Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response

doi:10.1016/j.isci.2021.102181

. 2021 Feb 12;24(3):102181.

doi: 10.1016/j.isci.2021.102181. eCollection 2021 Mar 19.

Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response

Seul Gi Kang^{1

2}, Min Jeong Choi^{1

2}, Saet-Byel Jung¹, Hyo Kyun Chung¹, Joon Young Chang^{1

2}, Jung Tae Kim^{1

2}, Yea Eun Kang^{1

3}, Ju Hee Lee^{1

3}, Hyun Jung Hong^{1

2}, Sang Mi Jun^{4

5}, Hyun-Joo Ro^{4

5}, Jae Myoung Suh⁶, Hail Kim⁶, Johan Auwerx⁷, Hyon-Seung Yi^{1

2

3}, Minho Shong^{1

2

3}

Affiliations

¹ Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea.
² Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon 35015, Republic of Korea.
³ Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea.
⁴ Center for Research Equipment, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.
⁵ Convergent Research Center for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
⁶ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
⁷ Laboratory for Integrative Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne 1015, Switzerland.

PMID: 33718833
PMCID: PMC7920832
DOI: 10.1016/j.isci.2021.102181

Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response

Seul Gi Kang et al. iScience. 2021.

. 2021 Feb 12;24(3):102181.

doi: 10.1016/j.isci.2021.102181. eCollection 2021 Mar 19.

Authors

Affiliations

¹ Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea.
² Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon 35015, Republic of Korea.
³ Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea.
⁴ Center for Research Equipment, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.
⁵ Convergent Research Center for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
⁶ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
⁷ Laboratory for Integrative Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne 1015, Switzerland.

PMID: 33718833
PMCID: PMC7920832
DOI: 10.1016/j.isci.2021.102181

Abstract

Perturbation of mitochondrial proteostasis provokes cell autonomous and cell non-autonomous responses that contribute to homeostatic adaptation. Here, we demonstrate distinct metabolic effects of hepatic metabokines as cell non-autonomous factors in mice with mitochondrial OxPhos dysfunction. Liver-specific mitochondrial stress induced by a loss-of-function mutation in Crif1 (LKO) leads to aberrant oxidative phosphorylation and promotes the mitochondrial unfolded protein response. LKO mice are highly insulin sensitive and resistant to diet-induced obesity. The hepatocytes of LKO mice secrete large quantities of metabokines, including GDF15 and FGF21, which confer metabolic benefits. We evaluated the metabolic phenotypes of LKO mice with global deficiency of GDF15 or FGF21 and show that GDF15 regulates body and fat mass and prevents diet-induced hepatic steatosis, whereas FGF21 upregulates insulin sensitivity, energy expenditure, and thermogenesis in white adipose tissue. This study reveals that the mitochondrial integrated stress response (ISR^mt) in liver mediates metabolic adaptation through hepatic metabokines.

