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Abnormal mitochondrial structure and function in IL10 deficiency

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Author(s):
José Carlos de Lima Júnior
Total Authors: 1
Document type: Doctoral Thesis
Institution: Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Defense date:
Advisor: Licio Augusto Velloso
Abstract

Adaptive thermogenesis is a metabolic process of heat generation by uncoupling the proton-motor force of the electron transport chain dependent on uncoupling protein 1 (UCP1), present in the internal mitochondrial membrane of brown adipocytes and activated by free fatty acids released in the cytosolic environment by lipolysis. Lipolysis is conditioned by the activation of a sympathetic pathway induced by cold or by other adrenergic stimuli. Activation of the ß3-adrenergic receptor induces energy expenditure by brown adipose tissue (BAT) or promotes induction of beige adipocytes expressing UCP1. Recruitment of precursor cells with genetic potential to turn into brown, white or beige adipocytes depends on environmental cues. Recent studies have shown that type 2 cell signaling through the release of interleukin-4 by eosinophils in response to cold control the synthesis of norepinephrine in alternatively activated macrophages to maintain sympathetic tone for the development of beige adipocytes. Thus, type 2 innate immunity can control browning. Here, we demonstrate that IL10 KO mice, a key immunosuppressive cytokine in the innate immunity, exhibited impaired basal respiration in vivo, as well as decreased tolerance to thermal stress after 4h cold test, although maintaining adaptive response elements such as the overall amount of UCP1 per depot and cold-induced 18F-fluordeoxyglucose uptake. Concomitantly, we recruited obese individuals to undergo bariatric surgery and after weight loss, we observed that there was a BAT recruitment and that its BAT activity was associated with serum Il-10 levels. In addition, we demonstrated that mitochondria isolated from IL10 KO mice BAT present decreased state 2 respiration in relation to wild type mice, as well as UCP1-dependent respiration also decreased. Finally, we performed transmission electron microscopy and IL10 KO mice showed a mitochondrial cristae ultrastructure disruption in addition to a sphere-shaped mitochondria, compatible with a state of greater mitochondrial fission. In addition, we treated immortalized brown adipocyte cell line with either IL10 recombinant or an immunoneutralizing IL10 antibody, which resulted in the increase of the proportion of fusion-deficient formof Opa1. Thus, we conclude that IL10 plays a relevant role in UCP1-dependent respiration and structural organization of mitochondria (AU)

FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
Grantee:Licio Augusto Velloso
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC