Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine

Kim, Kook Hwan; Jeong, Yeon Taek; Oh, Hye Young; Kim, Seong Hun; Cho, Jae Min; Kim, Yona; Kim, Su Sung; Kim, Do Hoon; Hur, Kyu Yeon; Kim, Hyoung Kyu; Ko, Tae-Hee; Han, Jin; Kim, Hong Lim; Kim, Jin; Back, Sung Hoon; Komatsu, Masaaki; Chen, Hsiuchen; Chan, David C.; Konishi, Morichika; Itoh, Nobuyuki; Choi, Cheol Soo; Lee, Myung-Shik

doi:10.1038/nm.3014

Cited by 696 publications

(739 citation statements)

References 65 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: 55%

“…The link between 'browning' and the beneficial pharmacological effects of FGF21 is currently in the focus of metabolic disease research [20e22]. Similarly, a role of myokine FGF21 action in WAT remodeling is speculated [9], suggesting that muscle FGF21 signals to peripheral tissues to enhance substrate utilization/mobilization, although the biological function is debated. On one hand, FGF21 might sequester energy substrates into adipose tissue, thus bypassing the muscle to avoid overload and metabolic stress [23].…”

Section: Introductionmentioning

confidence: 99%

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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: 55%

Section: Introductionmentioning

confidence: 99%

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

et al. 2016

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“…Recent studies of mice in which autophagy was selectively inhibited in skeletal muscle further illustrate how autophagy ablation in specific tissue systemically affects lipid metabolism and energy homeostasis; these mice exhibit increased glucose tolerance and insulin sensitivity, reduced adiposity and resistance to diet-induced obesity 85 . This phenotype arises from an increase in dysfunctional mitochondria due to impaired mitophagy in muscle cells, which results in the increased expression of a stressinduced mitokine, fibroblast growth factor21 (FGF21).…”

Section: Hepatic Steatosismentioning

confidence: 99%

Autophagy at the crossroads of catabolism and anabolism

Kaur

Debnath

2015

Nat Rev Mol Cell Biol

843

801

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“…It has been reported that FGF21 gene expression is directly regulated by ATF4 (7,8,12,22) and potentially XBP-1 (9). A previous study reported that FGF21 repressed ER stress by inhibiting phosphorylation of eIF2a, an upstream activating factor of ATF4 (9).…”

Section: Discussionmentioning

confidence: 98%

“…Subsequently, ATF4 induces a series of target genes involved in amino acid metabolism, redox balance and apoptosis (5). Recent studies revealed that expression of FGF21 is induced in response to ER stress and amino acid deprivation via activation of ATF4 (6)(7)(8)(9)(10)(11). The promoter region of FGF21 contains three response elements for ATF4, suggesting FGF21 is a direct target of ATF4 (12).…”

mentioning

confidence: 99%

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

Maruyama

Shimizu

Hashidume

et al. 2018

Journal of Nutritional Science and Vitaminology

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Summary Fibroblast growth factor 21 (FGF21), mainly synthesized and secreted from the liver, is an endocrine FGF that regulates glucose and fatty acid metabolism to maintain whole body energy homeostasis. Gene expression of FGF21 was previously reported to be induced by endoplasmic reticulum (ER) stress through activating transcription factor 4 (ATF4). It has been reported that drug-induced ER stress is reduced by overexpression of FGF21. However, the function of endogenous FGF21 under physiological conditions such as the postprandial state remains unknown. Here, we examined the effects of both endogenous and exogenous FGF21 on postprandial hepatic ER stress. In mice, postprandial and tunicamycin-induced ER stress was significantly reduced by overexpression of FGF21 using a recombinant adenovirus. FGF21-deficient mice exhibited a more considerable increase in drug-induced ER stress target gene expression than wild-type mice. Following refeeding after fasting, FGF21 deficiency caused severe ER stress in the liver. The postprandial ER stress response was significantly reduced when hepatic FGF21 gene expression was increased by feeding a diet containing the soy protein b-conglycinin which activates ATF4. Together, these results demonstrate that FGF21 reduces the increased expression of a subset of genes in the liver in response to ER stress and may correct metabolic disorders caused by ER stress. Key Words FGF21, ER stress, ATF4, b-conglycinin Fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily (also known as the FGF19 subfamily), is mainly produced by the liver. FGF21 is secreted into the blood circulation, after which it acts on target tissues through a cell-surface FGF receptor (FGFR) together with its coregulator, bKlotho (1). In adipose tissues, FGF21 induces lipolysis and glucose uptake by activation of hormone sensitive lipase and glucose transporter 4, respectively (2, 3). Some hepatic energy metabolic pathways, including ketogenesis and gluconeogenesis, are also regulated by FGF21 in response to fasting. Expression of FGF21 is transcriptionally regulated during fasting via peroxisome proliferator-activated receptor a (PPARa), a nuclear hormone receptor (2, 4). More importantly, several studies revealed that FGF21 improves whole-body insulin sensitivity, inhibits high-fat diet-induced body weight gain and reduces fatty liver disease. Thus, FGF21 is an attractive target molecule for the prevention of metabolic diseases.Endoplasmic reticulum (ER) stress is triggered by excess accumulation of either unfolded or misfolded proteins in the ER, which in turn activates three ER membrane proteins: activating transcription factor 6a (ATF6a), inositol-requiring enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK). During ER stress, activation of PERK results in the phosphorylation of eukaryotic initiation factor 2a (eIF2a) and translational activation of activating transcription factor 4 (ATF4). Subsequently, ATF4 induces a series of target genes involved in amino acid metabolism, red...

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Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine

Cited by 696 publications

References 65 publications

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

Autophagy at the crossroads of catabolism and anabolism

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

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