Differential effects of lung inflammation on insulin resistance in humans and mice

Abstract

Background:The rates of obesity, its associated diseases, and allergies are raising at alarming rates in most countries. House dust mites (HDM) are highly allergenic and exposure often associates with an urban sedentary indoor lifestyle, also resulting in obesity. The aim of this study was to investigate the epidemiological association and physiological impact of lung inflammation on obesity and glucose homeostasis.Methods: Epidemiological data from 2207 adults of the population-based KORA FF4 cohort were used to test associations between asthma and rhinitis with metrics of body weight and insulin sensitivity. To obtain functional insights, C57BL/6J mice were Funding informationThe KORA study was initiated and financed by the Helmholtz Zentrum München-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Mouse studies were supported by the HMGU Allergy Projects from the Helmholtz Center Munich.intranasally sensitized and challenged with HDM and simultaneously fed with either low-fat or high-fat diet for 12 weeks followed by a detailed metabolic and biochemical phenotyping of the lung, liver, and adipose tissues. Results:We found a direct association of asthma with insulin resistance but not body weight in humans. In mice, co-development of obesity and HDM-induced lung inflammation attenuated inflammation in lung and perigonadal fat, with little impact on body weight, but small shifts in the composition of gut microbiota. Exposure to HDM improved glucose tolerance, reduced hepatosteatosis, and increased energy expenditure and basal metabolic rate. These effects associate with increased activity of thermogenic adipose tissues independent of uncoupling protein 1.Conclusions: Asthma associates with insulin resistance in humans, but HDM challenge results in opposing effects on glucose homeostasis in mice due to increased energy expenditure, reduced adipose inflammation, and hepatosteatosis.

Insulin Resistance in Multiple Organs and Systems

“…In ammation can lead to the release of cytokines and other in ammatory molecules that interfere with insulin signaling pathways and promote resistance. 43 Another potential factor contributing to pulmonary IR would be oxidative stress. Increased production of reactive oxygen species can disrupt insulin signaling and impair lung function.…”

Protease-activated receptor-2: Role in asthma pathogenesis and utility as a biomarker of disease severity

“…Bronchial smooth muscle cells from asthmatic individuals maintain higher PAR 2 mRNA and protein expression than cells from normal individuals after ex vivo culture (86), suggesting the possibility that epigenetic changes due to the chronic inflammation in the airways may affect PAR 2 expression. We recently showed that insulin regulates PAR 2 expression in primary human airway epithelial cells through the FOXO1 transcription factor (87), which may indicate that insulin resistance, often associated with asthma (88,89), may be associated with alterations of PAR 2 expression. Finally, genetic factors regulating PAR 2 expression cannot be excluded as PAR 2 SNPs have been shown to increase mRNA stability and increase expression of PAR 2 in PBMCs (90) and synovial tissue (91).…”

Anti‐inflammatory effects of reticuline on the JAK2/STAT3/SOCS3 and p38 MAPK/NF‐κB signaling pathway in a mouse model of obesity‐associated asthma

“…22 The simultaneous exposure to low-fat (LFD) or high-fat diet (HFD) feeding and HDM extract have been widely used to establish the in vivo models of obesity-related asthma. [23][24][25] In this study, we investigated whether the effects of reticuline on obesity-related asthma in HFD and HDM-induced mouse models are mediated by the JAK/STAT signaling. We believe that this study would provide a theoretical basis for initiating novel promising therapeutic options for obese asthma.…”

“…House dust mites (HDM) are highly allergenic and exposure often associates with an urban sedentary indoor lifestyle, also resulting in obesity 22 . The simultaneous exposure to low‐fat (LFD) or high‐fat diet (HFD) feeding and HDM extract have been widely used to establish the in vivo models of obesity‐related asthma 23–25 . In this study, we investigated whether the effects of reticuline on obesity‐related asthma in HFD and HDM‐induced mouse models are mediated by the JAK/STAT signaling.…”