotonin neurotransmission in dorsal raphe and amygdala in mice.

Sidansvarig: Annie Sundling|Sidan uppdaterades: 2017-01-13
Dela:

På Göteborgs universitet använder vi kakor (cookies) för att webbplatsen ska fungera på ett bra sätt för dig. Genom att surfa vidare godkänner du att vi använder kakor.  Vad är kakor?

Denna text är utskriven från följande webbsida:
http://neurophys.gu.se/sektioner/fysiologi/forskning/metabol-fysiologi/karolina-skibicka/research/
Utskriftsdatum: 2019-10-20