GFRAL Is Widely Distributed in the Brain and Peripheral Tissues of Mice

Abstract

In 2017, four independent publications described the glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as receptor for the growth differentiation factor 15 (GDF15, also MIC-1, NAG-1) with an expression exclusively in the mice brainstem area postrema (AP) and nucleus tractus solitarii (NTS) where it mediates effects of GDF15 on reduction of food intake and body weight. GDF15 is a cell stress cytokine with a widespread expression and pleiotropic effects, which both seem to be in contrast to the reported highly specialized localization of its receptor. This discrepancy prompts us to re-evaluate the expression pattern of GFRAL in the brain and peripheral tissues of mice. In this detailed immunohistochemical study, we provide evidence for a more widespread distribution of this receptor. Apart from the AP/NTS region, GFRAL-immunoreactivity was found in the prefrontal cortex, hippocampus, nucleus arcuatus and peripheral tissues including liver, small intestine, fat, kidney and muscle tissues. This widespread receptor expression, not taken into consideration so far, may explain the multiple effects of GDF-15 that are not yet assigned to GFRAL. Furthermore, our results could be relevant for the development of novel pharmacological therapies for physical and mental disorders related to body image and food intake, such as eating disorders, cachexia and obesity.

GDF15, an Emerging Player in Renal Physiology and Pathophysiology

“…This soluble form of GFRAL, whose function is not clear, may block the action of GDF15 by acting as a soluble receptor (for review see [ 11 ]). GFRAL expression is limited to the brain (area postrema and nucleus of the solitary tract) and is not found in peripheral tissues [ 12 ], although a recent study suggests that it could be more widely expressed than established before [ 13 ]. This point, however, needs to be better characterized since, for instance in kidneys, the mRNA of GFRAL is not found [ 12 ] and the reported immunolocalization mainly shows intracellular labeling.…”

Body Image, Nutrition, and Mental Health

“…They found GFRAL in the prefrontal cortex, the hippocampus, the arcuate nucleus, and in peripheral tissues. GFRAL had already been implicated in food intake and body weight regulation, but these novel findings indicate a broader role of GFRAL in metabolism [ 12 ].…”

“…In summary, the use of social websites and social media, anxiety and depression, food-specific disgust, social pressure, physical fitness pressure, weight-related experienced stigmatization, and weight bias internalization were identified as risk factors for body image disturbances; disordered, restrictive, or over-eating; vomiting; laxative misuse; excessive exercise; and associated mental health problems [ 7 , 8 , 9 , 10 , 11 ]. The GDF-15 receptor GFRAL, which is known to be involved in appetite regulation, was found to be expressed across various central-nervous as well as peripheral tissues [ 12 ], and visfatin, S100B, and leptin are associated with the development of metabolic syndrome in people with bipolar depression [ 13 ]. Four articles of this Special Issue [ 14 , 15 , 16 , 17 ] summarized already available (e.g., nutritional interventions, psychological and family therapy) [ 14 ] and experimental (smart toy Purrble) [ 15 ] therapies for AN, effective therapies for the treatment of obesity (e.g., physical activity, dietary and nutritional intervention, cognitive behavioral therapy, clinical and self-monitoring) [ 16 ], as well as the preventive and therapeutic options for oral health consequences of EDs [ 17 ].…”