Keywords: Cell Biology; Physiology; Systems Biology.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Figure 1**
The livers of liver-specific *Crif1*-deficient mice exhibit altered glucose metabolism and impaired insulin signaling (A) Gross morphology of Ctrl and LKO mice at 8 weeks of age. (B) Western blot analysis showing lower levels of CRIF1 and subunits of the OxPhos complex in the livers of Ctrl and LKO mice. The results of one representative experiment of the two conducted are shown. (C) BN-PAGE analysis of the assembled OxPhos complex in the livers of Ctrl and LKO mice (∗: abnormal sub-complexes). (D) Representative transmission electron microscopic images of livers from Ctrl and LKO mice (n = 4). The white arrows indicate hepatic glycogen granules. (E and F) Quantitative PCR analysis of UPR^mt mediators (E) and UPR^er and transcription factors involved in the mitochondrial stress response (F) in the livers of Ctrl and LKO mice (n = 4–5 biological replicates from three independent experiments). (G) Western blot analysis of UPR^mt and UPR^er mediators in the livers of Ctrl and LKO mice. The results of one representative experiment out of the three conducted are shown. Data are mean ± SEM and were analyzed using Student's t test (∗p < 0.05 versus Ctrl). (H) OCR (left panel) and individual parameters (right panel) in primary hepatocytes isolated from Ctrl and LKO mice (n = 10 biological replicates from two independent experiments) treated with oligomycin (2 μg/mL), CCCP (10 μM), or rotenone (1 μM). Basal respiration, ATP production, and proton leakage were calculated after oligomycin treatment, and the maximal and non-mitochondrial respiration were calculated after CCCP and rotenone treatment, respectively. (I) Glycolysis assay (left panel) and glycolytic parameters (right panel) in primary hepatocytes isolated from the livers of Ctrl and LKO mice (n = 6 biological replicates from two independent experiments). Non-glycolytic acidification was calculated after the addition of 2-DG (50 mM). Glycolysis, glycolytic capacity, and glycolytic reserve were calculated after the addition of glucose (10 mM) and oligomycin (1 μM), respectively. (J) Quantitative PCR analysis of *Glut1* and *Glut2* mRNA expression in livers from 8-week-old Ctrl and LKO mice (n = 6 biological replicates from three independent experiments). (K) Glucose uptake by primary hepatocytes from Ctrl and LKO mice (n = 6 biological replicates from two independent experiments). Insulin (1 μM) was added 20 min before the measurements. (L) Western blot analysis of insulin signaling after the addition of insulin (200 nM) for 15 min to primary hepatocytes isolated from Ctrl and LKO mice. The results of one representative experiment of the two conducted are shown. Data are mean ± SEM and were analyzed using two-way ANOVA followed by Scheff's post-hoc test in (K) and Student's t test in (E and F) and (H–J) (∗p < 0.05 versus Ctrl or Ctrl-Vehicle). See also Figure S1.

**Figure 2**
Liver-specific *Crif1*-deficient mice exhibit superior energy metabolism and are protected against diet-induced obesity Mice fed a chow diet were used in (A–K) and mice fed an HFD for 8 weeks were used in (L–S). (A) Body masses of Ctrl and LKO mice from 6 to 31 weeks of age (n = 10 biological replicates from two independent experiments). (B) Body composition of Ctrl and LKO mice (n = 5–6 biological replicates from two independent experiments). (C) Glucose tolerance test (GTT) (left panel) and glucose area under the curve (AUC) (right panel) for Ctrl and LKO mice (n = 7 biological replicates from three independent experiments). (D) Insulin tolerance test (ITT) (left panel) and glucose area under the curve (AUC) (right panel) for Ctrl and LKO mice (n = 7 biological replicates from three independent experiments). (E) Blood glucose concentrations of Ctrl and LKO mice fasted for 6 h (n = 10 biological replicates from five independent experiments). (F) Serum insulin concentrations in Ctrl and LKO mice fasted for 6 h (n = 10–12 biological replicates from three independent experiments). (G) Measurement of energy expenditure (EE) per metabolic body mass of Ctrl and LKO mice (n = 7–8 biological replicates). (H and I) Correlation analysis between EE and total body mass (TBM) (H) and ANCOVA-adjusted EE (I) in Ctrl and LKO mice. (J and K) Daily food intake (J) and cumulative food intake over 7 days (K) in mice (n = 7–9 biological replicates from five experiments). (L) Body mass (n = 5 biological replicates from three independent experiments). (M) Body composition in Ctrl and LKO mice (n = 7 biological replicates from two independent experiments). (N) Representative images of H&E-stained liver sections, showing a central vein, from Ctrl and LKO mice (n = 5–6 biological replicates). (O) Quantitative PCR analysis of the expression of genes involved in lipid metabolism in the livers of Ctrl and LKO mice (n = 4–5 biological replicates from two independent experiments). (P) Glucose tolerance test (GTT, left panel) and glucose area under the curve (AUC, right panel) for Ctrl and LKO mice (n = 5 biological replicates from three independent experiments). (Q) Insulin tolerance test (ITT, left panel) and glucose area under the curve (AUC, right panel) for Ctrl and LKO mice (n = 5 biological replicates from three independent experiments). (R and S) EE per metabolic body mass (R) and ANCOVA-adjusted EE (S) in control and LKO mice (n = 7 biological replicates). Data are mean ± SEM. Statistical analyses were performed using Student's t test in (A–G), (J–M), and (O–R) or ANCOVA in (I) and (S) (∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 versus Ctrl). See also Figure S2.

