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Cited by 108Fibroblast Growth Factor ResearchAdipose Tissue and MetabolismAdipokines, Inflammation, and Metabolic Diseases

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Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/βKlotho Complex

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Kolumam, Ganesh, Chen, Mark Z., Tong, Raymond, Zavala-Solorio, Jose, Kates, Lance, van Bruggen, Nicholas, Ross, Jed, Wyatt, Shelby K., Gandham, Vineela D., Carano, Richard A.D., Dunshee, Diana Ronai, Wu, Ai-Luen, Haley, Benjamin, Anderson, Keith, Warming, Søren, Rairdan, Xin Y., Lewin-Koh, Nicholas, Zhang, Yingnan, Gutierrez, Johnny, Baruch, Amos, Gelzleichter, Thomas R., Stevens, Dale, Rajan, Sharmila, Bainbridge, Travis W., Vernes, Jean-Michel, Meng, Y. Gloria, Ziai, James, Soriano, Robert H., Brauer, Matthew J., Chen, Yongmei, Stawicki, Scott, Kim, Hok Seon, Comps-Agrar, Laëtitia, Luis, Elizabeth, Spiess, Christoph, Wu, Yan, Ernst, James A., McGuinness, Owen P., Peterson, Andrew S., Sonoda, Junichiro·2015·EBioMedicine
DOI 10.1016/j.ebiom.2015.05.028PMC PMC4534681
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Abstract

Dissipating excess calories as heat through therapeutic stimulation of brown adipose tissues (BAT) has been proposed as a potential treatment for obesity-linked disorders. Here, we describe the generation of a humanized effector-less bispecific antibody that activates fibroblast growth factor receptor (FGFR) 1/βKlotho complex, a common receptor for FGF21 and FGF19. Using this molecule, we show that antibody-mediated activation of FGFR1/βKlotho complex in mice induces sustained energy expenditure in BAT, browning of white adipose tissue, weight loss, and improvements in obesity-associated metabolic derangements including insulin resistance, hyperglycemia, dyslipidemia and hepatosteatosis. In mice and cynomolgus monkeys, FGFR1/βKlotho activation increased serum high-molecular-weight adiponectin, which appears to contribute over time by enhancing the amplitude of the metabolic benefits. At the same time, insulin sensitization by FGFR1/βKlotho activation occurs even before the onset of weight loss in a manner that is independent of adiponectin. Together, selective activation of FGFR1/βKlotho complex with a long acting therapeutic antibody represents an attractive approach for the treatment of type 2 diabetes and other obesity-linked disorders through enhanced energy expenditure, insulin sensitization and induction of high-molecular-weight adiponectin.

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Fig. 1 Selective activation of FGFR1c/KLB complex by bFKB1 (A) A proposed model for FGFR1c–KLB–bispecific Ab (bFKB1) complex formation for signal activation. D1, D2 and D3 denote each of the Immunoglobulin-like domains in FGFR1 extra cellular domain (ECD). KD: kinase domain. (B) A predicted model for FGFR1c–KLB–FGF21 complex formation for signal activation. (C) GAL–ELK1 luciferase assay of human FGF21 and bFKB1 activity using FGFR1–KO HEK293T cells generated by CRISPR/Cas9-mediated genome editing. Cells were transfected to express indicated receptors. h: human, c: cynomolgus monkey, and m: murine. Mean relative luciferase unit (RLU) ± SEM is shown. (D) GAL–ELK1 luciferase assay in L6 cells. Cells were co-transfected to express indicated receptors. Transfected cells were incubated with various concentrations of bFKB1, hFGF21, hFGF19 or R1MAb1. Mean fold change ± SEM in RLU is shown. (E) Western blot analysis of primary human adipocytes treated with indicated protein (hFGF21 (100 nM) or IgG (33 nM)) for 1 h. Each treatment was performed in duplicate. (F) Expression of UCP1 mRNA in primary human adipocytes treated with indicated protein at 30 nM for 48 h. N = 3. p < 0.005 (**). Data are presented as mean fold over vehicle control ± SEM.
