Glucagon-like-peptide-1 (GLP-1) agonists are front-line medications for the management of obesity. Whilst GLP-1 agonism modestly reduces body weight (6.4% after 56 weeks treatment)1 in overweight patients (>27-30 BMI), these effects weaken in obese patients (30-35 BMI) and are negligible in morbidly-obese patients (>40 BMI). The clinical inefficacy of GLP-1 agonists in the most needed patients limits their therapeutic significance for obesity treatment.
Why GLP-1 agonists demonstrate limited efficacy in obese cohorts is unknown. We hypothesise that cellular GLP-1 resistance develops at the level of the GLP-1 receptor in obesity limiting its action and signalling. We demonstrate that GLP-1 agonists signal directly to cells within the arcuate hypothalamic nucleus (ARC) through a selective mitogen-activated protein kinase signalling cascade. This occurs in a heterogenous ARC population of both canonical (neuropeptide-Y neurons (42%), pro-opiomelanocortin neurons (6.57%), tanycytes (23.38%)) and non-canonical cells (28.05%). Remarkably, GLP-1 receptor signalling is strikingly attenuated in the ARC of diet-induced-obese mice, demonstrating ARC GLP-1 resistance.
To explore the mechanisms underlying GLP-1 resistance we posited that impaired extravasation of circulating GLP-1 agonists into the ARC parenchyma may account for the attenuated signalling in obesity. To explore this we peripherally administered a fluorescently tagged GLP-1 agonist and observed a marked attenuation of its appearance within the ARC of obese compared to lean mice. To define what was gating entry into the ARC, we examined the role of the chondroitin-sulphate-proteoglycan extracellular matrix, as it is known to become augmented in obesity and sequester the extravasation of metabolic hormones. Enzymatic digestion of the chondroitin-sulphate-proteoglycan extracellular matrix within the ARC reinstated GLP-1 agonist extravasation and ARC signalling to promote remission of metabolic disease. Our findings pioneer both the concept and mechanism underlying central GLP-1 resistance and identify a novel therapeutic approach capable of enhancing the actions of GLP-1 agonists for the treatment of obesity.