Central Glucagon-Like Peptide-1 Agonism Ameliorates Colonic Inflammation in a Murine Model of Inflammatory Bowel Disease
Year: 2026
Type: preprint
Abstract: ABSTRACT Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the treatment of obesity and type 2 diabetes (T2D). These drugs also have anti-inflammatory effects that have recently been extended to the treatment of inflammatory bowel disease (IBD). Whether the mechanism underlying this benefit involves a direct action on the intestine or instead is mediated via GLP-1Rs in the brain, however, is unknown. Based on evidence implicating the brain as the target for the anti-obesity and anti-inflammatory effects of GLP-1RAs, we sought to determine if central GLP-1R signaling is sufficient to explain its intestinal anti-inflammatory effects. To this end, we compared the efficacy of peripheral vs central administration of the GLP-1RA, semaglutide (SEMA), in diet-induced obese (DIO) mice with dextran sodium sulfate (DSS)-induced colitis. We report that compared to vehicle, both colitis severity and histopathological injury following DSS administration are reduced by peripheral administration of SEMA. We also report that this benefit is largely recapitulated by intracerebroventricular administration of SEMA at a low dose that, when administered peripherally, is below that needed to affect food intake and body weight. We conclude that in a mouse model of colitis, activation of GLP-1Rs in the brain is sufficient to explain the intestinal anti-inflammatory effect conferred by GLP-1R agonism.
Authors: Biren Desai, Kendra L. Francis, Caeley L. Bryan, Jessie Connolly, Thanushree Karunagaran, Sara Mathan, Karina Sharma, Vincent Damian, Christina A. Watts, Pique P. Choi, Kelly Kadlec, Bao Anh Phan, Maria C. Pacheco, Kimberly M. Alonge, Gregory J. Morton, Michael W. Schwartz, Jarrad M. Scarlett
Language: English
Topic: Inflammatory Bowel Disease
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Neurocircuits that regulate circadian rhythms, G1948980911, G2398048825, G2645273860, Novel Anti-Diabetic Actions of Hypothalamic FGF19-FGFR1 Signaling, G3736763701, G4310634654, G9000121482, G9000208812, Nutrition Obesity Research Center, Identifying and characterizing molecular and circuitry-based heterogeneity of AgRP neurons., Diabetes Research Center, Divergent Mechanisms Underlying Anorexic and Antidiabetic Actions of FGF1 in the Brain, Diabetes, Obesity and Metabolism Training Program
OpenAlex ID: W7223457251