Fig. 1 Selective activation of FGFR1c/KLB complex by bFKB1 (A) A proposed model for FGFR1c–KLB–bispecific Ab (bFKB1) complex formation for signal activation. D1, D2 and D3 denote each of the Immunoglobulin-like domains in FGFR1 extra cellular domain (ECD). KD: kinase domain. (B) A predicted model for FGFR1c–KLB–FGF21 complex formation for signal activation. (C) GAL–ELK1 luciferase assay of human FGF21 and bFKB1 activity using FGFR1–KO HEK293T cells generated by CRISPR/Cas9-mediated genome editing. Cells were transfected to express indicated receptors. h: human, c: cynomolgus monkey, and m: murine. Mean relative luciferase unit (RLU) ± SEM is shown. (D) GAL–ELK1 luciferase assay in L6 cells. Cells were co-transfected to express indicated receptors. Transfected cells were incubated with various concentrations of bFKB1, hFGF21, hFGF19 or R1MAb1. Mean fold change ± SEM in RLU is shown. (E) Western blot analysis of primary human adipocytes treated with indicated protein (hFGF21 (100 nM) or IgG (33 nM)) for 1 h. Each treatment was performed in duplicate. (F) Expression of UCP1 mRNA in primary human adipocytes treated with indicated protein at 30 nM for 48 h. N = 3. p < 0.005 (**). Data are presented as mean fold over vehicle control ± SEM.CC BY-NC-ND · PubMed Central
Fig. 2 Interaction between bFKB1 and FGFR1/KLB complex (A) Schematic representation of the TR-FRET experiment (left) and normalized TR-FRET ratio on COS7 cells expressing labeled SNAP-tagged hFGFR1c protein with or without untagged hKLB measured at 15 min after addition of indicated ligands (right). bFKB1, hFGF21, hFGF1 and hFGF2 were used at 67 nM, 50 nM, 62.5 nM, 125 nM, respectively. The data represents TR-FRET intensity at 665 nm divided by the donor emission at 620 nm (FRET ratio), and mean ± SEM of three independent experiments. N = 3. p < 0.05 (*), < 0.01 (**), < 0.0001 (***). (B) Evidence for a ternary complex formation by bFKB1, hFGFR1–ECD, and hKLB–ECD by SPR. hFGFR1–ECD–Fc fusion protein was immobilized on the chip, and binding of bFKB1 or preformed bFKB1/hKLB complex at 6.25, 12.5, 25, 50, 100, and 200 nM was analyzed. To generate preformed bFKB1/hKLB complex, bFKB1 and recombinant hKLB–ECD protein was preincubated at 1:1 ratio. Note the dissociation rate was slower with bFKB1/hKLB complex than with bFKB1 alone, but only when hFGFR1c, but not hFGFR1b, was captured on the chip. (C) Binding of hFGF21 and hFGF19 to bFKB1/hKLB complex by SPR. bFKB1 was captured on the chip, and hKLB–ECD protein and FGF protein (at 0.2, 0.8, or 2 μM) were sequentially injected as indicated by schematic diagram above. (D) Western blot to monitor ERK phosphorylation in H4IIE hepatoma cells. Note that bFKB1 did not block activity of hFGF19 to induce ERK phosphorylation as schematically shown on top.
