Fibroblast growth factor 21 and exercise-induced hepatic mitochondrial adaptations

Fletcher, Justin A.; Linden, Melissa A.; Sheldon, Ryan D.; Meers, Grace M.; Morris, E. Matthew; Butterfield, Anthony; Perfield, James W.; Thyfault, John P.; Rector, R. Scott

doi:10.1152/ajpgi.00355.2015

Cited by 24 publications

(27 citation statements)

References 47 publications

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“…Thus, mitochondria-related markers were assessed in WAT and BAT to determine the potential impact of loss of FGF21 on the ability of exercise to affect these parameters. Consistent with our previous observation that hepatic mitochondrial function is impaired in FGF21KO mice and almost completely restored by exercise training (Fletcher et al 2016), our current findings revealed important roles of both FGF21 and exercise in mediating adipose tissue mitochondrial adaptations.…”

Section: Discussionsupporting

confidence: 93%

“…As previously reported (Fletcher et al 2016), no differences existed in running distance between FGF21KO-EX and WT-EX groups, and both groups experienced an increase in energy intake and relative cardiac tissue mass, suggestive of similar training adaptations. However, compared to WT-EX, FGF21KO-EX animals weighed more, had a higher total body fat percentage, and consumed more total energy (Table 1).…”

Section: Resultssupporting

confidence: 83%

“…Uncoupling protein 1 ( Ucp1) mRNA was virtually undetectable in subcutaneous and visceral WAT of FGF21 KO mice. For Pgc1alpha , which induces mitochondrial biogenesis (Fletcher et al 2016), a significant genotype × EX interaction was observed in both WAT depots (Figure 3). That is, in both visceral and subcutaneous WAT, FGF21KO animals had lower Pgc1alpha expression, suggesting that lack of FGF21 may reduce mitochondrial biogenesis in WAT; this effect of FGF21 ablation was partially rescued by EX.…”

Section: Resultsmentioning

confidence: 96%

“…Circulating fasting plasma levels of glucose, lipids, FGF21 and adiponectin were assessed as previously described and reported (Fletcher, et al 2016); those data are also included in Table 2 because of their relevance to the new adipose tissue data reported herein. Homeostatic model assessment of insulin resistance (HOMA-IR) (Matthews, et al 1985) and adipose tissue insulin resistance (Adipo-IR), calculated as fasting NEFA × fasting insulin (Lomonaco, et al 2012), were used to assess insulin resistance.…”

Section: Methodsmentioning

confidence: 99%

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Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21

Porter

Rowles

Fletcher

et al. 2017

Journal of Endocrinology

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Exercise enhances insulin sensitivity; it also improves adipocyte metabolism and reduces adipose tissue inflammation through poorly-defined mechanisms. Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone-like protein whose insulin-sensitizing properties are predominantly mediated via receptor signaling in adipose tissue (AT). Recently, FGF21 has also been demonstrated to have anti-inflammatory properties. Meanwhile, an association between exercise and increased circulating FGF21 levels has been reported in some, but not all studies. Thus, the role that FGF21 plays in mediating the positive metabolic effects of exercise in AT are unclear. In this study, FGF21 knock-out (KO) mice were used to directly assess the role of FGF21 in mediating the metabolic and anti-inflammatory effects of exercise on white AT (WAT) and brown AT (BAT). Male FGF21KO and wild-type mice were provided running wheels or remained sedentary for 8 weeks (n=9–15/group) and compared for adiposity, insulin sensitivity (i.e., HOMA-IR, Adipo-IR), and AT inflammation and metabolic function (e.g., mitochondrial enzyme activity, subunit content). Adiposity and Adipo-IR were increased in FGF21KO mice and decreased by EX. The BAT of FGF21KO animals had reduced mitochondrial content and decreased relative mass, both normalized by EX. WAT and BAT inflammation was elevated in FGF21KO mice, reduced in both genotypes by EX. EX increased WAT Pgc1alpha gene expression, citrate synthase activity, COX I content, and total AMPK content in WT but not FGF21KO mice. Collectively, these findings reveal a previously unappreciated anti-inflammatory role for FGF21 in WAT and BAT, but do not support that FGF21 is necessary for EX-mediated anti-inflammatory effects.

