José María Moreno-Navarrete1, Jèssica Latorre2, Aina Lluch2, Francisco J Ortega2, Ferran Comas2, María Arnoriaga-Rodríguez3, Wifredo Ricart3, José Manuel Fernández-Real4. 1. Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Institut d'Investigació Biomèdica de Girona (IdIBGi), Girona, Spain; CIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain. Electronic address: jmoreno@idibgi.org. 2. Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Institut d'Investigació Biomèdica de Girona (IdIBGi), Girona, Spain; CIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain. 3. Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Institut d'Investigació Biomèdica de Girona (IdIBGi), Girona, Spain; CIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain. 4. Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Institut d'Investigació Biomèdica de Girona (IdIBGi), Girona, Spain; CIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain. Electronic address: jmfreal@idibgi.org.
Abstract
BACKGROUND & AIMS: Several proteins of the innate immune system are known to be deregulated with insulin resistance. We here aimed to investigate the relationship among circulating lysozyme (both plasma concentration and activity) and obesity-associated metabolic disturbances. METHODS: Plasma lysozyme concentration was determined cross-sectionally in a discovery (Cohort 1, n = 137) and in a replication cohort (Cohort 2, n = 181), in which plasma lysozyme activity was also analyzed. Plasma lysozyme was also evaluated longitudinally in participants from the replication cohort (n = 93). Leukocyte lysozyme expression (LYZ mRNA) were also investigated in an independent cohort (Cohort 3, n = 76), and adipose tissue (AT) LYZ mRNA (n = 25) and plasma peptidoglycan levels (n = 61) in subcohorts from discovery cohort. RESULTS: Translocation of peptidoglycan (as inferred from its increased circulating levels) was linked to plasma lysozyme, hyperinsulinemia and dyslipidemia in obese subjects. In both discovery and replication cohorts, plasma lysozyme levels and activity were significantly increased in obesity in direct association with obesity-associated metabolic disturbances and inflammatory parameters, being circulating lysozyme negatively correlated with fasting glucose, HbA1c and insulin resistance (HOMA-IR) in obese subjects. Of note, total cholesterol (p < 0.0001) and LDL cholesterol (p = 0.003) contributed independently to age-, gender- and BMI adjusted plasma lysozyme activity. Longitudinally, changes in HbA1c levels and serum LDL cholesterol were negatively associated with circulating lysozyme antimicrobial activity. On the contrary, the change in glucose infusion rate during the clamp (insulin sensitivity) was positively associated with lysozyme concentration. CONCLUSIONS: Increased plasma lysozyme levels and activity are found in obese subjects. The longitudinal findings suggest that plasma lysozyme might be protective on the development of obesity-associated metabolic disturbances.
BACKGROUND & AIMS: Several proteins of the innate immune system are known to be deregulated with insulin resistance. We here aimed to investigate the relationship among circulating lysozyme (both plasma concentration and activity) and obesity-associated metabolic disturbances. METHODS: Plasma lysozyme concentration was determined cross-sectionally in a discovery (Cohort 1, n = 137) and in a replication cohort (Cohort 2, n = 181), in which plasma lysozyme activity was also analyzed. Plasma lysozyme was also evaluated longitudinally in participants from the replication cohort (n = 93). Leukocyte lysozyme expression (LYZ mRNA) were also investigated in an independent cohort (Cohort 3, n = 76), and adipose tissue (AT) LYZ mRNA (n = 25) and plasma peptidoglycan levels (n = 61) in subcohorts from discovery cohort. RESULTS: Translocation of peptidoglycan (as inferred from its increased circulating levels) was linked to plasma lysozyme, hyperinsulinemia and dyslipidemia in obese subjects. In both discovery and replication cohorts, plasma lysozyme levels and activity were significantly increased in obesity in direct association with obesity-associated metabolic disturbances and inflammatory parameters, being circulating lysozyme negatively correlated with fasting glucose, HbA1c and insulin resistance (HOMA-IR) in obese subjects. Of note, total cholesterol (p < 0.0001) and LDL cholesterol (p = 0.003) contributed independently to age-, gender- and BMI adjusted plasma lysozyme activity. Longitudinally, changes in HbA1c levels and serum LDL cholesterol were negatively associated with circulating lysozyme antimicrobial activity. On the contrary, the change in glucose infusion rate during the clamp (insulin sensitivity) was positively associated with lysozyme concentration. CONCLUSIONS: Increased plasma lysozyme levels and activity are found in obese subjects. The longitudinal findings suggest that plasma lysozyme might be protective on the development of obesity-associated metabolic disturbances.