Fig. 2 Interaction between bFKB1 and FGFR1/KLB complex (A) Schematic representation of the TR-FRET experiment (left) and normalized TR-FRET ratio on COS7 cells expressing labeled SNAP-tagged hFGFR1c protein with or without untagged hKLB measured at 15 min after addition of indicated ligands (right). bFKB1, hFGF21, hFGF1 and hFGF2 were used at 67 nM, 50 nM, 62.5 nM, 125 nM, respectively. The data represents TR-FRET intensity at 665 nm divided by the donor emission at 620 nm (FRET ratio), and mean ± SEM of three independent experiments. N = 3. p < 0.05 (*), < 0.01 (**), < 0.0001 (***). (B) Evidence for a ternary complex formation by bFKB1, hFGFR1–ECD, and hKLB–ECD by SPR. hFGFR1–ECD–Fc fusion protein was immobilized on the chip, and binding of bFKB1 or preformed bFKB1/hKLB complex at 6.25, 12.5, 25, 50, 100, and 200 nM was analyzed. To generate preformed bFKB1/hKLB complex, bFKB1 and recombinant hKLB–ECD protein was preincubated at 1:1 ratio. Note the dissociation rate was slower with bFKB1/hKLB complex than with bFKB1 alone, but only when hFGFR1c, but not hFGFR1b, was captured on the chip. (C) Binding of hFGF21 and hFGF19 to bFKB1/hKLB complex by SPR. bFKB1 was captured on the chip, and hKLB–ECD protein and FGF protein (at 0.2, 0.8, or 2 μM) were sequentially injected as indicated by schematic diagram above. (D) Western blot to monitor ERK phosphorylation in H4IIE hepatoma cells. Note that bFKB1 did not block activity of hFGF19 to induce ERK phosphorylation as schematically shown on top.CC BY-NC-ND · PubMed Central
Fig. 3 Metabolic improvements in obese mice by bFKB1 (A) Blood glucose levels (day 7), % body weight change (days 0–7) and daily food intake (days 0–3) of lean (+/+) and db/db mice after a single i.p. injection of bFKB1 or control IgG at 3 mg/kg (mpk) (+/+) or 5 mpk (db/db). N = 7–8 mice per group. Pre-dose body weight was 25.8 ± 0.4 (lean, IgG), 25.9 ± 0.5 (lean, bFKB1), 39.7 ± 0.7 (db/db, IgG) and 39.8 ± 1.1 (db/db, bFKB1) g. (B) Body weight and blood glucose levels of DIO mice received i.p. injection of indicated IgG at 3 mpk on days 0 and 6 (arrows). (C) Glucose tolerance test with the same mice used in (b) on day 14. (D) Hepatic triglycerides, and serum parameters in the same mice shown in (b–c) on day 17. N = 9 mice per group. p < 0.05 (*), < 0.005 (**), < 0.0001 (***) vs control. Data are mean ± SEM.
Fig. 3 Metabolic improvements in obese mice by bFKB1 (A) Blood glucose levels (day 7), % body weight change (days 0–7) and daily food intake (days 0–3) of lean (+/+) and db/db mice after a single i.p. injection of bFKB1 or control IgG at 3 mg/kg (mpk) (+/+) or 5 mpk (db/db). N = 7–8 mice per group. Pre-dose body weight was 25.8 ± 0.4 (lean, IgG), 25.9 ± 0.5 (lean, bFKB1), 39.7 ± 0.7 (db/db, IgG) and 39.8 ± 1.1 (db/db, bFKB1) g. (B) Body weight and blood glucose levels of DIO mice received i.p. injection of indicated IgG at 3 mpk on days 0 and 6 (arrows). (C) Glucose tolerance test with the same mice used in (b) on day 14. (D) Hepatic triglycerides, and serum parameters in the same mice shown in (b–c) on day 17. N = 9 mice per group. p < 0.05 (*), < 0.005 (**), < 0.0001 (***) vs control. Data are mean ± SEM.CC BY-NC-ND · PubMed Central
Fig. 4 Sustained induction of EE by FKB1 without altering RQ (A) Mean EE and RQ values of DIO mice received single i.p. injection of 10 mpk IgG at the indicated time (arrow). (B) Mean EE and RQ values of lean mice received single i.p. injection of 10 mpk IgG at the indicated time (arrow). Mice were maintained at 21 °C, then cage temperature was shifted to thermoneutrality (30 °C) after 6 days post IgG injection. (C) Mean EE values ± SEM in indirect calorimetry shown in (A) and (B). Mean fold increase value is shown under the graphs. (D) Daily mean EE values ± SEM per mouse (left) and body weight (right) of DIO mice received single i.p. injection of 10 mpk IgG at the indicated time (arrow). Mice were pre-acclimated at 30 °C for 4 weeks prior to the injection and then maintained at 30 °C throughout the experiment. Error bars omitted in (A) and (B) for clarity. p < 0.05 (*), < 0.005 (**) vs control.
