Hippocampal and Prefrontal Cortical Brain Tissue Levels of Irisin and GDF15 Receptor Subunits in Children

Abstract

Cold-stress hormones (CSHs) stimulate thermogenesis and have direct neuroprotective effects on the brain. The obligatory receptor components of two new CSHs (irisin and growth differentiation factor-15 [GDF15]) were recently discovered. Irisin binds integrin-αV/β5 heterodimers while GDF-15 binds to the orphan receptor glial cell-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL). In addition, integrin-αV/β5 was just identified as the key receptor mediating Zika virus infection in the CNS. We measured integrin-αV, integrin-β5, and GFRAL protein levels across 78 high-quality human male/female brain tissues in infants, toddlers, preschoolers, adolescent, and adults—providing the most robust analysis to date on their levels in the human cortex and hippocampus. We report that integrin-αV was detected at all ages in the prefrontal cortex with levels greatest in adults. Integrin-αV was also detected in the hippocampus in all age groups. In contrast, integrin-β5 was detected in cortex and hippocampus largely restricted to infants. Co-expression of integrin-αV/β5 in the human infant hippocampus and cortex suggests the possibility that irisin has a more robust effect on the developing vs. the adult brain and may have implications for Zika virus infection in infants and young children.

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

“…It should be noted that mRNA levels are not the final output of gene expression, but that they mechanistically represent the templates required for biological systems’ potential highly controlled protein synthesis on demand [ 37 ]. This implies the possibility of an upregulation of GFRAL under challenging conditions, like specific developmental stages in mice and humans [ 19 , 38 ] or obesity. The low or even missing detection of GFRAL transcripts apart from AP/NTS may have prevented the investigation of such demanding circumstances in more detail so far.…”

The effects of peripheral hormone responses to exercise on adult hippocampal neurogenesis

“…discovered a peroxisome proliferator-activated receptor-gamma co-activator 1α (PGC-1α)-dependent myokine named irisin and demonstrated that PGC-1α stimulates expression of the membrane protein FNDC5, which is cleaved and released from muscle as the hormone irisin ( 198 ). The irisin receptors in the brain were recently identified as integrin αVβ5 heterodimers ( 199 ).…”

Effects of the FNDC5/Irisin on Elderly Dementia and Cognitive Impairment

“…Irisin bound and modified the function of neurotransmitter receptors in the forebrain, then neurons. The receptor of irisin in the brain was integrin-αV/β5 heterodimers ( Jackson et al, 2021 ). Recombinant irisin stimulated the cAMP/PKA/CREB pathway in human cortical slices ( Lourenco et al, 2019 ).…”