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Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis
- Source :
- The Journal of Cell Biology
- Publisher :
- Rockefeller Univ Press
-
Abstract
- Chung et al. show that the myomitokine GDF15 can act to modulate oxidative and lipolytic function in a non–cell-autonomous manner, thereby regulating systemic energy homeostasis in skeletal muscle-specific Crif1-deficient mice. This pathway may be a potential therapeutic target for preventing the onset of obesity and insulin resistance.<br />Reduced mitochondrial electron transport chain activity promotes longevity and improves energy homeostasis via cell-autonomous and –non-autonomous factors in multiple model systems. This mitohormetic effect is thought to involve the mitochondrial unfolded protein response (UPRmt), an adaptive stress-response pathway activated by mitochondrial proteotoxic stress. Using mice with skeletal muscle–specific deficiency of Crif1 (muscle-specific knockout [MKO]), an integral protein of the large mitoribosomal subunit (39S), we identified growth differentiation factor 15 (GDF15) as a UPRmt-associated cell–non-autonomous myomitokine that regulates systemic energy homeostasis. MKO mice were protected against obesity and sensitized to insulin, an effect associated with elevated GDF15 secretion after UPRmt activation. In ob/ob mice, administration of recombinant GDF15 decreased body weight and improved insulin sensitivity, which was attributed to elevated oxidative metabolism and lipid mobilization in the liver, muscle, and adipose tissue. Thus, GDF15 is a potent mitohormetic signal that safeguards against the onset of obesity and insulin resistance.
- Subjects :
- Leptin
Male
0301 basic medicine
Time Factors
medicine.medical_treatment
Mice, Obese
Adipose tissue
Cell Cycle Proteins
Mitochondria, Liver
Mitochondrion
Weight Gain
Oxidative Phosphorylation
Energy homeostasis
Mice
0302 clinical medicine
Homeostasis
Research Articles
Mice, Knockout
Recombinant Proteins
Phenotype
Adipose Tissue
Liver
RNA Interference
Oxidation-Reduction
Signal Transduction
medicine.medical_specialty
Growth Differentiation Factor 15
Lipolysis
Biology
Transfection
Article
03 medical and health sciences
Insulin resistance
3T3-L1 Cells
Internal medicine
Mitochondrial unfolded protein response
medicine
Animals
Genetic Predisposition to Disease
Obesity
Muscle, Skeletal
Insulin
Cell Biology
medicine.disease
Mitochondria, Muscle
Mice, Inbred C57BL
030104 developmental biology
Endocrinology
Unfolded Protein Response
Unfolded protein response
Insulin Resistance
Energy Metabolism
Transcription Factor CHOP
030217 neurology & neurosurgery
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- The Journal of Cell Biology
- Accession number :
- edsair.doi.dedup.....caa84601dbb68ac2f6e6cda7ff85eb19