Fig. 4 Sustained induction of EE by FKB1 without altering RQ (A) Mean EE and RQ values of DIO mice received single i.p. injection of 10 mpk IgG at the indicated time (arrow). (B) Mean EE and RQ values of lean mice received single i.p. injection of 10 mpk IgG at the indicated time (arrow). Mice were maintained at 21 °C, then cage temperature was shifted to thermoneutrality (30 °C) after 6 days post IgG injection. (C) Mean EE values ± SEM in indirect calorimetry shown in (A) and (B). Mean fold increase value is shown under the graphs. (D) Daily mean EE values ± SEM per mouse (left) and body weight (right) of DIO mice received single i.p. injection of 10 mpk IgG at the indicated time (arrow). Mice were pre-acclimated at 30 °C for 4 weeks prior to the injection and then maintained at 30 °C throughout the experiment. Error bars omitted in (A) and (B) for clarity. p < 0.05 (*), < 0.005 (**) vs control.CC BY-NC-ND · PubMed Central
Fig. 5 BAT stimulation and WAT browning by bFKB1 (A) Tissue FDG-uptake in DIO mice at 40 h after single i.p. injection of indicated IgG at 10 mpk. Mice were fasted overnight before FDG-uptake measurement. Data is mean ± SEM and represents % of dose given, normalized by tissue weight. (B) Western blot analysis of ingWAT harvested on day 7 after single i.p. injection (bFKB1 or control IgG at 10 mpk) and surgical implantation of an osmotic pump (CL-316,243 at 0.75 nmol/h or vehicle). (C) Core body temperature measurement in DIO mice. Mice received 10 mpk of bFKB1 or control IgG. The data shown are the mean values of 5 days in predose and postdose periods. (D) The same experimental result in (C) was plotted to show the fitted difference in core body temperature between mice received bFKB1 or control IgG over the course of the study. The black line is the estimated difference and the blue lines are the 95% pointwise confidence intervals of the difference. IgG was administered on day 0 (arrow). (E) Core body temperature measurement in DIO mice. Mice received 10 mpk of bFKB1 or control IgG. Cage temperature was elevated to thermoneutrality on day 8 after the injection. The data shown are the mean values of 3–4 days in predose and postdose periods. Error bars omitted in (C) and (E) for clarity. p < 0.05 (*), < 0.005 (**) vs control. (F) Gene expression profile in iBAT of DIO mice received single 10 mpk of IgG and hFGF21 b.i.d. at 2 mpk per day or vehicle PBS b.i.d. for 5 days. Tissue RNA was prepared on day 5 after the IgG injection. Of all the genes that were significantly altered by bFKB1 and hFGF21, only representative genes are listed. The results represent Z-score shown as a heat map and each column represents independent animal. N = 5 mice per group.
