FGF21 Signals Protein Status to the Brain and Adaptively Regulates Food Choice and Metabolism

Abstract

Highlights d Mice adaptively alter metabolism and food choice during protein restriction d The liver hormone FGF21 is robustly increased by protein restriction d Metabolic responses to protein restriction require FGF21 signaling in the brain d Brain FGF21 also mediates adaptive changes in macronutrient selection

Restriction of essential amino acids dictates the systemic response to dietary protein dilution

“…This highlights that a low Thr diet can induce many of the positive effects of dietary AA restriction while avoiding some negative side effects such as lean tissue wasting. On this, similar to that previously shown for dietary protein/AA dilution 14,16,21,49,65 , and SCAA or BCAA restriction 21,38,[42][43][44] , low Thr feeding also retarded development of obesity-induced metabolic dysfunction in a mouse model ( Fig. 5).…”

“…Several studies have demonstrated that systemic 14,16,24,25,32,40,44,65 or liver-restricted 14,26 Fgf21loss retards the downstream metabolic effects of dietary protein/AA restriction. In particular, these effects are likely to be mediated by central nervous system FGF21 signalling 65 , to stimulate nutrient uptake/oxidation in adipose tissue and heart 14,16 . Here we extend upon these findings and demonstrate that adult, liver-specific FGF21 loss completely abrogates the systemic metabolic remodelling with dietary Thr restriction (Fig.…”

Age dependent effects of protein restriction on dopamine release

“…These results suggest that in protein restricted animals, 'phasic' bursting activity of dopamine mesolimbic neurons evokes greater dopamine release, relative to control animals. As phasic responses of mesolimbic dopamine neurons are well known to convey important information about primary reinforcers like food and associated stimuli [16,19,23,63,65], an increase in NAc dopamine levels in response to salient events may alter motivated behaviors like food preferences [11,13] and increase the rewarding properties of protein-enriched food in restricted/deprived animals [12]. Interestingly, protein restriction did not alter the phasic/tonic ratio either in NAc or dorsal striatum, suggesting that protein restriction at adulthood may induce a more general increase in capacity of terminals for dopamine release rather than by enhancing the contrast between different dopamine signaling modes [57,66].…”

“…The effects of insulin on the dopamine system and dopamine-related behaviors are complex and depend on insulin concentration, brain region, cell type and the current physiological state [71]. Protein restriction is known to increase insulin sensitivity and glucose metabolism [13,72], which may then modulate dopamine's neurobiological and behavioral functions. The interaction of the dopamine and insulin systems in response to different context of protein diet warrants further ex vivo and in vivo investigation.…”

“…Furthermore, protein deficiency and severe protein malnutrition are especially detrimental during development and early life when demand is highest [5][6][7]. Numerous species, including humans and rodents, regulate their food intake and food-related behaviors to avoid protein deficiency [8][9][10][11][12][13]. Increasing evidence implicates broad hypothalamic and limbic circuits in the regulation of protein appetite [10,[13][14][15].…”