Abstract
Changes in mitochondrial function in a variety of cells/tissues are critical for orchestrating systemic energy homeostasis and are linked to the development of obesity and many of its comorbidities. The mitochondrial translocator protein of 18kDa (TSPO) is expressed in organs throughout the body, including the brain, liver, adipose tissue, gonads and adrenal glands, where it is implicated in regulating steroidogenesis and cellular metabolism. Prior work from our group and others has shown that, in rodents, TSPO levels are altered in adipose tissue by obesity and that modulation of TSPO activity may impact systemic glucose homeostasis. Furthermore, in vitro studies in a variety of cell types have implicated TSPO in mediating cellular energetics and substrate utilisation. Although mice with germline global TSPO deficiency (TSPO-/- ) have no reported changes in body weight under standard husbandry conditions, we hypothesised that, given the roles of TSPO in regulating mitochondrial function and cellular metabolic flexibility, these animals may have alterations in their systemic response to altered energy availability, either nutritional excess or insufficiency. In agreement with published work, compared to wild-type (TSPO+/+ ) littermates, TSPO-/- mice of both sexes did not exhibit differences in body weight on standard chow. Furthermore, following a 12-hour overnight fast, there was no difference in weight loss or compensatory food intake during re-feeding. Five weeks of feeding a high-fat diet (HFD) did not reveal any impact of the absence of TSPO on body weight gain in either male or female mice. Basal blood glucose levels and glucose clearance in a glucose tolerance test were influenced by feeding a HFD diet but not by genotype. In conclusion, in the paradigms examined, germline global deletion of TSPO did not change the physiological response to deviations in systemic energy availability at the whole organism level.
Highlights
Mitochondrial function is critical for regulating both cellular and systemic energy homeostasis, with mitochondrial dysfunction within metabolic tissues being a key feature of obesity and many of its comorbidities.1-3 The mitochondrial translocator protein of 18 kDa (TSPO) resides in the outer mitochondrial membrane and contributes to a range of mitochondrial processes, including cellular metabolism, cholesterol transport and reactive oxygen species (ROS) production.[4]
Based on published data indicating regulation of translocator protein of kDa (TSPO) expression in rodents by obesity[13] and a role for TSPO in modulation of mitochondrial function,4-8 we hypothesised that germline deletion of the Tspo gene in mice could impact the adaptive physiological response to alterations in energy availability
Using the Tspotm1b(EUCOMM)Wtsi mouse line, we found that germline global loss of TSPO did not impact growth curves of male or female mice maintained on standard laboratory chow
Summary
Mitochondrial function is critical for regulating both cellular and systemic energy homeostasis, with mitochondrial dysfunction within metabolic tissues being a key feature of obesity and many of its comorbidities.1-3 The mitochondrial translocator protein of 18 kDa (TSPO) resides in the outer mitochondrial membrane and contributes to a range of mitochondrial processes, including cellular metabolism, cholesterol transport and reactive oxygen species (ROS) production.[4] For example, transfection of Tspo into Jurkat lymphocyte T-cells, which ordinarily do not express TSPO, enhances ATP production compared to wild-type T-cells.[5] Knockout of Tspo in Leydig MA- 10 cells, which typically express high levels of Tspo, enhances fatty acid oxidation (FAO).[6,7] In addition, knockdown of Tspo in U118MG glioblastoma cells attenuates mitochondrial ROS production in an experimental hypoxia paradigm.[8] These studies, as well as others,5,9-12 suggest a key role of TSPO in various aspects of mitochondrial function including cellular energetics and substrate utilisation. We postulated that, when fed a high-fat diet (HFD), the TSPO knockout mice would be resistant to weight gain, hepatic lipid accumulation and macrophage infiltration in adipose tissue because, in the absence of TSPO, mitochondria may be better equipped to metabolise excess free-fatty acids as a result of enhanced FAO, resulting in reduced mitochondrial dysfunction
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