FGF21 Regulates Sweet and Alcohol Preference - PubMed (original) (raw)

. 2016 Feb 9;23(2):344-9.

doi: 10.1016/j.cmet.2015.12.008. Epub 2015 Dec 24.

Bryn M Owen 2, Parkyong Song 2, Genaro Hernandez 2, Yuan Zhang 2, Yingjiang Zhou 1, William T Scott 2, Bhavna Paratala 3, Tod Turner 1, Andrew Smith 3, Barbara Bernardo 3, Christian P Müller 4, Hao Tang 5, David J Mangelsdorf 6, Bryan Goodwin 1, Steven A Kliewer 7

Affiliations

FGF21 Regulates Sweet and Alcohol Preference

Saswata Talukdar et al. Cell Metab. 2016.

Abstract

Fibroblast growth factor 21 (FGF21) is a hormone induced by various metabolic stresses, including ketogenic and high-carbohydrate diets, that regulates energy homeostasis. In humans, SNPs in and around the FGF21 gene have been associated with macronutrient preference, including carbohydrate, fat, and protein intake. Here we show that FGF21 administration markedly reduces sweet and alcohol preference in mice and sweet preference in cynomolgus monkeys. In mice, these effects require the FGF21 co-receptor β-Klotho in the central nervous system and correlate with reductions in dopamine concentrations in the nucleus accumbens. Since analogs of FGF21 are currently undergoing clinical evaluation for the treatment of obesity and type 2 diabetes, our findings raise the possibility that FGF21 administration could affect nutrient preference and other reward behaviors in humans.

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Figures

Figure 1

Figure 1. FGF21 decreases sweet preference ratio in mice by acting on the CNS

(A) Two-bottle preference assay in wild-type (WT) and Tg(Fgf21) mice administered water vs. 3% sucrose. Representative 24 hour data from day 2 after initiating the assay are shown as the sucrose preference ratio (sucrose intake volume/total fluid intake volume). n = 10–11/group. (B) Two-bottle preference assay in WT and Tg(Fgf21) mice administered water vs. 0.2% saccharin. Representative 24 hour data from day 2 after initiating the assay are shown. n = 10–11/group. (C) Two-bottle preference assay with water vs. 0.2% saccharin for Klbfl/fl and KlbCamk2a mice administered either FGF21 (1 mg/kg/day) or vehicle. Representative 24 hour data from day 3 after initiating the assay are shown. n = 6–9/group. (D) Two-bottle preference assay with water vs. 2 mg/dl quinine for Klbfl/fl and KlbCamk2a mice administered either FGF21 (1 mg/kg/day) or vehicle. n = 4/group. Values are means ±S.E.M. *, p<0.05; ***, p<0.001; ###, p<0.001 by Student’s _t_-test. See also Figure S1, Table S1 and S2.

Figure 2

Figure 2. A stable FGF21 analog decreases saccharin preference in mice and monkeys

(A) Two bottle preference assay with 0.1% saccharin in diet-induced obese mice administered either PF-05231023 (10 mg/kg) or vehicle on days 0, 3, 7 and 10. Data are shown as the mean ± S.E.M.; n = 8/group. **p < 0.01, ***p < 0.001 versus vehicle group. (B) Two bottle preference assay with 0.2% saccharin in obese cynomolgus monkeys administered either PF-05231023 (n=8; 10 mg/kg) or vehicle (n=7) on days 1, 4 and 7. Data are presented as mean percentage change in saccharin water intake ± S.E.M. for vehicle-treated (closed blue circles) and PF-05231023-treated (open red circles) monkeys. Solid lines are locally weighted scatterplot smoothing fits to the means of percent change. Mixed effect modeling fitted to these longitudinal data using R, version 3.1.2 (Pinheiro et al., 2013), showed a significant difference (p = 0.003) between groups. Number of days after first treatment, treatment type, and the interaction term between treatment groups and time were specified as fixed effects and monkey labels as a random effect.

Figure 3

Figure 3. FGF21 affects dopamine signaling

(A) β-Klotho (Klb) mRNA levels in the suprachiasmatic nucleus/paraventricular nucleus (SCN/PVN) region of the hypothalamus, ventral tegmental area (VTA), nucleus accumbens (NAc), medial prefrontal cortex (PFC) and caudate putamen of Klb+/− and _Klb_−/− mice (n = 6/group). Ct values are shown in the bars. ND, not detected. (B) Concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) in the NAc of mice administered either vehicle or FGF21 for 2 weeks by osmotic minipump (n = 12/group). (C) mRNA levels of dopamine transporter (Slc6a3) or (D) catechol-O-methyl transferase (Comt) in VTA, NAc and caudate putamen of mice administered either vehicle or FGF21 for 2 weeks by osmotic minipump (n = 7–8/group). Ct values are shown. Values are means ±S.E.M. *, p<0.05; **, p<0.01; ***, p<0.001 versus control group by Student’s _t_-test. See also Figure S2.

Figure 4

Figure 4. FGF21 decreases alcohol preference

(A) Ethanol preference ratio in wild-type (WT) and Tg(Fgf21) mice at the indicated ethanol concentrations (n = 9/group). (B) Plasma ethanol concentrations in groups of WT and Tg(Fgf21) mice 1 or 3 hours after i.p. injection of ethanol (4g/kg) (n = 4–5/group). Values are means ±S.E.M. *, p<0.05; **, p<0.01; and ***, p<0.001 versus control group by Student’s _t_-test. See also Table S3.

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