Fig. 5 BAT stimulation and WAT browning by bFKB1 (A) Tissue FDG-uptake in DIO mice at 40 h after single i.p. injection of indicated IgG at 10 mpk. Mice were fasted overnight before FDG-uptake measurement. Data is mean ± SEM and represents % of dose given, normalized by tissue weight. (B) Western blot analysis of ingWAT harvested on day 7 after single i.p. injection (bFKB1 or control IgG at 10 mpk) and surgical implantation of an osmotic pump (CL-316,243 at 0.75 nmol/h or vehicle). (C) Core body temperature measurement in DIO mice. Mice received 10 mpk of bFKB1 or control IgG. The data shown are the mean values of 5 days in predose and postdose periods. (D) The same experimental result in (C) was plotted to show the fitted difference in core body temperature between mice received bFKB1 or control IgG over the course of the study. The black line is the estimated difference and the blue lines are the 95% pointwise confidence intervals of the difference. IgG was administered on day 0 (arrow). (E) Core body temperature measurement in DIO mice. Mice received 10 mpk of bFKB1 or control IgG. Cage temperature was elevated to thermoneutrality on day 8 after the injection. The data shown are the mean values of 3–4 days in predose and postdose periods. Error bars omitted in (C) and (E) for clarity. p < 0.05 (*), < 0.005 (**) vs control. (F) Gene expression profile in iBAT of DIO mice received single 10 mpk of IgG and hFGF21 b.i.d. at 2 mpk per day or vehicle PBS b.i.d. for 5 days. Tissue RNA was prepared on day 5 after the IgG injection. Of all the genes that were significantly altered by bFKB1 and hFGF21, only representative genes are listed. The results represent Z-score shown as a heat map and each column represents independent animal. N = 5 mice per group.CC BY-NC-ND · PubMed Central
Fig. 6 Role of adiponectin in the bFKB1 treatment (A, B) Body weight change, serum HMW adiponectin and serum human bFKB1 levels in DIO mice ((A), N = 6 mice per group) or cynomolgus monkeys ((B), N = 3 monkeys per group) received single i.v. injection of bFKB1 at indicated dose (mpk). Pre-dose mean body weight ± SEM of mice used in (A) was 44.0 ± 1.3 (vehicle), 44.7 ± 1.2 (0.3 mpk), 46.5 ± 0.5 (3 mpk) and 42.1 ± 1.3 (30 mpk) g. (C) Mean EE values per mouse of DIO mice (left: WT and right: Adipoq KO) received single i.p. injection of indicated IgG at 10 mpk (arrow). Error bars omitted for clarity. (D) Metabolic parameters in WT (+/+) and Adipoq KO (−/−) DIO mice treated with single i.p. injection of indicated IgG at 10 mpk. Pre-dose mean body weight ± SEM was 47.5 ± 2.3 (WT, IgG), 47.6 ± 2.1 (WT, bFKB1), 47.3 ± 1.7 (KO, IgG) and 47.6 ± 1.6 (KO, bFKB1) g. N = 5–6 mice per group. AUC: area under the curve in GTT or ITT (T = 0–2 h). p < 0.05 (*), < 0.005 (**) vs control. In (B), p values are calculated using % change from the base line. Data are mean ± SEM.
