Targeting leptin may ease some Rett-like symptoms, mouse study finds
Benefits were seen in breathing, weight, and brain signaling measures
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Blocking the signaling of leptin — a hormone involved in appetite regulation, motor function, and behavior — eased some Rett syndrome-like symptoms in a mouse model of the disease, a study found.
Data showed that reducing leptin signaling either pharmacologically or genetically in male mice with Rett-like symptoms helped preserve aspects of overall health, prevented weight loss, and improved breathing and locomotor activity, but not motor coordination. It also restored measures of brain signaling balance.
Leptin may help drive Rett-like symptoms in mice
“These findings uncover leptin as a key contributor to [Rett mechanisms] and position leptin-targeted interventions as a promising therapeutic strategy for this currently untreatable disorder,” the researchers wrote.
The study, “Leptin antagonism improves Rett syndrome phenotype in symptomatic Mecp2-deficient mice,” was published in Neurotherapeutics.
Rett syndrome is usually caused by mutations in the MECP2 gene that disrupt the function of MeCP2, a protein that regulates the activity of several genes and helps support brain cell health. These mutations disrupt normal brain development and function, ultimately leading to disease symptoms.
The disease mainly affects females because the MECP2 gene is on the X chromosome and females have two copies, meaning they can inherit one X chromosome with a mutated gene copy and the other with a healthy copy. Males have only one X chromosome, so if the MECP2 gene is mutated, it cannot be compensated for by a healthy one, which often makes the disease much more severe in males.
Higher levels of leptin, a hormone that regulates several biological functions, including appetite, cognitive function, motor activity, and behavior, have been observed in people with Rett and mouse models of the disease. However, “their contribution to disease progression has remained unclear,” the researchers wrote.
Study examined effects of lowering leptin signaling
To learn more, researchers performed a series of experiments in a mouse model of Rett syndrome.
They found that male mice lacking a functional copy of the MECP2 gene had significantly higher leptin levels compared with healthy, or wild-type, mice.
MECP2-deficient male mice had progressively worsening breathing difficulties, accompanied by weight loss, changes in appearance and posture, reduced motor activity and coordination compared with wild-type mice. They also displayed behaviors consistent with lower anxiety.
Pharmacologically reducing leptin signaling with a 10-day anti-leptin treatment prevented the progression of breathing problems and weight loss, and improved some measures of the animals’ overall health and motor activity. However, it had no effects on motor coordination or anxiety-related behavior.
At the nerve cell level, MECP2-deficient mice had increased excitability and reduced synaptic plasticity — the brain’s ability to strengthen or weaken the connections between neurons — compared with wild-type mice. Anti-leptin treatment restored the excitatory/inhibitory balance and rescued synaptic plasticity.
Genetic approach also lowered leptin and delayed symptoms
Similar results were observed in MECP2-deficient mice that had been genetically modified to carry only one working copy of the ob gene, which encodes leptin, effectively lowering the amount of leptin they could produce.
Researchers also studied female mice with one functional copy of the MECP2 gene and one functional copy of the ob gene, which reduced leptin production. In these mice, leptin levels were normalized only at early stages, when some Rett syndrome-like symptoms and brain signaling changes were delayed or improved.
“Our data indicate that treatment with the leptin antagonist during the symptomatic period delays the progression of certain symptoms,” and that “modulation of leptin signaling may represent a strategy to improve functional outcomes and quality-of-life,” the researchers wrote.
“More broadly, our findings suggest that leptin-targeting approaches could be integrated into combination therapies aimed at addressing multiple [disease-causing] mechanisms simultaneously, which may ultimately be required to impact survival,” they added.