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Section: Discussionsupporting

confidence: 93%

Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

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Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21

Porter

Rowles

Fletcher

et al. 2017

Journal of Endocrinology

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“…FGF‐2 is one of the most studied FGFs, involved in various endocrine signaling trails, serum phosphate regulation, angiogenesis, wound healing, and embryonic development; additionally, FGF‐2 plays a significant role in the morphogenesis, bone signaling, and cartilage metabolism . Among all these features, FGF‐2 was also shown to (1) influence cell proliferation and stimulate DNA synthesis; (2) mediate the metabolic function of tissues, leading to repair by its releasing from the extracellular matrix (ECM) and regeneration of lost tissues, being used against different cardiovascular disorders; and (3) augment ECM synthesis …”

Section: Introductionmentioning

confidence: 99%

Chip‐based high resolution tandem mass spectrometric determination of fibroblast growth factor—chondroitin sulfate disaccharides noncovalent interaction

et al. 2018

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Fibroblast growth factor-2 (FGF-2) is involved in wound healing and embryonic development. Glycosaminoglycans (GAGs), the major components of the extracellular matrix (ECM), play fundamental roles at this level. FGF-GAG noncovalent interactions are in the focus of research, due to their influence upon cell proliferation and tissue regeneration. Lately, high resolution mass spectrometry (MS) coupled with chip-nanoelectrospray (nanoESI) contributed a significant progress in glycosaminoglycomics by discoveries related to novel species and their characterization. We have employed a fully automated chip-nanoESI coupled to a quadrupole time-of-flight (QTOF) MS for assessing FGF-GAG noncovalent complexes. For the first time, a CS disaccharide was involved in a binding assay with FGF-2. The experiments were conducted in 10 mM ammonium acetate/formic acid, pH 6.8, by incubating FGF-2 and CS in buffer. The detected complexes were characterized by top-down in tandem MS (MS/MS) using collision induced-dissociation (CID). CID MS/MS provided data showing for the first time that the binding process occurs via the sulfate group located at C4 in GalNAc. This study has demonstrated that chip-MS may generate reliable data upon the formation of GAG-protein complexes and their structure. Biologically, the findings are relevant for studies focused on the identification of the active domains in longer GAG chains.

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Hepatocyte‐specific eNOS deletion impairs exercise‐induced adaptations in hepatic mitochondrial function and autophagy

Cunningham

Moore

Dashek

et al. 2022

Obesity

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Objective: Endothelial nitric oxide synthase (eNOS) is a potential mediator of exerciseinduced hepatic mitochondrial adaptations.Methods: Here, male and female hepatocyte-specific eNOS knockout (eNOS hep−/− ) and intact hepatic eNOS (eNOS fl/fl ) mice performed voluntary wheel-running exercise (EX) or remained in sedentary cage conditions for 10 weeks.Results: EX resolved the exacerbated hepatic steatosis in eNOS hep−/− male mice. Elevated hydrogen peroxide emission (~50% higher in eNOS hep−/− vs. eNOS fl/fl mice) was completely ablated with EX. Interestingly, EX increased [1-14 C] palmitate oxidation in eNOS fl/fl male mice, but this was blunted in the eNOS hep−/− male mice. eNOS hep−/− mice had lower markers of the energy sensors AMP-activated protein kinase (AMPK)/ phospho-(p)AMPK and mammalian target of rapamycin (mTOR) and p-mTOR, as well as the autophagy initiators serine/threonine-protein kinase ULK1 and pULK1, compared with eNOS fl/fl mice. Females showed elevated electron transport chain protein content and markers of mitochondrial biogenesis (transcription factor A, mitochondrial, peroxisome proliferator-activated receptor-gamma coactivator 1α). Conclusions:Collectively, this study demonstrates for the first time, to the authors' knowledge, the requirement of eNOS in hepatocytes in the EX-induced increases in hepatic fatty acid oxidation in male mice. Deletion of eNOS in hepatocytes also appears to impair the energy-sensing ability of the cell and inhibit the activation of the autophagy initiating factor ULK1. These data uncover the important and novel role of hepatocyte eNOS in EX-induced hepatic mitochondrial adaptations.

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Fibroblast growth factor 21 and exercise-induced hepatic mitochondrial adaptations

Cited by 24 publications

References 47 publications

Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21

Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21

Chip‐based high resolution tandem mass spectrometric determination of fibroblast growth factor—chondroitin sulfate disaccharides noncovalent interaction

Hepatocyte‐specific eNOS deletion impairs exercise‐induced adaptations in hepatic mitochondrial function and autophagy

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