Fig. 6 Role of adiponectin in the bFKB1 treatment (A, B) Body weight change, serum HMW adiponectin and serum human bFKB1 levels in DIO mice ((A), N = 6 mice per group) or cynomolgus monkeys ((B), N = 3 monkeys per group) received single i.v. injection of bFKB1 at indicated dose (mpk). Pre-dose mean body weight ± SEM of mice used in (A) was 44.0 ± 1.3 (vehicle), 44.7 ± 1.2 (0.3 mpk), 46.5 ± 0.5 (3 mpk) and 42.1 ± 1.3 (30 mpk) g. (C) Mean EE values per mouse of DIO mice (left: WT and right: Adipoq KO) received single i.p. injection of indicated IgG at 10 mpk (arrow). Error bars omitted for clarity. (D) Metabolic parameters in WT (+/+) and Adipoq KO (−/−) DIO mice treated with single i.p. injection of indicated IgG at 10 mpk. Pre-dose mean body weight ± SEM was 47.5 ± 2.3 (WT, IgG), 47.6 ± 2.1 (WT, bFKB1), 47.3 ± 1.7 (KO, IgG) and 47.6 ± 1.6 (KO, bFKB1) g. N = 5–6 mice per group. AUC: area under the curve in GTT or ITT (T = 0–2 h). p < 0.05 (*), < 0.005 (**) vs control. In (B), p values are calculated using % change from the base line. Data are mean ± SEM.CC BY-NC-ND · PubMed Central
Fig. 7 Adiponectin-independent insulin sensitization by bFKB1 in hyperinsulinemic–euglycemic clamp (A) Body weight on the day of the clamp experiment. WT (+/+) and Adipoq KO (−/−) mice on HFD received bFKB1 or control IgG at 10 mpk on 3 days before the clamp experiment. N = 8–10 mice per group. (B) Arterial blood glucose at baseline and during the steady state (left) and glucose infusion rate during the steady state (right). (C) Whole body glucose utilization plotted against plasma insulin level. (D) Insulin-stimulated tissue glucose uptake. (E) % suppression of endogenous glucose production (EGP). (F) Body weight on the day of the second clamp experiment. DIO mice received bFKB1 or control IgG at 10 mpk on 5 days before the clamp experiment. N = 11–12 mice per group. (G) Arterial blood glucose at baseline and during the steady state (left) and glucose infusion rate during the steady state (right). (H) Whole body glucose utilization plotted against plasma insulin level. (I) Insulin-stimulated tissue glucose uptake. (J) EGP and % suppression. In (C) and (H), the arrows indicate the direction of changes from the basal to the insulin-stimulated state. p < 0.05 (*), < 0.005 (**) vs control. Data are mean ± SEM.
Fig. 7 Adiponectin-independent insulin sensitization by bFKB1 in hyperinsulinemic–euglycemic clamp (A) Body weight on the day of the clamp experiment. WT (+/+) and Adipoq KO (−/−) mice on HFD received bFKB1 or control IgG at 10 mpk on 3 days before the clamp experiment. N = 8–10 mice per group. (B) Arterial blood glucose at baseline and during the steady state (left) and glucose infusion rate during the steady state (right). (C) Whole body glucose utilization plotted against plasma insulin level. (D) Insulin-stimulated tissue glucose uptake. (E) % suppression of endogenous glucose production (EGP). (F) Body weight on the day of the second clamp experiment. DIO mice received bFKB1 or control IgG at 10 mpk on 5 days before the clamp experiment. N = 11–12 mice per group. (G) Arterial blood glucose at baseline and during the steady state (left) and glucose infusion rate during the steady state (right). (H) Whole body glucose utilization plotted against plasma insulin level. (I) Insulin-stimulated tissue glucose uptake. (J) EGP and % suppression. In (C) and (H), the arrows indicate the direction of changes from the basal to the insulin-stimulated state. p < 0.05 (*), < 0.005 (**) vs control. Data are mean ± SEM.CC BY-NC-ND · PubMed Central
Fig. 8 Evidence for FGFR1- and KLB-dependent activity of bFKB1 in vivo. (A) Western blot analysis of epididymal WAT (eWAT) from WT (+/+) or Klb-deficient (−/−) mice. (B) Mean EE values per mouse during 4–5 days post IgG injection at 10 mpk in Klb-deficient DIO mice measured by indirect calorimetry. N = 6 mice per group. (C) GTT with DIO mice heterozygous (+/−) or homozygous (−/−) for the Klb-deficient allele. Mice received 4 weekly injections of bFKB1 or control IgG at 3 mpk. GTT was conducted on day 23, on 3 days after the final injection. N = 5 mice per group. (D) Serum parameters in DIO mice on day 7 after i.p. injection of bFKB1 or R1MAb1 at 50 mpk or vehicle. N = 6 mice per group. (E) MAPK signal activation by bFKB1 or hFGF21 in mouse tissues. Tissues were harvested at 1 h (liver, pancreas and eWAT) or 2 h (iBAT or ingWAT) after i.p. injection of lean mice at 10 mpk (bFKB1) or 1 mpk (FGF21). p < 0.05 (*), < 0.01 (**). Data are mean ± SEM.
