Modeling anorexia nervosa: transcriptional insights from human iPSC-derived neurons

Abstract

Anorexia nervosa (AN) is a complex and multifactorial disorder occurring predominantly in women. Despite having the highest mortality among psychiatric conditions, it still lacks robust and effective treatment. Disorders such as AN are most likely syndromes with multiple genetic contributions, however, genome-wide studies have been underpowered to reveal associations with this uncommon illness. Here, we generated induced pluripotent stem cells (iPSCs) from adolescent females with AN and unaffected controls. These iPSCs were differentiated into neural cultures and subjected to extensive transcriptome analysis. Within a small cohort of patients who presented for treatment, we identified a novel gene that appears to contribute to AN pathophysiology, TACR1 (tachykinin 1 receptor). The participation of tachykinins in a variety of biological processes and their interactions with other neurotransmitters suggest novel mechanisms for how a disrupted tachykinin system might contribute to AN symptoms. Although TACR1 has been associated with psychiatric conditions, especially anxiety disorders, we believe this report is its first association with AN. Moreover, our human iPSC approach is a proof-of-concept that AN can be modeled in vitro with a full human genetic complement, and represents a new tool for understanding the elusive molecular and cellular mechanisms underlying the disease.

Chronic stress and adipose tissue in the anorexic state: endocrine and epigenetic mechanisms

“…DGKG expression increases in the prefrontal cortex in response to chronic stress exposure [87] and decreases in sWAT and vWAT in the obese state [88] in mice. Collectively, these results indicate that aberrant regulation of the genes involved in lipid metabolism may contribute to the pathogenesis of AN in a synergistic manner [84].…”

“…Transcriptomic analysis on cortical neurons differentiated from induced pluripotent stem cells revealed higher expression of the TSH receptor and diacylglycerol kinase gamma (DGKG) in AN than in healthy females [84]. As a component of the HPT axis, TSH is involved in central regulation of energy homoeostasis [85].…”

Molecular neuroanatomy of anorexia nervosa

“…More broadly, CGRP neurons in the parabrachial are thought to serve as a general purpose alarm that encodes diverse danger signals (Saper 2016;Palmiter 2018) . The CALCB gene, which encodes the beta isoform of CGRP is the 23rd most differentially expressed gene from the AN derived stem cell study (Negraes et al 2017) . Within the AN associated genes we studied, CALCB has the most specific expression in the medial parabrachial nucleus in both the adult and fetal human brain data and ranks 2nd and 4th in the fetal and adult lateral parabrachial nuclei respectively (Supplement Table 3).…”

“…We first characterized the expression pattern of the genes that were differentially expressed in iPSC-derived neurons from AN patients in comparison to controls (Negraes et al 2017) . We used the adult and prenatal human gene expression data from the Allen Brain atlases to evaluate brain-wide expression patterns.…”

“…Specifically, three past studies have used genome-wide scans to associate genes and genetic variants with the disorder. First, a transcriptomic study that compared induced neural stem cells of anorexia nervosa patients and controls identified hundreds of differentially expressed genes (Negraes et al 2017) . Second, a genome-wide association study has reported a single significant locus for anorexia nervosa (rs4622308) that overlaps with six genes (Duncan et al 2017) .…”