Central Agonism of GPR120 Acutely Inhibits Food Intake and Food Reward and Chronically Suppresses Anxiety-Like Behavior in Mice

Abstract

Background:GPR120 (FFAR4) is a G-protein coupled receptor implicated in the development of obesity and the antiinflammatory and insulin-sensitizing effects of omega-3 (ω-3) polyunsaturated fatty acids. Increasing central ω-3 polyunsaturated fatty acid levels has been shown to have both anorectic and anxiolytic actions. Despite the strong clinical interest in GPR120, its role in the brain is largely unknown, and thus we sought to determine the impact of central GPR120 pharmacological activation on energy balance, food reward, and anxiety-like behavior.Methods:Male C57Bl/6 mice with intracerebroventricular cannulae received a single injection (0.1 or 1 µM) or continuous 2-week infusion (1 µM/d; mini-pump) of a GPR120 agonist or vehicle. Free-feeding intake, operant lever-pressing for palatable food, energy expenditure (indirect calorimetry), and body weight were measured. GPR120 mRNA expression was measured in pertinent brain areas. Anxiety-like behavior was assessed in the elevated-plus maze and open field test.Results:GPR120 agonist injections substantially reduced chow intake during 4 hours postinjection, suppressed the rewarding effects of high-fat/-sugar food, and blunted approach-avoidance behavior in the open field. Conversely, prolonged central GPR120 agonist infusions reduced anxiety-like behavior in the elevated-plus maze and open field, yet failed to affect free-feeding intake, energy expenditure, and body weight on a high-fat diet.Conclusion:Acute reductions in food intake and food reward suggest that GPR120 could mediate the effects of central ω-3 polyunsaturated fatty acids to inhibit appetite. The anxiolytic effect elicited by GPR120 agonist infusions favors the testing of compounds that can enter the brain to activate GPR120 for the mitigation of anxiety.

Interplay Between the Gut-Brain Axis, Obesity and Cognitive Function

“…The connection between obesity and behavioral deficits is further supported by evidence showing that some anti-obesity therapies exert anxiolytic effects. Thus, several drugs used to treat obesity have attenuated behavioral alterations in mice, such as sibutramine (Santos et al, 2014 ), duloxetine (Chudasama and Bhatt, 2009 ), pioglitazone (Kurhe and Mahesh, 2016 ), celecoxib (Kurhe et al, 2014a ), ondansetron (Kurhe and Mahesh, 2015 ), 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) (Kurhe et al, 2014b , 2015 ), GPR120 agonist (Auguste et al, 2016 ). These findings suggest that obesity and emotional disorders, such as anxiety and depression, could share a common base.…”

Food for Mood: Relevance of Nutritional Omega-3 Fatty Acids for Depression and Anxiety

“…In addition, anxiety-like behavior and sucrose preference, a behavioral sign of anhedonia, are reduced in GPR40 knock-out mice further highlighting the role of GPR40 signaling in the pathophysiology of mood disorders ( Aizawa et al, 2016 ). GPR120, another GPR which signals DHA activity, is highly expressed in the arcuate nucleus of the hypothalamus and the NAc, a structure involved in emotional behavior ( Auguste et al, 2016 ). Interestingly, GPR120 activation by a specific agonist reduces obesity-induced emotional behavior alteration ( Auguste et al, 2016 ).…”

Comprehensive Analysis Reveals A Six-Gene Signature and Associated Drugs in Alzheimer Disease

“…Evidence suggests that FFAR4 has a role in regulating energy balance, including controlling blood sugar and intestinal hormone secretion (22). Current research shows that sustained FFAR4 stimulation in the brain can reduce anxiety behaviors, thus indicating that FFAR4 acts as a potential pathway through omega-3 (ω-3) polyunsaturated fatty acids (PUFA) central anti-anxiety behavior (23). It is recognized the that TRIO plays an important role in cell division, cell migration, and other functions and plays a role in synapse formation by regulating excitatory synaptic transmission (24)(25)(26).…”