Mice Deficient in the Respiratory Chain Gene Cox6a2 Are Protected against High-Fat Diet-Induced Obesity and Insulin Resistance

Quintens, Roel; Singh, Sarvjeet; Lemaire, Katleen; Bock, Katrien De; Granvik, Mikaela; Schraenen, Anica; Vroegrijk, Irene O.C.M.; Costa, Veronica; Noten, Pieter Van; Lambrechts, Dennis; Lehnert, Stefan; Lommel, Leentje Van; Thorrez, Lieven; Faudeur, Geoffroy de; Romijn, Johannes A.; Shelton, John M.; Scorrano, Luca; Lijnen, H. Roger; Voshol, Peter J.; Carmeliet, Peter; Mammen, Pradeep P.A.; Schuit, Frans

doi:10.1371/journal.pone.0056719

Cited by 62 publications

(66 citation statements)

References 79 publications

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“…5 and 6). These findings are interesting since in numerous mouse models (6,41,58,60), DIO resistance is accompanied by improved glucose homeostasis. Compared with controls, IL-15R␣ Ϫ/Ϫ mice had hyperglycemia, hyperinsulinemia, and higher insulin secretion during GTT, independently of age (Figs.…”

Section: Discussionmentioning

confidence: 91%

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

Loro

Seifert

Moffat

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15R␣ take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15R␣ promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15R␣ on metabolism and obesity are currently unknown. We report that mice lacking IL-15R␣ (IL-15R␣ Ϫ/Ϫ ) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15R␣ Ϫ/Ϫ mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15R␣ Ϫ/Ϫ are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15R␣ in metabolism and obesity.interleukin-15 receptor alpha; diet-induced obesity; muscle; fatty acid oxidation; fatigue recovery; glucose homeostasis ACCUMULATION OF EXCESSIVE body fat is a physiological consequence of unnecessary caloric intake. With greater worldwide food production, often the caloric intake largely exceeds the physiological energy requirements, and as a result, the obesity pandemic is growing at alarming rates in both developed and developing countries (21,47). Apart from the role of environmental factors, particularly an energy-dense diet and sedentary lifestyle, obesity also has important genetic determinants that have been conserved across species. Identifying the molecular mechanisms regulating metabolic efficiency (the capacity to convert energy intake into storable energy forms) is of great interest because of the low success in using caloric restriction as a means to manage obesity. Indeed, a number of pathways have been recently identified that reduce the extent of dietinduced obesity (DIO) by decreasing metabolic efficiency rather than energy input (8,10,11,43,56,59,60). Targeting these pathways with pharmacological approaches may also have the advantage of reproducing some of the benefits normally associated with physical exercise. Together with caloric restriction, exercise is a mainstay of a healthy life style and contributes to the control of metabolic efficiency. In addition to converting energy into movement, exercise increases the rates of lipolysis and fat oxidation, promotes heat dissipation (49, 53), and causes long-term changes in the expression of numerous genes, including IL-15R␣/IL-15 (55).IL-15 and its primary binding partner IL-15R␣ have emerged as important regulators of cell functions in both lymphoid and nonlymphoid tissues. Their transcripts are detectable in a variety of tissues, including skeletal muscle, liver, or adipose (http://biogps.org/#gotoϭwelcome). Some of the proposed noncanonical roles of IL-15/IL-15R␣ signaling are mediating anabolic...

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Section: Discussionmentioning

confidence: 91%

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

Loro

Seifert

Moffat

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…3C). COX6A2 is a subunit of respiratory cytochrome c oxidase (complex IV) expressed in striated muscle and shown to play a role in respiratory uncoupling in muscle (35). Studies in yeast demonstrated that COX6 expression is up-regulated by heme (36), thus the increase in Cox6a2 expression in Flvcr -deleted thymocytes may result from increased heme levels.…”

Section: Resultsmentioning

confidence: 99%

Heme Exporter FLVCR Is Required for T Cell Development and Peripheral Survival

Philip

Funkhouser

Chiu

et al. 2015

The Journal of Immunology

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All aerobic cells and organisms must synthesize heme from the amino acid glycine and the tricarboxylic acid (TCA) cycle intermediate succinyl Coenzyme A for incorporation into hemoproteins such as the cytochromes needed for oxidative phosphorylation. Most studies on heme regulation have been done in erythroid cells or hepatocytes; however much less is known about heme metabolism in other cell types. The feline leukemia virus subgroup C receptor (FLVCR) is a 12 transmembrane domain surface protein that exports heme from cells and was previously shown to be required for erythroid development. Here we show that deletion of Flvcr in murine hematopoietic precursors caused a complete block in αβ T cell development at the CD4+CD8+ double-positive stage, though other lymphoid lineages were unaffected. Moreover, FLVCR was required for the proliferation and survival of peripheral CD4+ and CD8+ T cells. These studies identify a novel and unexpected role for FLVCR, a major facilitator superfamily (MFS) metabolite transporter, in T cell development and suggest that heme metabolism is particularly important in the T lineage.

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“…In addition, modification of mitochondrial dynamics has been highlighted as a potential mechanism in muscle IR, as muscle from obese subjects and from T2DM patients has shown reduced expression of mitofusin-2 (Mfn2) [23], and amelioration of insulin sensitivity by bariatric surgery has been associated with increased Mfn2 expression in muscle [24]. Nevertheless, other studies performed in mice with genetic ablation of different components of mitochondria have minimalized the role of mitochondrial dysfunction in muscle IR [25][26][27][28][29], and further interventional studies have also supported the controversy [30,31], questioning the causal implication of mitochondria in alterations of insulin signalling. Consistent with this, we have demonstrated that mitochondrial dysfunction in T2DM is not an early abnormality playing a causal role in the development of the disorder, but rather a complication of oxidative stress associated with hyperglycaemia and hyperlipidaemia-at least in diet-induced diabetic mice [32].…”

Section: Mitochondrial Dysfunction and Skeletal Muscle Insulin Resistmentioning

confidence: 99%

Contribution of mitochondria and endoplasmic reticulum dysfunction in insulin resistance: Distinct or interrelated roles?

Rieusset

2015

Diabetes & Metabolism

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Mice Deficient in the Respiratory Chain Gene Cox6a2 Are Protected against High-Fat Diet-Induced Obesity and Insulin Resistance

Cited by 62 publications

References 79 publications

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

Heme Exporter FLVCR Is Required for T Cell Development and Peripheral Survival

Contribution of mitochondria and endoplasmic reticulum dysfunction in insulin resistance: Distinct or interrelated roles?

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