Dual Therapy with GLP-1 Agonists and T Cell Modulation Outperforms GLP-1 Alone in Obesity Treatment 4792

Abstract Description The global obesity epidemic has intensified metabolic disorders like insulin resistance (IR), type 2 diabetes (T2D), and metabolic dysfunction-associated fatty liver disease (MAFLD), which can progress to steatohepatitis (MASH) and cirrhosis. Chronic systemic inflammation is central to these pathologies. While GLP-1 receptor agonists (GLP1-RAs), such as Semaglutide, offer significant weight loss and glycemic control, their effects are reversible upon discontinuation and do not target inflammation or fibrosis in adipose tissue and the liver. Our study introduces nasal anti-CD3 as a novel immunomodulatory strategy to complement GLP1-RAs. In diet-induced obese (DIO) mice, nasal anti-CD3 reduces systemic inflammation, improves glucose metabolism, and restores tissue homeostasis without affecting weight or energy expenditure. Unlike oral anti-CD3, nasal delivery localizes in cervical lymph nodes, reprograms T-cell metabolism, and expands regulatory T cells (Tregs), reducing pro-inflammatory immune cells in adipose tissue and the liver. In MASH, nasal anti-CD3 reduces liver inflammation, reverses fibrosis, and enhances metabolic homeostasis. Combined with Semaglutide, it amplifies GLP1-RA benefits at lower doses, improving tissue remodeling, lipid metabolism, and systemic glucose control. These findings position nasal anti-CD3 as a potent adjunct to GLP1-RAs, addressing inflammation and fibrosis while enhancing metabolic outcomes. Funding Sources Ann Romney Center for Neurologic Diseases Topic Categories Vaccines and Immunotherapy (VAC)