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. 2016 Feb 9;23(2):335-43.
doi: 10.1016/j.cmet.2015.12.003. Epub 2015 Dec 24.

FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver

Stephanie von Holstein-Rathlou  1 , Lucas D BonDurant  2 , Lila Peltekian  2 , Meghan C Naber  2 , Terry C Yin  3 , Kristin E Claflin  4 , Adriana Ibarra Urizar  1 , Andreas N Madsen  5 , Cecilia Ratner  5 , Birgitte Holst  5 , Kristian Karstoft  6 , Aurelie Vandenbeuch  7 , Catherine B Anderson  7 , Martin D Cassell  8 , Anthony P Thompson  8 , Thomas P Solomon  9 , Kamal Rahmouni  2 , Sue C Kinnamon  7 , Andrew A Pieper  3 , Matthew P Gillum  10 , Matthew J Potthoff  11
Affiliations

FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver

Stephanie von Holstein-Rathlou et al. Cell Metab. .

Abstract

The liver is an important integrator of nutrient metabolism, yet no liver-derived factors regulating nutrient preference or carbohydrate appetite have been identified. Here we show that the liver regulates carbohydrate intake through production of the hepatokine fibroblast growth factor 21 (FGF21), which markedly suppresses consumption of simple sugars, but not complex carbohydrates, proteins, or lipids. Genetic loss of FGF21 in mice increases sucrose consumption, whereas acute administration or overexpression of FGF21 suppresses the intake of both sugar and non-caloric sweeteners. FGF21 does not affect chorda tympani nerve responses to sweet tastants, instead reducing sweet-seeking behavior and meal size via neurons in the hypothalamus. This liver-to-brain hormonal axis likely represents a negative feedback loop as hepatic FGF21 production is elevated by sucrose ingestion. We conclude that the liver functions to regulate macronutrient-specific intake by producing an endocrine satiety signal that acts centrally to suppress the intake of "sweets."

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Figures

Figure 1
Figure 1. Loss of FGF21 alters macronutrient-specific intake
(A) High sucrose diet (HSD) preference ratio (g HSD intake/g Chow intake) in 12-13 week old, male wild-type (WT), FGF21 heterozygous (HET), and FGF21 total knockout (FGF21 KO) littermates (n = 7-8/group). (B) Body weights of mice in (A). (C-G) 16 week old, male WT, HET, and FGF21 KO littermates were offered a two-bottle choice of different nutrients (n = 6-14/group; see methods). Fluid intake per day of (C) 10% sucrose, (D) 10% fructose, (E) 10% glucose, (F) 2% maltodextrin, and (F) 20% intralipid for the indicated mice. Values are mean +/− SEM. (*, P< 0.05; ***, P< 0.005; and #, P<0.001 compared to WT).
Figure 2
Figure 2. Ingestion of carbohydrate stimulates FGF21 production from liver
(A) Hepatic Fgf21 mRNA and (B) plasma FGF21 protein levels in 11-13 week old, male WT C57Bl/6 mice ad libitum fed chow and provided water, 0.2% saccharin (sacc), 10% glucose (gluc), 10% fructose (fruc), or 10% sucrose (sucr) ad libitum in a drinking bottle for 24 hours (n = 5/group). (C) Hepatic Fgf21 mRNA and (D) plasma FGF21 protein levels in 11-13 week old, male WT C57Bl/6 mice ad libitum fed chow and provided 10% sucrose ad libitum for the indicated time (n = 5/group). (E) Hepatic Fgf21 mRNA and (F) plasma FGF21 protein levels in 10-12 week old, male WT and FGF21 LivKO mice ad libitum fed chow and 10% sucrose ad libitum for 24 hours (n = 5-7/group). (G) HSD preference ratio in 10-12 week old, male WT (FGF21fl/fl) and FGF21 liver-specific knockout (FGF21 LivKO) mice (n = 5/group). (H) Plasma FGF21 levels in human subjects maintained at hyperglycemia via dextrose infusion for 0, 2, and 24 hours (n = 10). (I) Plasma FGF21 levels in WT and ChREBP KO mice ad libitum fed chow and 10% sucrose ad libitum for 24 hours (n = 5-8/group). Values are mean +/− SEM. (*, P< 0.05; **, P< 0.01; ***, P< 0.005; ***, #, P< 0.001 compared to WT).
Figure 3
Figure 3. FGF21 suppresses the intake of sweet tastants
(A) Percent intake of chow and high sucrose diet (HSD) in 12-16 week old, male WT and FGF21 transgenic (TG) mice (n = 7-12/group). (B) HSD preference ratio (g HSD intake/g Chow intake) in WT C57BL/6 mice receiving the indicated amount of FGF21 (n = 4/group). (C) Sucrose intake was assessed before (Pre), during (Treat), or after (Post) treatment with vehicle or FGF21 (1 mg/kg) via i.p. injection (Treat) for 3 days (n = 7-8/group). (D-M) WT male C57Bl/6 mice were implanted with identification chips and osmotic minipumps delivering vehicle or human FGF21 protein (n = 16/group). Sucrose and sucralose intake (D,I), preference (E,J), meal size (F,K), meal count (G,L), and meal interval (H,M) (n = 8/group) versus water (n = 8/group). (N) Sucrose and (O) sucralose intake per day of mice in (D) and (I), respectively. Values are mean +/− SEM. (*, P< 0.05; **, P< 0.01; ***, P< 0.005; #, P< 0.001 compared to WT; statistical significance in N,O for body weight are relative to the starting value on day 1 for each group.).
Figure 4
Figure 4. FGF21 signaling to the PVN suppresses sucrose preference
(A-B) Chorda tympani nerve recordings in male C57Bl/6 mice administered FGF21 (1 mg/kg) or vehicle (n = 5/group). (A) Ratio of nerve recording responses after sucrose (500 mM), glucose (500 mM), sucralose (50 mM), saccharin (50 mM), and NaCl (100 mM) relative to NH4Cl (100 mM). (B) Representative nerve recording tracings from the indicated mice. (C-D) PVN or suprachiasmatic nucleus (SCN) β-klotho (KLB) knockout (KO) mice and control mice were generated by performing bilateral stereotactic injections of AAV-Cre or AAV-GFP into the PVN or SCN of KLBfl/fl mice. Sucrose preference was assessed in each mouse while receiving daily injections of vehicle (3 days) followed by daily injections of FGF21 (3 days). (C) Percent change in sucrose intake in 12 week old male PVN or SCN KLB KO mice and littermate controls by i.p. administration of FGF21 (1 mg/kg) (n = 7-12/group). (D) Klb mRNA expression in the PVN or SCN from brain punches of the indicated mice in (C) as determined by QPCR. (E) Representative photomicrographs depicting the effect of intraperitoneal (i.p.) administration of FGF21 (1 mg/kg) on c-Fos immunoreactivity in the paraventricular nucleus (PVN) in mice. (F) Comparison of the number of immunoreactive c-Fos-positive cells in the PVN between vehicle- and FGF21-treated mice (n = 6/group). (G) High sucrose diet (HSD) preference ratio (g HSD intake/g Chow intake) in a separate cohort of 12 week old male PVN KLB KO mice and WT controls (n = 7-12/group). Values are mean +/− SEM. (*, P< 0.05; **, P< 0.01; #, P< 0.001 compared to WT).
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