In order to investigate whether a central nervous system penetrant anti‐inflammatory could augment or sustain obesity treatment with semaglutide (Wegovy), a glucagon‐like peptide‐1 receptor (GLP‐1R) agonist, we tested two hypotheses in models of diet‐induced obesity (DIO): 1) a centrally penetrant NLPR3 inhibitor, NT‐0796, drives enhanced weight loss when combined with low‐dose semaglutide, compared to monotherapy; and 2) NT‐0796 monotherapy sustains weight loss induced by semaglutide. The gene discussed is GLP1R; the disease is obesity due to melanocortin 4 receptor deficiency.