Is FAM19A5 an adipokine? Peripheral FAM19A5 in wild-type, FAM19A5 knockout, and LacZ knockin mice

Abstract

FAM19A5 (also called TAFA5) is a novel secretory protein that is primarily expressed in the brain. However, a recent study reported that FAM19A5 is an adipocyte-derived adipokine that regulates vascular smooth muscle function. Furthermore, genome-wide association study (GWAS) and RNA-seq analyses revealed that the FAM19A5 was associated with a variety of diseases and tumorigenesis in peripheral tissues. We investigated FAM19A5 transcript and protein levels in the FAM19A5 peripheral expression 2 peripheral tissues, including adipose tissues from wild-type, FAM19A5 knock-out, and LacZ knock-in mice. In general, total FAM19A5 transcript levels in the central and peripheral nervous systems were higher than levels in any of the peripheral tissues including adipose tissues. Brain tissues expressed similar levels of the FAM19A5 transcript isoforms 1 and 2, whereas expression in the peripheral tissues predominantly expressed isoform 2. In the peripheral tissues, but not the brain, FAM19A5 protein levels in adipose and reproductive tissues were below detectable limits for analysis by Western blot. Additionally, we found that FAM19A5 protein did not interact with the S1PR2 receptor for G-protein-mediated signal transduction, β-arrestin recruitment, and ligandmediated internalization. Instead, FAM19A5 was internalized into HEK293 cells in an extracellular matrix protein-dependent manner. Taken together, the present study determined basal levels of FAM19A5 transcripts and proteins in peripheral tissues, which provides compelling evidence to further investigate the function of FAM19A5 in peripheral tissues under pathological conditions, including metabolic diseases and/or tumorigenesis.

FAM19A (TAFA): An Emerging Family of Neurokines with Diverse Functions in the Central and Peripheral Nervous System

“…38 It is worth noting that neither the predominant adipose expression nor binding of FAM19A5 to its receptor (S1PR2) has been independently confirmed. 79 These discrepancies warrant further clarification.…”

“…By a candidate gene approach, sphingosine-1-phosphate receptor 2 (S1PR2) was identified as the GPCR receptor mediating the inhibitory effects of FAM19A5 on VSMC activation and migration . It is worth noting that neither the predominant adipose expression nor binding of FAM19A5 to its receptor (S1PR2) has been independently confirmed . These discrepancies warrant further clarification.…”

“…While these data support the notion that S1PR2 is a putative receptor for FAM19A5 (Figure 3C), the findings have recently been challenged and disputed. 79 Future studies using VSMC derived from S1PR2 knockout mice are needed to help resolve the issue and clarify whether FAM19A5 can bind two different GPCRs (FPR2 and S1PR2).…”

Cortico-thalamic development and disease: From cells, to circuits, to schizophrenia

“…Since the development of the cortex and the thalamus is intricate and the CT-TC circuit establishment needs to be finely synchronized, several insults in diverse crucial spots could lead to incorrect regionalization, impaired neuronal migration, and aberrant innervation of the involved areas. All these alterations may lead to a series of neurodevelopmental disorders, among which SCZ, autism spectrum disorders, and bipolar disorder have increasingly been associated with severe CT-TC network disturbances, which have been coupled with several clinical outcomes (Anticevic et al, 2014;Castelnovo et al, 2015;Murray and Anticevic, 2017;Hwang et al, 2022). Intriguingly, SCZ also appears to be specifically linked to TRN alterations, which could play a pivotal role in overall CT-TC network disruption.…”

Blocking the FAM19A5-LRRC4B complex enhances neurite growth and synapse assembly.(science ver.)

“…The amino acid (aa) sequence of the secreted FAM19A5 is highly conserved across vertebrate species, suggesting a physiologically relevant function in vertebrates (15,16). FAM19A5 transcripts are abundant in the brain but less so in peripheral tissues (17). Advances in single-cell RNA-seq (scRNA-seq) analysis of mouse brain tissue have provided more detailed expression pattern, showing that Fam19a5 transcripts are mainly found in excitatory and inhibitory neurons in various regions including layers 2/3 and 5 of the cortex and in the CA1 and CA3 regions of the hippocampus in mice and humans (18,19).…”