The Role of Autoantibodies Against G-protein Coupled Receptors in Obesity

The present study aims to investigate the role of GLP1-R autoantibodies in a large, deeply phenotyped obesity cohort. In an unblinded exploratory analysis, GLP1-R, GIP-R and ghrelin-R autoantibody levels will be measured using proprietary assay. The central hypothesis is that the presence and concentration of these autoantibodies is positively associated with the degree of obesity. Secondary we hypothesize that the presence and concentration of GLP1-R or GIP-R autoantibodies are associated with the presence of insulin resistance and prediabetes. As an exploratory approach we hypothesize that the presence and concentration of GLP1-R, GIP-R or ghrelin-R autoantibodies is associated with eating behavior as assessed by the validated questionnaire Adult Eating Behavior Questionnaire.

At present, it is unknown whether these autoantibodies exert an inhibitory, neutral, or agonistic effect on GLP1R, GIP-R or ghrelin-R signaling. Furthermore, it remains unclear whether individuals with obesity and diabetes-conditions associated with impaired GLP-1 signaling-exhibit a higher prevalence of GLP1R autoantibodies, or whether these autoantibodies differ functionally between diabetic and non-diabetic individuals. Addressing these questions may help explain interindividual variability in weight loss responses and uncover a novel immuno-endocrine mechanism relevant to obesity and metabolic disease.

The project will take advantage of the South Danish Obesity Initiative (SDOI) cohort. This is an ongoing clinical initiative offering screening of a broad panel of obesity related diseases to individuals with BMI above 30 kg/m² and age between 18 and 60 years. People are referred from their general practitioners or from hospital departments and undergo screening for diabetes, dyslipidemia, obstructive sleep apnea, metabolic-associated steatohepatitis and hypertension. In addition, the participants answer questionnaires including the Adult Eating Behavior Questionnaire. A Danish translation of this questionnaire has been validated, and the questionnaire allows evaluation of eating habits (Kolin M.E.I. et al, 2025. DOI:10.3390/nu17243824). A cohort of people with BMI 18.5 to 30 kg/m² has been assessed with an identical screening program with the purpose of serving as a control group. Only participants who gave informed consent to use their data for research purposes are included in this study. The SDOI screening protocol and initial results have previously been published (Juhl C.B. et al 2024. DOI:10.2147/DMSO.S456028).

In the present study we will include 160 participants from the SDOI cohort, of which 120 will be individuals living with obesity. Where 40 participants will have a BMI above 50 kg/m², 40 will have a BMI 40-50 kg/m², 40 will have a BMI 30-40 kg/m². The remaining 40 participants will be from the control cohort (BMI 18.5 to 25 kg/m²). The groups will be matched on sex and age (within 2 years). Individuals with type 1 diabetes and individuals treated with GLP-1RAs for any indication and individuals who have previously undergone bariatric surgery will not be included in the trial.

• Exploring the association between GPCR-autoantibodies and obesity related diseases [Time frame: At the time of enrolment]