Lupus Seen to Be Triggered in Mice by Leptin, a Hormone Often Elevated in Patients

Lupus Seen to Be Triggered in Mice by Leptin, a Hormone Often Elevated in Patients

Leptin, a hormone produced by fat cells in the body, was seen to actively promote systemic lupus erythematosus (SLE) in mouse models of the disease, allowing the formation of autoantibodies and changing the activities of immune cells.

Patients with lupus have increased levels of leptin, but until now researchers did not know if the hormone was a consequence of the disease or could, in fact, be contributing to its development.

The study, “Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation,” published in the journal Proceedings of the National Academy of Sciences (PNAS), demonstrated that mice without leptin did not develop lupus — a crucial finding that may allow the development of new treatment approaches for the condition.

Researchers at the University of California, Los Angeles, investigated the role of leptin in lupus in several different ways. Using an engineered mouse that is unable to produce the hormone, they first treated this model with a chemical known to trigger lupus in mice. They then gave the same chemical to normal mice, and compared the results.

Normal mice soon started producing increased amounts of leptin and multiple autoantibodies known to be involved in lupus. But mice unable to produce the hormone did not; researchers could detect no autoantibodies. Normal mice also developed lupus kidney disease, which again was not seen in the leptin-deficient mice.

Researchers next examined how the presence of leptin affected mice that spontaneously develop lupus. In this mouse strain, lupus levels increase with age — but when researchers treated young mice with the hormone, the mice developed lupus sooner. Blocking leptin production in these mice, whose lupus had been allowed to advance until they developed kidney disease, was seen to slow further disease progression.

The team also explored how leptin affected immune cells in the mice, and found that the hormone changes the composition of certain immune T-cells. A lack of leptin lowered the numbers of T-cells not carrying the surface markers CD4 and CD8 — known to promote lupus — and instead promoted the formation of so-called regulatory T-cells, or Tregs. Tregs are a crucial part of the immune system, working to resolve inflammatory reactions. Researchers also noted that increased levels of leptin made inflammatory T-cell responses more effective, and increased the reactivity of the cells toward the body.

“The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease,” the team concluded.

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