Global glucagon-like peptide-2 receptor activation linked to increased obesity risk in the UK Biobank

The glucagon-like peptide-2 receptor (GLP-2R) is recognized as a potential target for the treatment of obesity and type 2 diabetes (T2D). Yet, the impact and mechanism of GLP-2R activation on these metabolic traits remain unclear in humans.

We conducted in vitro pharmacological characterization of 30 naturally occurring GLP-2R missense variants identified from the UK Biobank, assessing receptor activity via cyclic adenosine monophosphate (cAMP) production and β-arrestin 2 recruitment. To study the effect of GLP-2R activation on metabolic traits, we categorized variants into functional groups based on their signaling profiles and performed genetic association tests in ∼500,000 UK Biobank participants.

We experimentally identified variants with both increased and decreased effects on receptor signaling and computationally identified an additional 34 predicted Loss-of-Function (pLoF) variants. Notably, the most frequent GLP-2R variant, D470N, with an allele frequency of 32% in the UK population, displayed increased cAMP production. Mechanistically, the increased cAMP production of D470N is likely linked to reduced β-arrestin recruitment and reduced internalization. Genetic associations showed that D470N was linked to increased risk of obesity, T2D, and higher Body Mass Index (BMI), body fat, glycated hemoglobin (HbA1c), and diastolic/systolic blood pressure. In contrast, Loss-of-Function (LoF) variants were associated with a decreased risk of obesity and reduced body fat percentage.

Our findings suggest that global GLP-2R activation, encompassing the effects across all tissues, is associated with increased risk of obesity. This study highlights the role of the GLP-2R in metabolic diseases, guiding the future development of biased GLP-2R ligands and the potential adverse effects of GLP-2R modulation.