1. Volume 26, Issue 5, Pages 709-718.e3 (November 2017)
FGF19, FGF21, and an FGFR1/β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia 
Tian Lan, Donald A. Morgan, Kamal Rahmouni, Junichiro Sonoda, Xiaorong Fu, Shawn C. Burgess, William L. Holland, Steven A. Kliewer, David J. Mangelsdorf 
Cell Metabolism 
Volume 26, Issue 5, Pages e3 (November 2017)
DOI: /j.cmet
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2. Cell Metabolism 2017 26, 709-718.e3DOI: (10.1016/j.cmet.2017.09.005)
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3. Figure 1
FGF19 but Not FGF21 Has Robust Direct Effects on Hepatocytes under Acute Treatment Conditions
(A) DIO Klbfl/fl and KlbAlb littermates were i.p. injected with 1 mg/kg FGF19, FGF21, or vehicle and killed 6 hr later. Cyp7a1 mRNA in liver was measured by qPCR. n = 5/group.
(B and C) DIO Klbfl/fl and KlbAlb littermates were i.p. injected with 1 mg/kg FGF19, FGF21, or vehicle and killed 30 min later.
(B) Phosphorylated ERK1/2 normalized to total ERK1/2 protein in liver was measured by western blot.
(C) Egr1 mRNA levels in liver were measured by qPCR. n = 6/group. qPCR cycle time values are shown for the vehicle-treated Klbfl/fl group.
Data are shown as the mean ± SEM. ∗∗p < 0.01, ∗∗∗p < compared with control. N.S., not significant. Significant interactions between genotype (Klbfl/fl versus KlbAlb) and treatment (vehicle versus FGF19) were detected for p-ERK1/2/T-ERK/1/2 (p = ) and Egr1 mRNA (p = 0.004). See also Figure S1 and Table S1.
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4. Figure 2
β-Klotho in Liver Is Not Required for FGF19 and FGF21 to Cause Weight Loss
(A and B) DIO Klbfl/fl and KlbAlb littermates were treated with FGF19, FGF21, or vehicle for 2 week. (A) Body weight change, plasma insulin and glucose levels, (B) hepatic triglyceride and cholesterol levels, and plasma adiponectin levels were measured. n = 5–6/group.
Data are shown as the mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < compared with control. See also Figures S1 and S2, and Table S1.
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5. Figure 3
β-Klotho in Adipose Tissue Is Required for the Acute Insulin-Sensitizing Actions of FGF21 and FGF19
(A) DIO Klbfl/fl and KlbAdipoq littermates were treated with FGF21 or vehicle during a hyperinsulinemic-euglycemic clamp and the glucose infusion rate, endogenous glucose production, and whole-body glucose uptake during the clamp and basal endogenous glucose production were measured. n = 5–6/group.
(B) DIO Klbfl/fl and KlbAdipoq littermates were treated with FGF19 or vehicle during a hyperinsulinemic-euglycemic clamp and the glucose infusion rate, endogenous glucose production, and whole-body glucose uptake during the clamp and basal endogenous glucose production were measured. n = 6–8/group.
Data are shown as the mean ± SEM. ∗p < 0.05, ∗∗p < 0.01 compared with control. Significant interactions between genotype (Klbfl/fl versus KlbAdipoq) and treatment (vehicle versus FGF21) were detected for glucose infusion rate (p = 0.03) and endogenous glucose production (p = 0.02). See also Table S1.
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6. Figure 4
β-Klotho in Adipose Tissue Is Not Required for FGF19 and FGF21 to Cause Weight Loss
DIO Klbfl/fl and KlbAdipoq littermates were treated with FGF19 (A), FGF21 (B), or vehicle for 2 weeks. Body weight change, plasma insulin and glucose levels, hepatic triglyceride levels, plasma adiponectin levels, and hepatic ceramide concentrations were measured. n = 5–6/group.
Data are shown as the mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < compared with control. See also Figures S1 and S3, and Table S1.
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7. Figure 5 FGF19 Acts on the Nervous System to Cause Weight Loss
(A) DIO Klbfl/fl and KlbCamk2a littermates were administered FGF19 or vehicle for 2 weeks. Body weight, plasma insulin and glucose levels, hepatic triglyceride levels, and plasma adiponectin levels were measured. n = 5–6/group.
(B) Percent change in sympathetic nerve activity subserving BAT was recorded in mice following i.c.v. (top panel) or i.v. (bottom panel) injection of FGF19 at the indicated doses or vehicle. n = 7–8/group.
(C) Representative 24 hr energy expenditure in DIO mice administered FGF19 or vehicle (left). Quantification of 24 hr energy expenditure for the same mice (right). n = 5/group.
(D) 24 hr food intake (left and middle) and activity (right) in DIO mice treated with FGF19 or vehicle as in (C). n = 5/group.
Data are shown as the mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < compared with control.
Significant interactions between genotype (Klbfl/fl versus KlbCamk2a) and treatment (vehicle versus FGF19) were detected for body weight change at week 2 (p = 0.04) and plasma glucose (p = 0.02). See also Figures S1 and S4, and Table S1.
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8. Figure 6
The FGFR1c/β-Klotho Activating Antibody Acts Directly on the Nervous System to Regulate Body Weight and Circulating Glucose and Insulin Levels
(A) DIO Klbfl/fl and KlbAdipoq littermates were administered either bFKB1 or control antibody (trastuzumab) for 4 weeks, with dosing every 2 weeks. Body weight change, plasma insulin and glucose levels, hepatic triglyceride levels, and plasma adiponectin levels were measured. n = 6/group.
(B) DIO Klbfl/fl and KlbCamk2a littermates were administered bFKB1 or control antibody (trastuzumab) for 4 weeks. Body weight change, plasma insulin and glucose levels, hepatic triglyceride levels, and plasma adiponectin levels were measured. n = 6/group.
(C) bFKB1 levels in the cerebrospinal fluid (CSF) and plasma were measured in DIO mice 10 days after i.p. injection of bFKB1 or PBS (left and middle panels). CSF/plasma ratio for bFKB1 (right panel). n = 4–5/group.
Data are shown as the mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < compared with control. ND, not detected. Significant interactions between genotype (Klbfl/fl versus KlbCamk2a) and treatment (control IgG versus bFKB1) were detected for body weight change at week 4 (p = 0.04) and plasma glucose (p = 0.004).
See also Figure S5 and Table S1.
Cell Metabolism  , e3DOI: ( /j.cmet )
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