1. Volume 25, Issue 4, Pages 935-944.e4 (April 2017)
FGF21 Regulates Metabolism Through Adipose-Dependent and -Independent Mechanisms 
Lucas D. BonDurant, Magdalene Ameka, Meghan C. Naber, Kathleen R. Markan, Sharon O. Idiga, Michael R. Acevedo, Susan A. Walsh, David M. Ornitz, Matthew J. Potthoff 
Cell Metabolism 
Volume 25, Issue 4, Pages e4 (April 2017)
DOI: /j.cmet
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2. Cell Metabolism 2017 25, 935-944.e4DOI: (10.1016/j.cmet.2017.03.005)
Copyright © 2017 Elsevier Inc. Terms and Conditions

3. Figure 1
FGF21 Signaling to Adipose Tissues Is Required for Its Acute Insulin-Sensitizing Effects but Does Not Require Adiponectin
(A) Klb mRNA levels in epididymal WAT (eWAT), subcutaneous WAT (scWAT), interscapular BAT, and liver of 12- to 13-week-old wild-type (WT) and β-klotho adipose-specific knockout mice (KLB AdipoKO) (n = 6/group).
(B) Western blot analysis of phospho-ERK1/2 and total ERK1/2 levels from eWAT of 12- to 13-week-old WT and KLB AdipoKO mice administered vehicle (Veh) or FGF21 (1 mg/kg) for 15 min.
(C) Percent change in plasma glucose levels in lean, 12- to 14-week-old, male KLB AdipoKO mice and WT littermate controls coinjected with insulin and either vehicle or FGF21 (1 mg/kg) (n = 6/group).
(D) Percent change in plasma glucose levels in 16- to 18-week-old, male, diet-induced obese (DIO) KLB AdipoKO mice and WT littermate controls coinjected with insulin and either vehicle or FGF21 (1 mg/kg) (n = 5–6/group).
(E and F) Plasma adiponectin levels at the indicated time points in (E) 12- to 13-week-old, chow-fed, male WT (KLBfl/fl) and (F) DIO 16- to 18-week-old, male WT (KLBfl/fl) mice on high-fat diet for 12 weeks after i.p. administration of vehicle or FGF21 (1 mg/kg) (n = 8/group).
(G) Percent change in plasma glucose levels in 12- to 14-week-old, male WT (+/+ and +/−) and Adiponectin-knockout (Adipoq-KO) littermates coinjected with insulin and either vehicle or FGF21 (1 mg/kg) (n = 6/group).
Values are mean ± SEM (∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.005; and #, p < 0.001).
Cell Metabolism  , e4DOI: ( /j.cmet )
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4. Figure 2
Adiponectin Is Dispensable for the Chronic Effects of FGF21 on Energy Expenditure and Insulin Sensitivity
(A–J) 16- to 18-week-old DIO WT and Adipoq-KO mice were administered vehicle or FGF21 (1 mg/kg) via i.p. injection daily for 3 weeks (n = 5–9/group). (A) Plasma adiponectin levels, (B) Adipoq mRNA levels in the indicated tissues, (C) daily percent change in body weight, (D) final percent change in body weight, (E) percent fat mass, (F) hepatic triglyceride levels, (G) plasma cholesterol, (H) plasma insulin, and (I) plasma leptin levels in DIO WT and Adipoq KO mice administered vehicle or FGF21 for 3 weeks. (J) Insulin tolerance tests in DIO WT and Adipoq KO mice after 3 weeks (n = 5–7/group).
Values are mean ± SEM (∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.005; and #, p < 0.001).
Cell Metabolism  , e4DOI: ( /j.cmet )
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5. Figure 3
The Energy-Expending Effects of FGF21 Do Not Require Direct Signaling to Adipose Tissue
(A–H) 16- to 18-week-old DIO WT and KLB AdipoKO mice were implanted with osmotic minipumps delivering vehicle or FGF21 (1 mg/kg/day) for 2 weeks. (A) Plasma human FGF21, (B) plasma adiponectin, (C) final percent change in body weight, (D) hepatic triglycerides, (E) plasma triglycerides, (F) plasma glucose, (G) plasma insulin, and (H) plasma leptin levels are shown for the indicated mice (n = 5–7/group).
(I) Glucose tolerance tests in DIO WT and KLB AdipoKO mice after 2 weeks’ daily i.p. injection of vehicle or FGF21 (1 mg/kg) (n = 5–8/group).
(J) Area under the curve (AUC) for mice in (I).
(K) Insulin tolerance tests in DIO WT and KLB AdipoKO mice after 3 weeks’ daily i.p. injection of vehicle or FGF21 (1 mg/kg) (n = 5–8/group).
(L) Area under the curve for mice in (K).
(M) caFGFR1 mRNA levels in eWAT, scWAT, and BAT of WT, Adipo-rtTA transgenic, TRE-caFGFR1 transgenic, and Adipo-rtTA/TRE-caFGFR1 double-transgenic mice given water with or without doxycycline (DOX) for 5 days.
(N–S) WT, TRE-caFGFR1 transgenic, and Adipo-rtTA/TRE-caFGFR1 double-transgenic mice were induced to obesity by 12 weeks of HFD feeding. Groups of mice were then switched to HFD + DOX for 2 weeks (n = 7–10/group). (N) Western blot analysis of Myc and phospho-ERK1/2 levels in eWAT from mice with the indicated genotypes. (O) Egr1 and cFos mRNA expression in eWAT of the indicated mice. Final percent body weight change (P), hepatic triglycerides (Q), plasma insulin (R), and plasma glucose levels (S) are shown in the indicated mice on HFD + DOX for 2 weeks.
Values are mean ± SEM (∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.005; and #, p < 0.001).
Cell Metabolism  , e4DOI: ( /j.cmet )
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6. Figure 4
FGF21 Signaling to Brown Adipocytes Is Required for Its Acute Insulin-Sensitizing Effects
(A) Klb mRNA levels in eWAT, scWAT, BAT, and liver of 12- to 14-week-old WT and β-klotho brown adipose-specific knockout mice (KLB BatKO) (n = 6/group).
(B) Percent change in plasma glucose levels in 12- to 14-week-old, male KLB BatKO mice and WT controls coinjected with insulin and either vehicle or FGF21 (1 mg/kg) (n = 6/group).
(C) Percent change in plasma glucose levels in 12- to 14-week-old, male adipose-specific insulin-receptor knockout (IR AdipoKO) mice and WT controls coinjected with insulin and either vehicle or FGF21 (1 mg/kg) (n = 5–7/group).
(D) PET/CT images of relative [18F]-FDG uptake in WT and KLB BatKO mice coinjected with insulin and either vehicle or FGF21 (1 mg/kg).
(E) Average standard uptake value in interscapular BAT of the indicated mice (n = 5–8/group).
(F) Tissue-specific glucose uptake assays using [3H]-2-deoxyglucose in WT and KLB BatKO mice coinjected with insulin and either vehicle or FGF21 (1 mg/kg) for 90 min (n = 5–13/group).
Values are mean ± SEM (∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.005; and #, p < 0.001).
Cell Metabolism  , e4DOI: ( /j.cmet )
Copyright © 2017 Elsevier Inc. Terms and Conditions