A potential role of fatty acid binding protein 4 in the pathophysiology of autism spectrum disorder

Abstract

Autism spectrum disorder is a neurodevelopmental disorder characterized by difficulties in social communication and interaction, as well as repetitive and characteristic patterns of behavior. Although the pathogenesis of autism spectrum disorder is unknown, being overweight or obesity during infancy and low weight at birth are known as risks, suggesting a metabolic aspect. In this study, we investigated adipose tissue development as a pathophysiological factor of autism spectrum disorder by examining the serum levels of adipokines and other metabolic markers in autism spectrum disorder children (n = 123) and typically developing children (n = 92) at 4–12 years of age. Among multiple measures exhibiting age-dependent trajectories, the leptin levels displayed different trajectory patterns between autism spectrum disorder and typically developing children, supporting an adipose tissue-dependent mechanism of autism spectrum disorder. Of particular interest, the levels of FABP4 (fatty acid binding protein 4) were significantly lower in autism spectrum disorder children than in typically developing subjects, at preschool age (4–6 years old: n = 21 for autism spectrum disorder and n = 26 for typically developing). The receiver operating characteristic curve analysis discriminated autism spectrum disorder children from typically developing children with a sensitivity of 94.4% and a specificity of 75.0%. We re-sequenced the exons of the FABP4 gene in a Japanese cohort comprising 659 autism spectrum disorder and 1,000 control samples, and identified two rare functional variants in the autism spectrum disorder group. The Trp98Stop, one of the two variants, was transmitted to the proband from his mother with a history of depression. The disruption of the Fabp4 gene in mice evoked autism spectrum disorder -like behavioral phenotypes and increased spine density on apical dendrites of pyramidal neurons, which has been observed in the postmortem brains of autism spectrum disorder subjects. The Fabp4 knockout mice had an altered fatty acid composition in the cortex. Collectively, these results suggest that an “adipo-brain axis” may underlie the pathophysiology of autism spectrum disorder, with FABP4 as a potential molecule for use as a biomarker.

C1q/TNF-related protein-1: Potential biomarker for early diagnosis of autism spectrum disorder

“…M et al, recently have demonstrated the downregulation of fatty acid-binding protein 4 (FAB4) in preschool ASD children which was further supported by gene sequencing analysis and mice models knockout for FAB4 gene which showed Autism-like symptoms, suggesting an adipose-brain axis in ASD; they have also proposed FAB4 as a convenient biomarker in ASD. 46 Although we did not assess other inflammatory cytokines along with CTRP1 to test whether there is a correlation between them in ASD children participating in our study, it could be proposed that other inflammatory cytokines might be dysregulated in the ASD group, which needs further evaluations.…”

“… 87 , 88 In line with previous studies demonstrating the dysregulation of adipokines in ASD patients, our data also indicate that there might be an imbalance of adipokines in ASD children even in the absence of any identifiable metabolic or inflammatory diseases. 44 - 46 , 89 Regarding the high incidence of obesity due to different reasons such as sedimentary life, certain medications, or much desire for food, it has been proposed that ASD children are predisposed to metabolic diseases or dyslipidemia, resulting in aggravation of their inflammatory profile and worsening their symptoms. 90 , 91 …”

“… 43 The alteration of some adipokines in ASD has been reported in a limited number of studies, including downregulation of adiponectin, 44 upregulation of leptin, 45 and downregulation of Fatty acid-binding protein 4. 46 …”

Differences in circulating fatty acid-binding protein 4 concentration in the venous and capillary blood immediately after acute exercise

“…Circulating FABP4 concentration is known as a biomarker for several disorders; increased circulating FABP4 concentrations are associated with the increased risk of various diseases, such as atherosclerosis [7,8], insulin resistance [9], type 2 diabetes [10], hypertension [9,11], dyslipidemia [9,12], cardiovascular diseases [13,14], and cancer [15]. Notably, it has been also recently reported to be a potential biomarker for autism spectrum disorder in children [16]. Thus, circulating FABP4 concentration is increasingly useful as a biomarker of disorders.…”

Editorial

“…We have continued to publish papers on a wide range of conditions from neurodevelopmental disorders to neurodegeneration and studies ranging from fundamental neurobiology to diagnostic tools and results of clinical trials (see e.g. Landles et al , 2020 ; Luz et al , 2020 ; Maekawa et al , 2020 ; Ugalde et al , 2020 ; Van Damme et al , 2020 ). We have also published a few timely papers on the neurological and cognitive effects of COVID-19 ( Lleó and Alcolea, 2020 ; Ritchie et al , 2020 ; Woo et al , 2020 ).…”