**Figure 3**
The white adipose tissue of liver-specific *Crif1*-deficient mice exhibits greater insulin signaling and fatty acid metabolism (A–C) Western blot analysis of AKT phosphorylation in the liver (A), iWAT (B), and eWAT (C) of Ctrl and LKO mice (n = 3 biological replicates per group). Mice were fasted for 6 h and then administered intraperitoneally with insulin (4 U/kg). One representative experiment of the two conducted is shown. (D) Representative images of hematoxylin and eosin-stained iWAT and BAT sections from Ctrl and LKO mice (n = 4 biological replicates). (E) Quantitative PCR analysis of the expression of genes involved in glucose uptake and fatty acid metabolism in the iWAT of Ctrl and LKO mice (n = 6 biological replicates from two independent experiments). (F) Western blot analysis of signaling upstream of UCP1 in the iWAT of Ctrl and LKO mice (n = 3 biological replicates). The results of one representative experiment of the three conducted are shown. Mice were fed a chow diet. Data are mean ± SEM and were analyzed using two-way ANOVA followed by Scheff's post-hoc test in (A–C) and Student's t test in (E) and (F) (∗p < 0.05 versus Ctrl or Ctrl-Saline). See also Figure S3.

**Figure 4**
Liver-specific *Crif1* deficiency increases the production of metabokines in liver (A) Volcano plot showing the DEGs in the liver of LKO mice. The colored dots indicate the DEGs with ≥ ±1.5-fold difference from Ctrl mice. The red and blue dots indicate the upregulated and downregulated transcripts, respectively. (B) Gene set enrichment analysis (GSEA) using DEGs in the liver of Ctrl and LKO mice. (C and D) Volcano plot showing the DEGs (C) and top-ranked functional annotation chart (D) in the iWAT of LKO mice. Functional annotation was categorized using the KEGG pathway in DAVID (ver.6.8), and the results are ordered according to gene number. (E) GSEA showing the upregulated gene set in the iWAT of LKO mice. (F) Heatmap of the DEGs classified as “Secreted proteins” in the cellular compartment category (≥2-fold difference, p < 0.05 versus Ctrl mice). The genes in red were the two top-ranked transcripts, *Fgf21* and *Gdf15* in the liver of LKO mice. (G) Quantitative PCR analysis of *Gdf15* and *Fgf21* mRNA expression in Ctrl and LKO livers (n = 5–6 biological replicates from four independent experiments). (H) Serum GDF15 (n = 6–7 biological replicates) and FGF21 (n = 4–5 biological replicates) in Ctrl and LKO mice. Three independent experiments were performed. (I) Quantitative PCR analysis of *Klb* and *Fgfr1c* mRNA expression in adipose tissue of mice (n = 6 biological replicates). The mice were studied at 8–9 weeks of age and fed a chow diet. Data in (G–I) are mean ± SEM. Statistical analyses were performed using Student's t test in (G–I) (∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 versus Ctrl). The data in (D) were analyzed using a modified Fisher's exact p value (∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001). Un.d, undetectable. See also Figure S4.

**Figure 5**
GDF15 regulates body and fat mass, and FGF21 regulates glucose clearance in liver-specific *Crif1*-deficient mice fed a chow diet (A) Body masses of Ctrl, LKO, GKO, and LGKO mice (n = 7 biological replicates from five independent experiments). (B) Body composition, measured by DXA, of Ctrl, LKO, GKO, and LGKO mice (n = 7–11 biological replicates from three independent experiments). (C) Cumulative food intake over 5 days in Ctrl, LKO, GKO, and LGKO mice housed in individual cages (n = 7–11 biological replicates). (D) Body masses of Ctrl, LKO, FKO, and LFKO mice (n = 8–12 biological replicates from two independent experiments). (E) Body composition, measured by DXA, of Ctrl, LKO, FKO, and LFKO mice (n = 7–10 biological replicates from two independent experiments). (F) Cumulative food intake over 5 days in Ctrl, LKO, FKO, and LFKO mice (n = 8–12 biological replicates from two independent experiments). (G) Glucose tolerance test (left panel) and glucose area under the curve (AUC, right panel) after fasting for 6 h in Ctrl, LKO, GKO, and LGKO mice (n = 6–7 biological replicates per group from three independent experiments). (H) Insulin tolerance test (left panel) and glucose area under the curve (AUC, right panel) in Ctrl, LKO, GKO, and LGKO mice fasted for 6 h (n = 6–7 biological replicates per group from three independent experiments). (I) Glucose tolerance test (left panel) and glucose area under the curve (right panel) in Ctrl, LKO, FKO, and LFKO mice fasted for 6 h (n = 7–8 biological replicates from three independent experiments). (J) Insulin tolerance test (left panel) and glucose area under the curve (right panel) in Ctrl, LKO, FKO, and LFKO mice fasted for 6 h (n = 7–8 biological replicates from three independent experiments). The mice were studied at 8–10 weeks of age and fed a chow diet. Data are expressed as the mean ± SEM and were analyzed by ANOVA followed by Scheff's post-hoc test (∗p < 0.05 versus Ctrl, ∗∗p<0.001, #p < 0.05 for LKO versus DKO, &p < 0.05 for LKO versus GKO or FKO). See also Figure S5.

