The NLRP3 inhibitor NT‐0796 enhances and sustains GLP‐1R agonist‐mediated weight loss in a murine diet‐induced obesity model

Abstract Objective 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. Methods Mice fed a standard high‐fat or a polyunsaturated fatty acid diet served as models of DIO and were dosed with low‐dose semaglutide, NT‐0796, or combinations. Body weight, food intake, peripheral inflammatory markers, and hypothalamic glial fibrillary acidic protein expression were assessed. Results Combined dosing of NT‐0796 with semaglutide drove greater weight loss than either monotherapy alone, and this effect was enhanced in mice consuming the polyunsaturated fatty acid diet. In addition, NT‐0796 sharply limited weight regain following cessation of semaglutide therapy and normalized markers of both peripheral inflammation and hypothalamic astrogliosis to a far greater extent than either semaglutide or calorie restriction. Conclusions Alleviation of obesity‐associated inflammation via NLRP3 inhibition 1) constitutes an effective weight‐loss strategy as monotherapy in mice with DIO, 2) augments the weight‐loss efficacy of a subtherapeutic dose of semaglutide, and 3) blocks recovery of lost weight following cessation of semaglutide. image