Hyperleptinemia is associated with impaired pulmonary host defense

Abstract

We have previously reported that obesity attenuates pulmonary inflammation in both patients with acute respiratory distress syndrome (ARDS) and in mouse models of the disease. We hypothesized that obesity-associated hyperleptinemia, and not body mass per se, drives attenuation of the pulmonary inflammatory response and that this e_ect could also impair the host response to pneumonia. We examined the correlation between circulating leptin levels and risk, severity, and outcome of pneumonia in 2 patient cohorts (NHANES III and ARDSNet-ALVEOLI) and in mouse models of diet-induced obesity and lean hyperleptinemia. Plasma leptin levels in ambulatory subjects (NHANES) correlated positively with annual risk of respiratory infection independent of BMI. In patients with severe pneumonia resulting in ARDS (ARDSNet-ALVEOLI), plasma leptin levels were found to correlate positively with subsequent mortality. In obese mice with pneumonia, plasma leptin levels were associated with pneumonia severity, and in obese mice with sterile lung injury, leptin levels were inversely related to bronchoalveolar lavage neutrophilia, as well as to plasma IL-6 and G-CSF levels. These results were recapitulated in lean mice with experimentally induced hyperleptinemia. Our findings suggest that the association between obesity and elevated risk of pulmonary infection may be driven by hyperleptinemia.

Mouse Modeling of Obese Lung Disease. Insights and Caveats

“…We must consider the possibility that obesity may alter ARDS pathogenesis by "priming" the lung for inflammatory insult and amplifying the early inflammatory response (thus lowering the threshold to initiate ARDS), while at the same time accelerating a subsequent transition to the recovery phase. How obesity may change the "inflammatory twitch" of the lung (35) is only beginning to be understood, but on the basis of recent mouse modeling, this appears to include both baseline pulmonary vascular "priming" (34) and neutrophil functional impairment (28,36,37), as well as other effects of elements of the metabolic syndrome, including hyperglycemia (29,36), dyslipidemia (28,36,37), hypoadiponectinemia (34,38), and hyperleptinemia (39). For example, recent studies by Shah and colleagues (34), examining several mouse strains that vary in their susceptibility to diabetes in a dietinduced obesity (DIO) model, have highlighted the complex interplay between glucose intolerance and lung injury.…”

“…However, the adaptive immune response after both influenza infection and vaccination appears to be impaired in obese mice (47,49), suggesting that a complex immune defect underlies obesity's effects on influenza pathogenesis. In addition, using several strains of mutant mice, the roles of leptin signaling and its impairment have been implicated in obesity-associated alterations in the response to both bacterial and viral pneumonia (39,(50)(51)(52), as have diabetes and dyslipidemia (36,37,53), although these associations have yet to be demonstrated clearly in human pneumonia risk and severity. Variable expression of the metabolic syndrome in the mouse models studied is likely to contribute to the current lack of consensus on obesity's effects, as demonstrated elsewhere in this issue (36) in a comparative study of Klebsiella pneumoniae pneumonia in DIO, db/db, CPE fat/fat , and ob/ob mouse models, in which the timing and degree of bacterial containment failure differed significantly between models.…”

A clinical and biological framework on the role of visceral fat tissue and leptin in SARS-CoV-2 infection related respiratory failure

“…The clinical syndrome of critically ill patients with SARS-CoV-2 and respiratory failure is This report is the first to implicate a role of excessive adipose tissue and leptin production as a factor that may drive the development of respiratory failure and ARDS in SARS-CoV-2 infected patients. An association between obesity and an increased risk of pneumonia has already been identified and is amongst other factors hypothesized to be driven by hyperleptinemia 10,26 . The onset of respiratory failure usually takes around 8-12 days after the initial signs of infection.…”

Integrative Physiology of Pneumonia

“…Higher leptin levels associate with greater pneumonia risk in nonhospitalized adults, and with greater severity of pneumonia among hospitalized patients, independent of body mass (502). High circulating leptin content in mice, elevated by diverse strategies, can compromise innate immunity in the lungs (502). A specific role for leptin is further supported by the observation of no adverse effects on lung defense in a leptin-independent mouse model of obesity (307).…”

“…Conversely, excess leptin including hyperleptinemia, a hallmark of obesity, may increase risk of pneumonia (390). Higher leptin levels associate with greater pneumonia risk in nonhospitalized adults, and with greater severity of pneumonia among hospitalized patients, independent of body mass (502). High circulating leptin content in mice, elevated by diverse strategies, can compromise innate immunity in the lungs (502).…”