**Figure 6**
FGF21 increases insulin signaling and the expression of fatty acid metabolic genes in the iWAT of liver-specific *Crif1*-deficient mice (A) Western blot analysis of AKT phosphorylation in the iWAT of Ctrl, LKO, GKO, and LGKO mice. Mice were fasted for 6 h and then injected intraperitoneally with insulin (4 U/kg). The results of one representative experiment of the two conducted are shown. (B) Quantitative PCR analysis of genes involved in glucose transport and fatty acid oxidation in the iWAT of Ctrl, LKO, GKO, and LGKO mice (n = 5 biological replicates from two independent experiments). (C) Western blot analysis of AKT phosphorylation in the iWAT of Ctrl, LKO, FKO, and LFKO mice. Mice were fasted for 6 h and then injected intraperitoneally with insulin (4 U/kg). The results of one representative experiment of the two conducted are shown. (D) Quantitative PCR analysis of genes involved in glucose transport and fatty acid oxidation in the iWAT of Ctrl, LKO, FKO, and LFKO mice (n = 5 biological replicates from two independent experiments). (E) EE per metabolic body mass (BM^0.75) in Ctrl, LKO, GKO, and LGKO mice (n = 8–12 biological replicates). After 2 days of acclimatization, EE was measured for 2 days. (F) Locomotor activity in Ctrl, LKO, GKO, and LGKO mice housed in individual cages (n = 8–9 biological replicates). Activity was monitored after 1 day of acclimatization. (G) EE per metabolic body mass (BM^0.75) in Ctrl, LKO, FKO, and LFKO mice (n = 7 biological replicates). (H) Locomotor activity in Ctrl, LKO, FKO, and LFKO mice housed in individual cages (n = 8–11 biological replicates). Data are expressed as the mean ± SEM and were analyzed by ANOVA followed by Scheff's post-hoc test (∗p < 0.05 versus Ctrl, #p < 0.05 for LKO versus DKO, &p < 0.05 for LKO versus GKO or FKO). See also Figure S6.

**Figure 7**
Genetic ablation of *Gdf15* in LKO mice worsens hepatic steatosis, independent of insulin sensitivity (A) Body masses of Ctrl, LKO, GKO, and LGKO mice fed a high-fat diet (60% fat) from 6 to 14 weeks of age (n = 7 biological replicates from two independent experiments). (B) Body masses of Ctrl, LKO, FKO, and LFKO mice fed a high-fat diet from 6 to 14 weeks of age (n = 6–8 biological replicates from two independent experiments). (C) Tissue masses per unit body mass of Ctrl, LKO, GKO, and LGKO mice fed a high-fat diet (n = 7–8 biological replicates from two independent experiments). (D) Tissue masses per unit body mass of Ctrl, LKO, FKO, and LFKO mice fed a high-fat diet (n = 5 biological replicates from two independent experiments). (E and F) Glucose tolerance (E) and insulin tolerance test (F) data for Ctrl, LKO, GKO, and LGKO mice fed a high-fat diet (n = 5–8 biological replicates from two independent experiments). (G and H) Glucose tolerance (G) and insulin tolerance test (H) data for Ctrl, LKO, FKO, and LFKO mice fed a high-fat diet (n = 5 biological replicates from two independent experiments). (I) Representative hematoxylin and eosin-stained liver sections from Ctrl, LKO, GKO, LGKO, FKO, and LFKO mice fed a high-fat diet for 8 weeks (n = 4–5 biological replicates). (J) A schematic model showing consequence upon hepatic ISR^mt and action of GDF15 and FGF21 in those mice. All data are expressed as the mean ± SEM and were analyzed using ANOVA followed by Scheff's post-hoc test (∗p < 0.05 versus Ctrl, #p < 0.05 for LKO versus DKO, &p < 0.05 for LKO versus GKO or FKO).

