High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Wall, Christopher E.; Whyte, John; Suh, Jae Myoung; Fan, Weiwei; Collins, Brett; Liddle, Christopher; Yu, Ruth T.; Atkins, Annette R.; Naviaux, Jane C.; Li, Kefeng; Bright, A. Taylor; Alaynick, William A.; Downes, Michael; Naviaux, Robert K.; Evans, Ronald M.

doi:10.1073/pnas.1509930112

Cited by 49 publications

(52 citation statements)

References 34 publications

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“…Unexpectedly, despite the loss of circulating FGF21 (Figure 1D), the phenotype of TG/FGF21 À/À mice was almost identical to TG mice. Further, in contrast to prior expectations [9,26], endogenous FGF21 played only a minor role in regulating body weight gain and fat depot mass under LFD or HFD conditions (Figure 1AeD þ Figure S1). Strikingly, we obtained similar results from mice fed LFD or HFD for 16 wks starting from 8 wks of age ( Figure S2AeG).…”

Section: Resultscontrasting

confidence: 72%

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

et al. 2016

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Objective: Fibroblast growth factor 21 (FGF21) was recently discovered as stress-induced myokine during mitochondrial disease and proposed as key metabolic mediator of the integrated stress response (ISR) presumably causing systemic metabolic improvements. Curiously, the precise cell-non-autonomous and cell-autonomous relevance of endogenous FGF21 action remained poorly understood. Methods: We made use of the established UCP1 transgenic (TG) mouse, a model of metabolic perturbations made by a specific decrease in muscle mitochondrial efficiency through increased respiratory uncoupling and robust metabolic adaptation and muscle ISR-driven FGF21 induction. In a cross of TG with Fgf21-knockout (FGF21 À/À ) mice, we determined the functional role of FGF21 as a muscle stress-induced myokine under low and high fat feeding conditions. Results: Here we uncovered that FGF21 signaling is dispensable for metabolic improvements evoked by compromised mitochondrial function in skeletal muscle. Strikingly, genetic ablation of FGF21 fully counteracted the cell-non-autonomous metabolic remodeling and browning of subcutaneous white adipose tissue (WAT), together with the reduction of circulating triglycerides and cholesterol. Brown adipose tissue activity was similar in all groups. Remarkably, we found that FGF21 played a negligible role in muscle mitochondrial stress-related improved obesity resistance, glycemic control and hepatic lipid homeostasis. Furthermore, the protective cell-autonomous muscle mitohormesis and metabolic stress adaptation, including an increased muscle proteostasis via mitochondrial unfolded protein response (UPR mt ) and amino acid biosynthetic pathways did not require the presence of FGF21.Conclusions: Here we demonstrate that although FGF21 drives WAT remodeling, the adaptive pseudo-starvation response under elevated muscle mitochondrial stress conditions operates independently of both WAT browning and FGF21 action. Thus, our findings challenge FGF21 as key metabolic mediator of the mitochondrial stress adaptation and powerful therapeutic target during muscle mitochondrial disease.

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Section: Resultscontrasting

confidence: 72%

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

et al. 2016

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“…It is also not due to increased BAT hydrolysis of substrates due to the induction by high serum FGF21 or Ucp1 in BAT, as in the PolgA D257A mutator mouse (21), as the Ant1 −/− mouse serum FGF21 levels were reduced and Ucp1 is not induced in BAT. Therefore, because the muscle is the primary user of systemic glucose, the glucose tolerance and HFD resistance of the Ant1 −/− muscle is most likely due to increased muscle mitochondrial respiration, which depletes circulating glucose, nonesterified fatty acids, and triglycerides (30).…”

Section: Discussionmentioning

confidence: 97%

“…In the PolgA D257A mutator mouse, FGF21-mediated induction of Ucp1 with uncoupling of OXPHOS in BAT was proposed to remove the excess calories and account for increased insulin sensitivity and resistance to HFD-induced obesity (21). Because the PolgA D257A mutator mouse accumulates abnormally high levels of mtDNA mutations in all tissues (31), increased metabolism of fats and glucose through muscle mitochondrial might also contribute to the glucose tolerance and insulin resistance of the PolgA D257A mutator mice, and skeletal muscle mitochondrial function was not analyzed in these animals.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity

Morrow

Picard

Derbeneva

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Diabetes is associated with impaired glucose metabolism in the presence of excess insulin. Glucose and fatty acids provide reducing equivalents to mitochondria to generate energy, and studies have reported mitochondrial dysfunction in type II diabetes patients. If mitochondrial dysfunction can cause diabetes, then we hypothesized that increased mitochondrial metabolism should render animals resistant to diabetes. This was confirmed in mice in which the heart-muscle-brain adenine nucleotide translocator isoform 1 (ANT1) was inactivated. ANT1-deficient animals are insulin-hypersensitive, glucose-tolerant, and resistant to high fat diet (HFD)-induced toxicity. In ANT1-deficient skeletal muscle, mitochondrial gene expression is induced in association with the hyperproliferation of mitochondria. The ANT1-deficient muscle mitochondria produce excess reactive oxygen species (ROS) and are partially uncoupled. Hence, the muscle respiration under nonphosphorylating conditions is increased. Muscle transcriptome analysis revealed the induction of mitochondrial biogenesis, down-regulation of diabetes-related genes, and increased expression of the genes encoding the myokines FGF21 and GDF15. However, FGF21 was not elevated in serum, and FGF21 and UCP1 mRNAs were not induced in liver or brown adipose tissue (BAT). Hence, increased oxidation of dietary-reducing equivalents by elevated muscle mitochondrial respiration appears to be the mechanism by which ANT1-deficient mice prevent diabetes, demonstrating that the rate of mitochondrial oxidation of calories is important in the etiology of metabolic disease. mitochondria | skeletal muscle | ANT1 | insulin sensitivity

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“…This perspective is supported by the finding that young, pre-progeroid polgamma mutator mice (prior to the development of extensive mitochondrial dysfunction), appear to exhibit starvation as indicated by reduced body fat, lower glucose levels, increased ghrelin, decreased leptin, and dramatically increased fibroblast growth factor 21 levels. [21] The hetero zygous polymerase gamma mutator mice are an interesting counterpoint to the homo zygous mutator mice, as heterozygosity fails to promote the high levels of mtDNA deletion mutations observed in muscles from homozygous animals. [22] The absence of increased mtDNA deletion mutations in the heterozygous mutator mice may underlie the improvement in lifespan compared to homozygous mice.…”

Section: The Degree Of Mitochondrial Damage Impacts Insulin Sensitivitymentioning

confidence: 99%

Mitochondrial quality control in insulin resistance and diabetes

Wanagat

Hevener

2016

Current Opinion in Genetics & Development

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Diabetes is increasingly prevalent and a primary contributor to the major causes of disability and death. Despite the central role of mitochondria in metabolism, the relationship between mitochondrial quality and insulin action remains unclear. An increasing number of genetically-engineered and aging rodent models are shedding additional light on the mitochondrion’s role in regulating glucose metabolism and insulin sensitivity by modulating mitochondrial morphology, function and quality control pathways. Clarification of the role of mitochondria in regulating key cellular processes including metabolic flux, autophagy, and apoptosis will drive the development of novel therapeutic strategies for maintaining mitochondrial quality and improving human health.

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High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Cited by 49 publications

References 34 publications

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity

Mitochondrial quality control in insulin resistance and diabetes

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