Abstract
Fibroblast growth factor 21 (FGF21) is a stress hormone that is released from the liver in response to nutritional and metabolic challenges. In addition to its well-described effects on systemic metabolism, a growing body of literature now supports the notion that FGF21 also acts via the central nervous system to control feeding behavior. Here we review the current understanding of FGF21 as a hormone regulating feeding behavior in rodents, non-human primates, and humans. First, we examine the nutritional contexts that induce FGF21 secretion. Initial reports describing FGF21 as a ‘starvation hormone’ have now been further refined. FGF21 is now better understood as an endocrine mediator of the intracellular stress response to various nutritional manipulations, including excess sugars and alcohol, caloric deficits, a ketogenic diet, and amino acid restriction. We discuss FGF21’s effects on energy intake and macronutrient choice, together with our current understanding of the underlying neural mechanisms. We argue that the behavioral effects of FGF21 function primarily to maintain systemic macronutrient homeostasis, and in particular to maintain an adequate supply of protein and amino acids for use by the cells.
Highlights
Food provides both energy and the organic building blocks needed for somatic growth, maintenance, and repair
In the ARC, Fibroblast growth factor 21 (FGF21) administration increases the mRNA expression of the orexigenic peptides agouti-related peptide (AgRP) and neuropeptide Y (NPY), whereas reducing or not affecting anorexigenic peptides cocaine and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) [76,107,108]
How does the nervous system integrate information conveyed by FGF21 with other well-characterized signals of energy status? For example, does FGF21 influence leptin and insulin signaling in the arcuate and elsewhere [125,126,127,128]; glucose sensing via glucokinase in neurons of the VMH [97] and elsewhere [129,130]; and/or amino acid sensing via mTOR or general control nondepressible 2 (GCN2) in the mediobasal hypothalamus, hindbrain [131,132,133], and anterior piriform cortex [44]?
Summary
Food provides both energy and the organic building blocks needed for somatic growth, maintenance, and repair. This review will instead focus on our understanding of FGF21 as a hormone regulating feeding behavior. We examine the nutritional contexts that induce FGF21 release, beginning with its original characterization as a starvation hormone and continuing to our current understanding of FGF21 as a signal of a low dietary protein-to-carbohydrate (P:C) ratio. We summarize our current understanding of the neural mechanisms by which FGF21 regulates this change in feeding behavior. FGF21 is a polypeptide hormone secreted by hepatocytes It can be found in several other organs, including the adipose tissue, skeletal muscle, and pancreas, the primary action of FGF21 in these tissues is autocrine or paracrine [12,13] (effects summarized in [9]). Hepatic FGF21 expression and secretion is increased in response to disparate nutritional challenges, including starvation, a ketogenic diet, dietary protein restriction, and excess simple sugar or alcohol consumption
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