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References

1. Ameka M., Markan K.R., Morgan D.A., BonDurant L.D., Idiga S.O., Naber M.C., Zhu Z., Zingman L.V., Grobe J.L., Rahmouni K. Liver derived FGF21 maintains core body temperature during acute cold exposure. Scientific Rep. 2019;9:630. - PMC - PubMed
1. Badman M.K., Koester A., Flier J.S., Kharitonenkov A., Maratos-Flier E. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology. 2009;150:4931–4940. - PMC - PubMed
1. Badman M.K., Pissios P., Kennedy A.R., Koukos G., Flier J.S., Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007;5:426–437. - PubMed
1. Bhaskaran S., Pharaoh G., Ranjit R., Murphy A., Matsuzaki S., Nair B.C., Forbes B., Gispert S., Auburger G., Humphries K.M. Loss of mitochondrial protease ClpP protects mice from diet-induced obesity and insulin resistance. EMBO Rep. 2018;19:e45009. - PMC - PubMed
1. BonDurant L.D., Ameka M., Naber M.C., Markan K.R., Idiga S.O., Acevedo M.R., Walsh S.A., Ornitz D.M., Potthoff M.J. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab. 2017;25:935–944.e4. - PMC - PubMed

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[1] Ameka M., Markan K.R., Morgan D.A., BonDurant L.D., Idiga S.O., Naber M.C., Zhu Z., Zingman L.V., Grobe J.L., Rahmouni K. Liver derived FGF21 maintains core body temperature during acute cold exposure. Scientific Rep. 2019;9:630. - PMC - PubMed

[2] Ameka M., Markan K.R., Morgan D.A., BonDurant L.D., Idiga S.O., Naber M.C., Zhu Z., Zingman L.V., Grobe J.L., Rahmouni K. Liver derived FGF21 maintains core body temperature during acute cold exposure. Scientific Rep. 2019;9:630. - PMC - PubMed

[3] Badman M.K., Koester A., Flier J.S., Kharitonenkov A., Maratos-Flier E. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology. 2009;150:4931–4940. - PMC - PubMed

[4] Badman M.K., Koester A., Flier J.S., Kharitonenkov A., Maratos-Flier E. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology. 2009;150:4931–4940. - PMC - PubMed

[5] Badman M.K., Pissios P., Kennedy A.R., Koukos G., Flier J.S., Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007;5:426–437. - PubMed

[6] Badman M.K., Pissios P., Kennedy A.R., Koukos G., Flier J.S., Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007;5:426–437. - PubMed

[7] Bhaskaran S., Pharaoh G., Ranjit R., Murphy A., Matsuzaki S., Nair B.C., Forbes B., Gispert S., Auburger G., Humphries K.M. Loss of mitochondrial protease ClpP protects mice from diet-induced obesity and insulin resistance. EMBO Rep. 2018;19:e45009. - PMC - PubMed

[8] Bhaskaran S., Pharaoh G., Ranjit R., Murphy A., Matsuzaki S., Nair B.C., Forbes B., Gispert S., Auburger G., Humphries K.M. Loss of mitochondrial protease ClpP protects mice from diet-induced obesity and insulin resistance. EMBO Rep. 2018;19:e45009. - PMC - PubMed

[9] BonDurant L.D., Ameka M., Naber M.C., Markan K.R., Idiga S.O., Acevedo M.R., Walsh S.A., Ornitz D.M., Potthoff M.J. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab. 2017;25:935–944.e4. - PMC - PubMed

[10] BonDurant L.D., Ameka M., Naber M.C., Markan K.R., Idiga S.O., Acevedo M.R., Walsh S.A., Ornitz D.M., Potthoff M.J. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab. 2017;25:935–944.e4. - PMC - PubMed

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Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response

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Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response

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Abstract

Conflict of interest statement

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Abstract

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