Leptin Reduction as a Potent Mitigative Strategy for the Treatment of PASC

Summary/Abstract While many individuals infected with SARS-CoV2 have mild symptoms and may even be asymptomatic, some patients experience fulminant pathology that can cause severe sequelae or even death. For others, the effects of the acute response to the infection linger for many months ("Long-COVID"). The infection has the potential to exasperate pre-existing conditions, in particular those related to metabolic disease. Several lines of evidence suggest the potential for intervention to limit prolonged COVID-19 severity: 1) Infections are most problematic in individuals with high risk metabolic syndrome; 2) The severity of the infection is associated with parameters that are related to insulin resistance, including inflammation, elevated glucose levels with severe insulin resistance, and increased liver damage. Hyperleptinemia and diabetes are common among the obese population, and it has long been known that leptin plays an important role in regulating the immune system as well as metabolism. We have taken an intense interest in the connection of obesity/diabetes and enhanced disease severity/outcome over the past two years. Here, we aim to directly test the hypothesis that reducing plasma leptin levels or increasing MSH levels has a positive impact on the immune system and fibrosis. We will address these questions at the cellular, tissue and systemic level. Specifically, we want to: 1: Determine the role of -MSH towards leptin-POMC signaling in mediating immune responses in the context of Long- COVID centrally. 2: Determine whether leptin neutralization has an impact on lung fibrosis in the bleomycin fibrosis model. 3: Determine whether leptin neutralization has an impact on inflammation peripherally. 4: Determine the impact of leptin neutralization and leptin-lowering thiazolidinediones on Long-Covid. Combined, these studies will test the effect of leptin neutralization, -MSH and PPAR activation on disease outcome in long COVID. Both Scherer and Elmquist have track records in metabolism and have teamed up with Jyothi Nagajyothi, an established infectious disease specialist and are further supported by Deep Dixit at Yale and Jerry Colca from Cirius Inc. As a team between the three core laboratories, we believe we have unique expertise and tools in hand to assess the effectiveness of these interventions, including the increased subclinical inflammation, persistent fibrosis and deteriorated insulin sensitivity that persists during Long-COVID. Our preliminary data strongly support the premise of leptin involvement in the disease progression with leptin neutralizing antibodies reducing the viral load in a rodent COVID-19 model by 85% and effectively reconstituting at least partially adiponectin levels in the lung. Lipoblasts in the lung express adiponectin, but lose it as they convert to fibrosis generating myofibroblasts. Leptin reduction through the use of neutralizing anti-leptin antibodies seems to preserve lipoblast function. We believe this constitutes one of the most tangible and immediately translatable interventions in the context of Long-COVID.