Systemic Lupus Erythematosus (SLE) is a chronic multisystem autoimmune disorder characterized by profound immune dysregulation, metabolic dysfunction, and a high risk for hypertension, renal injury, and cardiovascular disease, with traditional immunosuppressive therapy unable to fully address this issue. In recent years, GLP-1/GIP-1 receptor agonists, drugs widely used in type 2 diabetes and obesity, have gained attention not just for their metabolic benefits, but also for their anti-inflammatory, heart-protective, and kidney-protective effects. Given the importance of metabolic-immune interactions in lupus pathogenesis, the present study tested the hypothesis that tirzepatide improves metabolic dysfunction and attenuates early markers of cardiovascular and renal injury in the lupus-prone NZBWF1 mouse. Beginning at 24 weeks of age, control (NZW=9) and SLE (NZBWF1, n=10) mice were randomized to receive vehicle or tirzepatide (Tz; 30 nmol/kg) for eight weeks (n=4-5/group). Body composition was assessed using EchoMRI, and plasma leptin concentrations were measured via ELISA. Glucose tolerance was evaluated by oral glucose tolerance test (OGTT). Pulse wave velocity (PWV) was used to estimate vascular stiffness, and albuminuria incidence was monitored by urine dipstick analysis. Tirzepatide significantly reduced body weight in both control and SLE mice (ptreat>0.0016) and markedly decreased fat mass compared to vehicle-treated groups (SLE-veh: 6.8± 0.8 g vs SLE-Tz: 3.6± 0.8 g). Lean mass was preserved despite reductions in total body mass in SLE animals (SLE-veh: 28.1±0.6 g vs SLE-tz: 27.6±0.8 g). Over the course of the study, tirzepatide produced a modest delay in albuminuria onset compared to SLE-vehicle mice. At the conclusion of the study, plasma leptin levels, as determined via an enzyme-linked immunosorbent assay (ELISA), was significantly lower in Tz-treated mice across strains (ptreat< 0.0016), especially in SLE treated vs untreated (SLE-veh: 7.0± 0.9 ng/mL vs. SLE-tz: 3.1 ± 0.7 ng/mL), indicating a substantial reduction in systemic metabolic stress driven by excess adiposity. Moreover, OGTT revealed improved glucose tolerance in Tz-treated SLE mice compared to vehicle. PWV, as measured by doppler flow velocity system, did not differ between groups. Furthermore, there were no adverse effects observed with tirzepatide treatment. Taken together, these data demonstrate that tirzepatide improves metabolic dysfunction, lowers plasma leptin, enhances glucose tolerance, and may delay progression of renal injury in the NZBWF1 mouse. These findings provide the first experimental evidence supporting the potential of GLP-1/GIP receptor agonism as a metabolic-immunomodulatory therapeutic strategy in SLE. Ongoing studies will determine the effects of tirzepatide on adipose, renal, and circulating immune cell populations to further define its mechanistic role in autoimmune disease. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Hart et al. (Fri,) studied this question.
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