Leptin Accelerates Autoimmune Disease Progression in an Experimental Model of Systemic Lupus Erythematosus
Authors: Taylor Erin , Bruno Christian , Ryan Michael 
Published: June 2021

Systemic lupus erythematosus (SLE) is a prototypic multisystem autoimmune disorder that is characterized by a loss of immunological tolerance and the expansion of autoreactive T and B lymphocytes, leading to the production of autoantibodies. The autoantibody production leads to downstream chronic inflammation resulting in high rates of hypertension, renal injury, and cardiovascular disease in patients with SLE. The immunomodulatory adipocytokine leptin plays a key role in the maintenance and development of inflammation, in part by promoting the expansion of proinflammatory helper T cells and inhibiting the differentiation of regulatory T cells (TREG). Circulating levels of leptin are elevated in patients with SLE, but it is unclear whether leptin plays a direct role in the pathogenesis of SLE. In the present study, we hypothesized that administration of leptin will accelerate the progression of disease in a female mouse model of SLE. To test this hypothesis, 30 week old female SLE (NZBWF1, n=10) and control (NZW, n=14) mice were implanted with microosmotic pumps to continuously deliver recombinant mouse leptin at a rate of 0.5 mg/kg/day or vehicle (0.9% NaCl) for four weeks. Plasma leptin levels, as measured by ELISA, were significantly increased in both control (10.6±1.6 ng/mL Control‐vehicle vs. 29.5±5.4 ng/mL Control‐leptin, p<0.01) and SLE mice who received leptin (21.0±6.4 ng/mL SLE‐vehicle vs. 50.3±17.5 ng/mL SLE‐leptin, p<0.05). Leptin administration significantly decreased food intake in SLE mice (4.0±0.15 g/day SLE‐vehicle vs. 3.2±0.10 g/day SLE‐leptin, p<0.05), but did not alter food intake in control mice (3.7±0.16 g/day Control‐vehicle vs. 3.3±0.25 g/day Control‐leptin, p=0.33). Body composition was assessed using Echo MRI and fat mass, as a percentage of body weight, was not changed in control mice (19.8±1.3% Control‐vehicle vs. 20.8±1.6% Control‐leptin p=0.99), but was significantly lower in SLE‐leptin treated mice (24.7±2.4% SLE‐vehicle vs. 12.2±4.8% SLE‐leptin, p<0.05). Circulating levels of anti‐dsDNA autoantibodies, a marker of SLE disease activity, were higher in SLE mice compared to controls (0.56±0.16 Control‐vehicle vs. 0.98±0.16 SLE‐vehicle OD450, p<0.05), and these levels were further increased in leptin infused SLE mice compared to vehicle‐infused controls (0.98±0.16 SLE‐vehicle vs. 1.3±0.12 SLE‐leptin OD450, p<0.05). Circulating CD4+FoxP3+ TREG, as assessed by flow cytometry, were lower in SLE mice than in control mice (2.88±0.44% Control‐vehicle vs. 1.44±0.16% SLE‐vehicle, p<0.05), as previously reported by our laboratory. Leptin administration decreased the levels of circulating TREG in both control and SLE animals. Leptin infusion also increased the prevalence of mice with albuminuria (60% of SLE mice administered leptin vs. 25% of vehicle‐treated mice), as measured by dipstick assay. Taken together, these data suggest that SLE mice may have enhanced sensitivity to leptin and that increased leptin levels exacerbate disease activity. In addition, therapeutics aimed at modulating leptin activity could have potential benefit for patients with SLE.Support or Funding InformationResearch supported by: VA merit award # I01BX002604‐01A2 to MJR and NHLBI F32HL137393 to EBT.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.