Cardiovascular effects of chronic GIPR and GLP-1R agonism in lean and diet-induced obese mice: sex differences and dose-dependent remodeling.

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate metabolism and are increasingly targeted in therapies for type 2 diabetes and obesity. Although GLP-1 receptor agonists confer cardiovascular benefits, the cardiovascular effects of GIP receptor (GIPR) stimulation remain controversial. This study aimed at defining the short-term cardiovascular consequences of GIPR and GLP-1 receptor (GLP-1R) agonism in lean and diet-induced obese mice, with emphasis on sex-specific cardiac remodeling patterns. Male and female mice received continuous infusion of a GIPR or GLP-1R agonist for 1 mo at 0.1, 0.4, 0.8, and 1.0 mg/kg/day under chow feeding or an effective dose of 0.8 mg/kg/day after 2 mo of high-fat diet (HFD)-induced obesity. Cardiovascular phenotyping included tail-cuff blood pressure, cardiac magnetic resonance imaging, metabolic testing, and assessment of plasma biomarkers of cardiac stress (ST2 or NT-proBNP). In lean mice, GIPR agonism dose-dependently increased end-diastolic volume, whereas GLP-1R agonism increased end-diastolic left-ventricular (LV) mass in male mice, resulting in divergent remodeling patterns without affecting systolic function. These structural changes occurred without alterations in ST2 or NT-proBNP, suggesting remodeling in the absence of overt myocardial stress. In obese mice, both agonists lowered mean arterial pressure and improved systolic function. GIPR agonism primarily increased LV volume in males, whereas GLP-1R agonism increased LV mass in females. Although ST2 levels were largely driven by HFD, NT-proBNP was reduced by both treatments, consistent with improved cardiac loading conditions. In conclusion, short-term incretin receptor agonism induces distinct, context-dependent cardiovascular remodeling patterns that depended on receptor specificity, metabolic state, and sex. Although both GIPR and GLP-1R agonists exerted beneficial hemodynamic and functional effects in obesity, GIPR stimulation in lean mice increased ventricular volume and GLP-1R stimulation increases mass without overt functional deterioration. These findings demonstrate distinct cardiac actions of incretin pathways and highlight the importance of metabolic context in their therapeutic effects.NEW & NOTEWORTHY Incretin-based therapies are reshaping metabolic disease care, yet the chronic cardiac effects of GIPR agonism remain uncertain. Using comprehensive cardiovascular phenotyping in lean and obese mice, we show that GIPR and GLP-1R agonists drive distinct, sex-dependent patterns of cardiac remodeling despite similarly improving hemodynamics in obesity. GIPR agonism primarily increased LV volume, whereas GLP-1R agonism increased LV mass. These receptor-specific adaptations clarify divergent cardiac responses to incretin therapies and inform evaluation of emerging dual-agonist treatments.