Leptin signaling maintains autonomic stability during severe influenza infection

ABSTRACT: Leptin is a pleiotropic hormone that is released by adipocytes and tightly controls energy balance by regulating a range of physiological processes. While leptin is best known for signaling through the hypothalamic arcuate nucleus to regulate feeding, it also supports the immune system by binding its cognate receptor Ob-R to activate various immunocyte populations. Indeed, patients with congenital leptin or leptin receptor deficiency not only display severe obesity but also exhibit increased mortality from infections. Leptin supplementation to leptin deficient mice and humans increases CD4+ cell numbers and augments proinflammatory Th1 responses ex vivo. However, whether this leptin-induced immune response is necessary for viral clearance in vivo is unknown. To better delineate the role of leptin in infection, we inoculated leptin deficient ob/ob mice with influenza and acutely supplemented leptin in physiologically relevant doses prior to infection. Although ob/ob mice and diet-induced obese (DIO) mice have comparable levels of insulin resistance and adiposity, a sublethal dose of influenza virus in DIO mice causes mortality in approximately 80% of ob/ob mice, which was completely reversed by leptin supplementation. Serum cytokine profiling and whole tissue RNA sequencing of spleen, lung, and visceral adipose tissue demonstrated increased inflammatory and anti-viral responses in leptin-supplemented mice and no signs of excessive immunopathology in either group. Further flow cytometric analysis indicated an elevated Th1 immune response locally and systemically in leptin-supplemented mice, along with a two-fold increase in spleen sizes and an expansion in the proportion of splenic B cells. Despite augmented anti-viral responses in leptin-supplemented mice, leptin deficient ob/ob mice were equally capable of clearing the virus. Moreover, pulse oximetry showed diminished oxygen saturation in both groups, a finding further corroborated by similar levels of histopathologic lung damage. Interestingly, leptin-supplementation in ob/ob mice prevented profound hypothermia and bradycardia, which occurred prior to death in control ob/ob mice. Taken together, we provide evidence that leptin is dispensable for immunologic control of viral infection and may instead confer a survival benefit by maintaining autonomic stability. These findings open new avenues for research on the role of leptin signaling in infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE274568 | GEO | 2024/12/30

REPOSITORIES: GEO