Abnormal brown adipose tissue mitochondrial structure and function in IL10 deficiency

Abstract

BackgroundInflammation is the most relevant mechanism linking obesity with insulin-resistance and metabolic disease. It impacts the structure and function of tissues and organs involved in metabolism, such as the liver, pancreatic islets and the hypothalamus. Brown adipose tissue has emerged as an important component of whole body energy homeostasis, controlling caloric expenditure through the regulation of non-shivering thermogenesis. However, little is known about the impact of systemic inflammation on the structure and function of brown adipose tissue.MethodsThe relations between IL10 and mitochondria structure/function and also with thermogenesis were evaluated by bioinformatics using human and rodent data. Real-time PCR, immunoblot, fluorescence and transmission electron microscopy were employed to determine the effect of IL10 in the brown adipose tissue of wild type and IL10 knockout mice.FindingsIL10 knockout mice, a model of systemic inflammation, present severe structural abnormalities of brown adipose tissue mitochondria, which are round-shaped with loss of cristae structure and increased fragmentation. IL10 deficiency leads to newborn cold intolerance and impaired UCP1-dependent brown adipose tissue mitochondrial respiration. The reduction of systemic inflammation with an anti-TNFα monoclonal antibody partially rescued the structural but not the functional abnormalities of brown adipose tissue mitochondria. Using bioinformatics analyses we show that in both humans and mice, IL10 transcripts correlate with mitochondrial lipid metabolism and caspase gene expression.InterpretationIL10 and systemic inflammation play a central role in the regulation of brown adipose tissue by controlling mitochondrial structure and function.FundSao Paulo Research Foundation grant 2013/07607-8.

The Functional Impact of Mitochondrial Structure Across Subcellular Scales

“…By extending across the entire organelle and minimizing the curved regions of the cristae, brown fat mitochondria thus have less available space to place ATP synthase dimers, while still maintaining a large region for placement of ETC complexes. In contrast, in heart and skeletal muscle mitochondria where energetic efficiency is critical to sustaining muscle contraction, the lamellar cristae display much more curvature than in brown adipose tissue despite similar cristae densities (Kang et al, 2009;Picard et al, 2015;de-Lima-Junior et al, 2019). In each case, cristae structure appears to be tuned to support the energetic needs of the respective cells.…”

Inflammatory Signaling and Brown Fat Activity

“…Using a mouse model of chronic systemic inflammation, which exhibits increased circulating levels of inflammatory cytokines and abnormal regulation of both innate and adaptive immune responses, mitochondrial swelling is detected with severe damage of the cristae, in addition to reduced cold-induced thermogenic capacity and UCP1-dependent mitochondrial respiration (197). Furthermore, low grade inflammation in BAT in obesity is found as a contributor to excess reactive oxygen species (ROS) production and associated oxidative stress, which may cause mitochondrial dysfunction (198)(199)(200)(201)(202).…”

Mesenchymal stem cells ameliorate lipid metabolism through reducing mitochondrial damage of hepatocytes in the treatment of post-hepatectomy liver failure

“…IL-10 can regulate lipid metabolism by affecting mitochondrial respiratory function. As an immunomodulatory factor, the function of regulating metabolic balance is easy to be ignored 41 . Through electron microscopy and oil red staining, we found that IL-10 secreted by MSCs can affect liver steatosis induced by hepatectomy.…”