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Research Summary

The answer to tackling the obesity epidemic is in the brain

Rates of obesity are growing rapidly and there is a great need for new effective treatments. Understanding the brain mechanisms that govern how much and when we eat is key to finding solutions to obesity. Knowledge about these mechanisms can be utilized to find novel anti-obesity drug targets. Our research aims to decipher these mechanisms by combining identification of new brain chemicals and new brain regions that regulate feeding and body weight with behavioral studies aimed at understanding behavioral processes that are co-regulated with appetite. The integration of all these aspects allows for a more holistic understanding of body weight regulation and provides opportunities for identification of new treatment targets.

Impact of gut-brain signals on food reinforcement

Reward-driven eating, eating for pleasure and not out of metabolic need, is crucial in the development of overeating and obesity. Neural substrates underlying reward control may differ from those responsible for homeostatic feeding. Reward or motivated behavior is closely linked to the mesocorticolimbic neurocircuitry, especially the ventral tegmental area and its dopaminergic projections to the nucleus accumbens. Increased dopamine release in the accumbens is typically associated with an increase in motivated behavior, and palatable food is known to induce dopamine release in this brain area. Dysfunction of this circuitry can lead to addictive behaviors.

GLP-1 is a key satiety hormone produced in the intestine and in the brainstem 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, surprisingly little is known about the impact of GLP-1 on the brain. We discovered that GLP-1 reduces the reinforcing value of food and does so by stimulating GLP-1 receptors directly on neurons in the mesolimbic circuitry (Journal of Neuroscience 2012). This finding challenged the view that GLP-1 is simply a glucoregulatory and homeostatic hormone, and opened up new therapeutic applications for the GLP-1 analogues. This novel action of GLP-1 analogues is now pursued in clinical trials. 

Identifying new neurochemical signals regulating feeding behavior and body weight

Another line of research in my laboratory focuses on finding new brain neurochemicals that are engaged by satiety hormones. We found an unexpected link between GLP-1 and brain cytokines (PNAS 2013): the clinically utilized GLP-1 analogue, Exendin-4, employs two immune system associated molecules – interleukins 1 and 6, in brain areas key for food intake regulation. We showed that this interaction is crucial for the beneficial food intake reducing effect of GLP-1. These findings paved the way to reconsidering brain immune signaling as a part of normal physiological component in regulation of body weight. We are now following up on this work to find whether other peripheral signals may use brain interleukins to reduce food intake, placing interleukins 1 and 6 as integral regulators of body weight.

Brain serotonin signaling is well known to reduce appetite. Overwhelming majority of obesity research focuses on the 5HT2C receptor, it is also the receptor believed to be key to the anti-obesity effect of the pharmaceutical – lorcaserin. Our recent findings (Diabetes 2017), however, suggest that it is the 5HT2A, and not 5HT2C receptor, in the CNS that is being activated downstream of GLP-1 receptor stimulation, to reduce food intake and body fat. This result is unexpected, and certainly warrants future research focusing on the 5HT2A receptor and ways its activity can be harnessed to reduce body weight, an idea we are currently actively pursuing.

The sex gap in preclinical obesity research and its consequences

Nearly half of the obese patient population is female, yet virtually all preclinical research on how the brain’s neural circuitry controls appetite and leads to obesity is done exclusively in male animals. That means that much of what we know about the mechanisms that steer overeating may not be entirely relevant to half of the human population. This is a problem since males and females, humans and rodents alike, may detect and respond to signals controlling eating differently. Understanding these differences may be crucial to finding new effective anti-obesity treatments and ignoring them likely already led to discarding treatments that may have been effective in women but were without much effect in men. In this project we aim to understand how the female gut communicates with the brain to control appetite and body weight and lastly how and why this communication fails in obesity. We also want to know to what degree this communication differs between females and males. In line with the idea of sex differences in CNS control of metabolism, our new rodent studies suggest that behavioral and metabolic responses of females to GLP-1 and testosterone differ from the well-established responses in males (PNAS 2015, Neuropharmacology 2016, Biology of Sex Differences 2016).

Food, and neurochemicals engaged by food, affect far more than just feeding behavior

There is a strong positive correlation between food reinforcement behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Our recent work 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 (Neuropsychopharmacology 2016). This is the first study to link an endogenous appetite-promoting gut-brain signal, ghrelin, to impulsive behavior in rodents.

In another study, we found that chronic treatment with GLP-1 reduces depression-like behavior in rodents and affects serotonergic signaling in brain areas normally associated with emotionality control (Psychoneuroendocrinology 2016). These preclinical results may have direct relevance to patients, if confirmed in a clinical study, and indicate that GLP-1 analogues may be especially useful for obese patients manifesting with comorbid depression.

Page Manager: Pontus Sundén|Last update: 3/29/2017

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