FGF21 Regulates Sweet and Alcohol Preference

Abstract

Summary 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.

A common allele in FGF21 associated with preference for sugar consumption lowers body fat in the lower body and increases blood pressure

“…For example, the allele associated with higher sugar intake, is also associated with reward-based behaviours, including higher alcohol intake. These associations are consistent with studies showing signalling effects of FGF21 to the paraventricular hypothalamus and behavioural studies in mice and non-human primates [1,2]. The FGF21 allele's association with blood pressure is not fully explained by altered alcohol intake, because the effects on blood pressure are larger than that of the KLB allele, and effects do not change when adjusting for self report alcohol intake.…”

“…Soberg et al showed that the carbohydrate preference was specific to sugary products, and may also increase alcohol intake [13]. These findings are consistent with data from animal studies showing that FGF21 signals to reward centres in the brain [1,2]. The human genetic studies found no detectable effect on the risk of type 2 diabetes and only nominal evidence for an effect on BMI [13].…”

“…In table 1 we show how each copy of the minor A allele was associated with higher self report estimates of carbohydrate and alcohol intake and lower fat and lower protein intake. These effects imply very strongly that the rs838133 A allele is a loss of FGF21 function allele because genetic and pharmacological lowering of FGF21 in animal models, including non human primates, has the same effect on carbohydrate and alcohol preferences [1,2]. The largest effect on macronutrient intake was with carbohydrate intake, where each A allele raised percentage intake by 0.21%.…”

“…Studies in mice and non human primates show that genetically and pharmacologically raising FGF21 levels suppresses sugar and alcohol intake [1,2]. Three human genetic studies have shown that the minor A allele at rs838133 (A/G, Minor Allele Frequency=44.7%), which results in a synonymous change to the first exon of FGF21, is associated with higher carbohydrate and lower protein and fat intake, with no effect on total calorie intake [12][13][14].…”

“…FGF21 is a hormone secreted primarily by the liver whose multiple functions include signalling to the paraventricular nucleus of the hypothalamus to suppress sugar and alcohol intake [1,2], stimulating insulin-independent glucose uptake by adipocytes [3] and acting as an insulin sensitizer [4]. These features and several other lines of evidence have prompted the development of FGF21 based therapies as potential treatments for obesity and type 2 diabetes, with consistent effects on triglyceride lowering, some effects on weight loss but little effect on glucose tolerance [5,6].…”