Oleoylethanolamide modulates glucagon-like peptide-1 receptor agonist signaling and enhances exendin-4-mediated weight loss in obese mice

Abstract

Long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RA), such as exendin-4 (Ex4), promote weight loss. On the basis of a newly discovered interaction between GLP-1 and oleoylethanolamide (OEA), we tested whether OEA enhances GLP-1RA-mediated anorectic signaling and weight loss. We analyzed the effect of GLP-1+OEA and Ex4+OEA on canonical GLP-1R signaling and other proteins/pathways that contribute to the hypophagic action of GLP-1RA (AMPK, Akt, mTOR, and glycolysis). We demonstrate that OEA enhances canonical GLP-1R signaling when combined with GLP-1 but not with Ex4. GLP-1 and Ex4 promote phosphorylation of mTOR pathway components, but OEA does not enhance this effect. OEA synergistically enhanced GLP-1- and Ex4-stimulated glycolysis but did not augment the hypophagic action of GLP-1 or Ex4 in lean or diet-induced obese (DIO) mice. However, the combination of Ex4+OEA promoted greater weight loss in DIO mice than Ex4 or OEA alone during a 7-day treatment. This was due in part to transient hypophagia and increased energy expenditure, phenotypes also observed in Ex4-treated DIO mice. Thus, OEA augments specific GLP-1RA-stimulated signaling but appears to work in parallel with Ex4 to promote weight loss in DIO mice. Elucidating cooperative mechanisms underlying Ex4+OEA-mediated weight loss could, therefore, be leveraged toward more effective obesity therapies.

Peroxisome Proliferator–Activated Receptor-α: A Pivotal Regulator of the Gastrointestinal Tract

“…Moreover, the use of OEA supplements has been approved by the FDA for the treatment of obesity and shows prospective effects ( Brown et al, 2018a ). This is contrary to some previous studies revealing the side effects of OEA, indicating the requirement for more detailed studies ( Nielsen et al, 2004 ; Brown et al, 2018b ). These regulations in general help with the maintenance of a proper level of PPAR-α in the intestine and the homeostasis under its regulation.…”

Intestinal NAPE-PLD contributes to short-term regulation of food intake via gut-to-brain axis

“…In detail, OEA activates GPR119 receptor expressed on the L cells and triggers GLP-1 release (4,27,32). In addition, recent evidence suggests that GLP-1(7-36) amide (i.e., active GLP-1) interacts with OEA, creating a complex with increased potency to activate GLP-1R (2,3). Importantly, among the different NAEs tested, OEA is the only one having this activity (3).…”

“…To explore this, we used exendin-4 (Ex-4), an agonist of GLP-1R whose potency is unaltered by OEA (2,3). After an overnight fast, we injected WT and Napepld DIEC mice with exendin-4 and precisely monitored HFD consumption over time by using metabolic cages.…”

SGLT2i and GLP-1RA in Cardiometabolic and Renal Diseases: From Glycemic Control to Adipose Tissue Inflammation and Senescence

“…The mechanism responsible for these effects seems to be associated with the ease with which GLP-1RA can penetrate the blood-brain barrier and with the presence of GLP-1R in certain areas of the brain (highlighting the insula, the amygdala, the putamen, and the orbitofrontal cortex) that are involved in appetite control and ingestion of foods [ 116 , 117 ] and that are more active in obese subjects [ 118 ]. In this sense, studies have shown that the binding of GLP-1RA to GLP-1R in these areas of the brain, along with its subsequent activation, seems to be involved in the suppression of certain metabolic pathways, including brain glycolysis, signaling of protein kinase A (PKA), AMP-activated protein kinase (AMPK), protein kinase B (PKB), and the mechanistic Target of Rapamycin (mTOR), promoting a reduction in caloric intake, which results in weight loss [ 119 ].…”

“…Journal of Diabetes Research its subsequent activation, seems to be involved in the suppression of certain metabolic pathways, including brain glycolysis, signaling of protein kinase A (PKA), AMP-activated protein kinase (AMPK), protein kinase B (PKB), and the mechanistic Target of Rapamycin (mTOR), promoting a reduction in caloric intake, which results in weight loss [119].…”