GLP-1 Agonist Alters Brain Response to Seeing, Eating Food

Marlene Busko

June 12, 2015

BOSTON — Individuals who received injections of the glucagonlike peptide-1 (GLP-1) receptor agonist exenatide (Bydureon, AstraZeneca) had dampened responses in the brain's reward system at the sight of chocolate milk and enhanced responses after drinking the chocolate milk, in a small functional MRI (fMRI) study.

These findings indicate that GLP-1 may play a role in the brain regarding anticipation of tasty food, and may reduce food cravings. The GLP-1 agonist also increased activation in the brain's reward system after consuming food, which may prevent overeating, Dr Liselotte van Bloemendaal (VU University Medical Center, Amsterdam, the Netherlands) explained in a press briefing at the American Diabetes Association (ADA) 2015 Scientific Sessions. The study was also presented at the ADA Presidents' Oral Session.

This was a small study in 16 lean patients, 16 nondiabetic obese patients, and 16 obese patients with type 2 diabetes, so it is too early to say what the clinical implications are, Dr van Bloemendaal cautioned. With GLP-agonists, there is "only a 5% body weight loss, so it doesn't mean the end of obesity, but maybe when you combine it with other hormones such as peptide YY or glucagon you can have synergistic effects and more weight loss," she told Medscape Medical News.

Press conference moderator Dr Celia C Low Wang (University of Colorado Denver School of Medicine, Aurora) said that this line of research is providing exciting insights into how the brain responds to food and how gut-hormone–based medications that are used to treat diabetes also have a neutral effect or reduce body weight. Interestingly, GLP-1 receptor agonists were originally developed to treat diabetes, and now just recently the US Food and Drug Administration (FDA) approved the use of the GLP-1 receptor agonist liraglutide (Saxenda, Novo Nordisk) to treat obesity, she told Medical Medical News. Moreover, this class of drugs appears to affect cravings, so they might have a future use in treating substance abuse.

How Does GLP-1 Agonist Alter the Brain Reward System?

Earlier fMRI research has shown that compared with lean individuals, obese individuals have increased activation of the brain's reward system when they see pictures of delicious food, but they have decreased activation in these areas of the brain when they eat satisfying food, which may induce overeating, Dr van Bloemendaal said.

Gut-derived hormones such as GLP-1 regulate food intake, and GLP-1 receptor agonists improve glycemic control and reduce food intake and body weight, but the mechanisms underlying these altered responses to food are unclear.

"GLP-1 is interesting in that it is secreted from the gut when you eat something, and it stimulates insulin secretions and lowers your blood glucose, but it also stimulates satiety, probably by acting on your brain," Dr van Bloemendaal explained.

The researchers hypothesized that giving people injections of the GLP-1 receptor agonist exenatide would alter brain responses in anticipation of drinking chocolate milk (which is appealing since it has both fat and sugar) and again after drinking it.

They enrolled participants into three groups: lean, nondiabetic and obese, or obese and diabetic. Each of these three groups consisted of eight men and eight women, and the participants had a mean age of 58.

The study subjects had three fMRI sessions. In each session, after fasting overnight, they were given one of three types of intravenous injections — exenatide, exenatide with a GLP-1 receptor antagonist (exendin 9-39), or placebo — before and after drinking chocolate milk or a tasteless solution.

After the fMRI scans, the participants could help themselves to a buffet, and their food intake was monitored.

Compared with the lean participants, the obese participants had increased activation in the brain's reward system when they anticipated receiving chocolate milk and decreased activation in the brain's reward system after they actually drank the chocolate milk. The changes were seen in the brain areas regulating reward (amygdala and caudate nucleus), appetite (insular cortex), and motivation (orbital frontal cortex). Exendin 9-39 largely prevented the effects of exenatide.

These changes in brain activation appeared to play a role when assessing how much food the subjects subsequently ate from the buffet. After the injection of exenatide, lean subjects and obese, nondiabetic subjects decreased their consumption of food by about 25%, whereas the subjects who were both obese and diabetic decreased their caloric intake by 14%, but this was not statistically significant, according to Dr van Bloemendaal.

Thus, GLP-1 receptor activation may reduce food cravings and potentially prevent overeating, the researchers conclude. "Our findings provide novel insights into the mechanisms by which GLP-1 regulates food intake and how GLP-1 receptor agonists induce weight loss," which may lead to the development of new treatments for obesity, Dr van Bloemendaal summarized.

Dr Van Bloemendaal has no relevant financial relationships. Disclosures for the coauthors are listed in the abstract.

American Diabetes Association 2015 Scientific Sessions; June 9, 2015; Boston, Massachusetts. Abstract 3842-OR

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