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1.
Science ; 368(6490)2020 05 01.
Article in English | MEDLINE | ID: mdl-32355002

ABSTRACT

Repeated bouts of exercise condition muscle mitochondria to meet increased energy demand-an adaptive response associated with improved metabolic fitness. We found that the type 2 cytokine interleukin-13 (IL-13) is induced in exercising muscle, where it orchestrates metabolic reprogramming that preserves glycogen in favor of fatty acid oxidation and mitochondrial respiration. Exercise training-mediated mitochondrial biogenesis, running endurance, and beneficial glycemic effects were lost in Il13-/- mice. By contrast, enhanced muscle IL-13 signaling was sufficient to increase running distance, glucose tolerance, and mitochondrial activity similar to the effects of exercise training. In muscle, IL-13 acts through both its receptor IL-13Rα1 and the transcription factor Stat3. The genetic ablation of either of these downstream effectors reduced running capacity in mice. Thus, coordinated immunological and physiological responses mediate exercise-elicited metabolic adaptations that maximize muscle fuel economy.


Subject(s)
Adaptation, Physiological/immunology , Glycogen/metabolism , Interleukin-13/metabolism , Mitochondria, Muscle/metabolism , Muscle, Skeletal/metabolism , Physical Endurance/immunology , Animals , Blood Glucose/metabolism , Cell Line , Fatty Acids/metabolism , Female , Humans , Interleukin-13/blood , Interleukin-13/genetics , Interleukin-13 Receptor alpha1 Subunit/genetics , Interleukin-13 Receptor alpha1 Subunit/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myoblasts/metabolism , Oxidation-Reduction , Physical Conditioning, Animal , Running , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism
2.
Elife ; 92020 05 12.
Article in English | MEDLINE | ID: mdl-32396064

ABSTRACT

Metabolic pathways and inflammatory processes are under circadian regulation. Rhythmic immune cell recruitment is known to impact infection outcomes, but whether the circadian clock modulates immunometabolism remains unclear. We find that the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial production of reactive oxygen species as well as Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, whereas administering the SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint that integrates macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.


Subject(s)
ARNTL Transcription Factors/metabolism , Macrophage Activation , Macrophages/metabolism , Mitochondria/metabolism , ARNTL Transcription Factors/genetics , Amino Acids/metabolism , Animals , Circadian Clocks , Gene Knockout Techniques , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Interferon-gamma , Lipopolysaccharides/immunology , Macrophages/immunology , Malonates/pharmacology , Melanoma, Experimental/immunology , Melanoma, Experimental/metabolism , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Oxidation-Reduction , Oxidative Stress , Succinate Dehydrogenase/metabolism , Transcription, Genetic , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/metabolism
3.
Cell Metab ; 22(4): 709-20, 2015 Oct 06.
Article in English | MEDLINE | ID: mdl-26365180

ABSTRACT

Mitochondria undergo architectural/functional changes in response to metabolic inputs. How this process is regulated in physiological feeding/fasting states remains unclear. Here we show that mitochondrial dynamics (notably fission and mitophagy) and biogenesis are transcriptional targets of the circadian regulator Bmal1 in mouse liver and exhibit a metabolic rhythm in sync with diurnal bioenergetic demands. Bmal1 loss-of-function causes swollen mitochondria incapable of adapting to different nutrient conditions accompanied by diminished respiration and elevated oxidative stress. Consequently, liver-specific Bmal1 knockout (LBmal1KO) mice accumulate oxidative damage and develop hepatic insulin resistance. Restoration of hepatic Bmal1 activities in high-fat-fed mice improves metabolic outcomes, whereas expression of Fis1, a fission protein that promotes quality control, rescues morphological/metabolic defects of LBmal1KO mitochondria. Interestingly, Bmal1 homolog AHA-1 in C. elegans retains the ability to modulate oxidative metabolism and lifespan despite lacking circadian regulation. These results suggest clock genes are evolutionarily conserved energetics regulators.


Subject(s)
ARNTL Transcription Factors/metabolism , Liver/metabolism , Mitochondria/metabolism , Mitochondrial Dynamics , ARNTL Transcription Factors/deficiency , ARNTL Transcription Factors/genetics , Animals , CLOCK Proteins/genetics , CLOCK Proteins/metabolism , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/antagonists & inhibitors , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Cells, Cultured , Cryptochromes/genetics , Cryptochromes/metabolism , Diet, High-Fat , Hepatocytes/cytology , Hepatocytes/metabolism , Insulin/metabolism , Longevity , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Oxidative Stress , RNA Interference , Signal Transduction
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