Fig. 8 Evidence for FGFR1- and KLB-dependent activity of bFKB1 in vivo. (A) Western blot analysis of epididymal WAT (eWAT) from WT (+/+) or Klb-deficient (−/−) mice. (B) Mean EE values per mouse during 4–5 days post IgG injection at 10 mpk in Klb-deficient DIO mice measured by indirect calorimetry. N = 6 mice per group. (C) GTT with DIO mice heterozygous (+/−) or homozygous (−/−) for the Klb-deficient allele. Mice received 4 weekly injections of bFKB1 or control IgG at 3 mpk. GTT was conducted on day 23, on 3 days after the final injection. N = 5 mice per group. (D) Serum parameters in DIO mice on day 7 after i.p. injection of bFKB1 or R1MAb1 at 50 mpk or vehicle. N = 6 mice per group. (E) MAPK signal activation by bFKB1 or hFGF21 in mouse tissues. Tissues were harvested at 1 h (liver, pancreas and eWAT) or 2 h (iBAT or ingWAT) after i.p. injection of lean mice at 10 mpk (bFKB1) or 1 mpk (FGF21). p < 0.05 (*), < 0.01 (**). Data are mean ± SEM.CC BY-NC-ND · PubMed Central

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Authors
Kolumam, G., Chen, M. Z., Tong, R., Zavala-Solorio, J., Kates, L., van Bruggen, N., Ross, J., Wyatt, S. K., Gandham, V. D., Carano, R. A. D., Dunshee, D. R., Wu, A.-L., Haley, B., Anderson, K., Warming, S., Rairdan, X. Y., Lewin-Koh, N., Zhang, Y., Gutierrez, J., Baruch, A., Gelzleichter, T. R., Stevens, D., Rajan, S., Bainbridge, T. W., Vernes, J.-M., Meng, Y. G., Ziai, J., Soriano, R. H., Brauer, M. J., Chen, Y., Stawicki, S., Kim, H. S., Comps-Agrar, L., Luis, E., Spiess, C., Wu, Y., Ernst, J. A., McGuinness, O. P., Peterson, A. S., & Sonoda, J.
Affiliations
  • Genentech (US)
  • Vanderbilt University (US)
Corresponding author
Sonoda, Junichiro
ORCID
Venue
EBioMedicine
Publisher
Elsevier BV
Published
2015-07
Volume
2
Issue
7
Pages
730-743
ISSN
2352-3964 (ISSN-L)
DOI
10.1016/j.ebiom.2015.05.028
PMC
PMC4534681
OpenAlex
W2156319327
Cited by
108
References
58
Citations by year
2026: 3 · 2025: 7 · 2024: 12 · 2023: 5 · 2022: 13 · 2021: 12 · 2020: 9 · 2019: 8 · 2018: 12 · 2017: 13 · 2016: 10 · 2015: 4
FWCI
5.65
Type
journal article
Language
en
Open access
Licence
Locations
  • EBioMedicine (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Genentech
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
  • Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Keywords
brown adipose tissue, humanized monoclonal antibody, FGF21, FGF19, energy expenditure, white adipose tissue browning, weight loss, insulin sensitization, high molecular weight adiponectin, obesity, type 2 diabetes, hepatic steatosis, dyslipidemia, hyperglycemia
MeSH terms
Klotho Proteins, Animals, Adipose Tissue, Brown, Cell Line, Energy Metabolism, Fibroblast Growth Factors, Humans, Insulin, Macaca fascicularis, Male, Membrane Proteins, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Obese, Protein Binding, Weight Loss, Antibodies, Bispecific, Thermogenesis, Receptor, Fibroblast Growth Factor, Type 1, Adiponectin, HEK293 Cells

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