Intestinal transepithelial permeability of oxytocin into the blood is dependent on the receptor for advanced glycation end products in mice

Higashida, Haruhiro; Furuhara, Kazumi; Yamauchi, Agnes-Mikiko; Deguchi, Kisaburo; Harashima, Ai; Munesue, Seiichi; Lopatina, Olga; Gerasimenko, Maria; Салмина, А. Б.; Zhang, Jiasheng; Kodama, Hikari; Kuroda, Hironori; Tsuji, Chiharu; Suto, Satoshi; Yamamoto, Hiroshi; Yamamoto, Yasuhiko

doi:10.1038/s41598-017-07949-4

Cited by 37 publications

(46 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RAGE-mediated oxytocin transport from the intestinal tract into the blood circulation across the intestinal barrier was also found to occur in mice 29 . This RAGE-dependent intestinal permeability was demonstrated following the oral administration of oxytocin in mouse pups at the very narrow window of postnatal days 4-6, during which the barrier will be formed but still digestion is not active.…”

Section: Possible Routes and Functions Of Oxytocinmentioning

confidence: 89%

“…This RAGE-dependent intestinal permeability was demonstrated following the oral administration of oxytocin in mouse pups at the very narrow window of postnatal days 4-6, during which the barrier will be formed but still digestion is not active. The blood oxytocin levels of the mice were high at approximately 1-3 days after birth, likely due to nonspecific bulk absorption, and no uptake of oxytocin was observed after 7 days when the same concentration of oxytocin was orally applied 29 . Although it was previously reported that oxytocin is absorbed in neonates and infants, our results show that oxytocin transport across the intestinal barrier is RAGE-dependent 29 .…”

Section: Possible Routes and Functions Of Oxytocinmentioning

confidence: 95%

See 1 more Smart Citation

RAGE regulates oxytocin transport into the brain

Yamamoto

Higashida

2020

Commun Biol

Self Cite

View full text Add to dashboard Cite

Oxytocin, a nonapeptide hormone, has a key role in female reproductive functions as well as in social memory in the brain. In our recent Communications Biology article, we reported that oxytocin is transported from the peripheral blood into the brain by the receptor for advanced glycation end-products (RAGE) in endothelial cells at the blood−brain barrier. Additionally, we found that oral oxytocin is absorbed by RAGE on intestinal epithelial cells at the blood−intestinal barrier. From a physiological perspective, we herein outline the continuing research regarding oxytocin and social behaviour. Oxytocin in female reproduction and beyond Oxytocin is primarily synthesized in the oxytocinergic neurons in the hypothalamus within the brain 1,2. Oxytocin in brain neurons is secreted somato-axono-dendritically into the brain 3,4 and released from the nerve terminals in the posterior pituitary into the circulation 1-4. Within the past decade, oxytocin in the brain has attracted increasing attention because of the importance of oxytocin in species-specific social memory functioning 5-7. Oxytocin in the blood circulation has a primary hormonal role in female reproduction but was not thought to re-enter the brain. Recently, however, based on the practical nasal administration of large doses of oxytocin to humans with and without social deficit-related psychiatric disorders, such as autism spectrum disorders and schizophrenia 8,9 , oxytocin has been thought to cross the blood−brain barrier (BBB) 3,10. However, there is little or no direct evidence for this transport process, with the exception of two reports that examined human cerebrospinal fluid (CSF) and microdialysates from the mouse and rat hippocampus and amygdala 11,12. They found that peak levels of oxytocin were observed 30-60 min after the nasal administration of oxytocin in three species 12,13 , which is confirmed in our study as well 14. Furthermore, if oxytocin is indeed transferred from the blood to the brain, the underlying molecular mechanism is unclear. How oxytocin crosses the blood−brain barrier The transport of peptides across the BBB requires specific or nonspecific interactions with proteins or receptors that are expressed on the luminal and/or abluminal surfaces of brain

show abstract

Section: Possible Routes and Functions Of Oxytocinmentioning

confidence: 89%

Section: Possible Routes and Functions Of Oxytocinmentioning

confidence: 95%

RAGE regulates oxytocin transport into the brain

Yamamoto

Higashida

2020

Commun Biol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, Higashida et al [145] reported that oxytocin is transmitted into blood in the intestinal tract via the mediation of receptors for glycation end products in adult mice. Oral oxytocin supplementation could be another potential anti-obesity treatment.…”

Section: Resultsmentioning

confidence: 99%

The Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication

et al. 2018

View full text Add to dashboard Cite

Oxytocin was discovered in 1906 as a peptide that promotes delivery and milk ejection; however, its additional physiological functions were determined 100 years later. Many recent articles have reported newly discovered effects of oxytocin on social communication, bonding, reward-related behavior, adipose tissue, and muscle and food intake regulation. Because oxytocin neurons project to various regions in the brain that contribute to both feeding reward (hedonic feeding) and the regulation of energy balance (homeostatic feeding), the mechanisms of oxytocin on food intake regulation are complicated and largely unknown. Oxytocin neurons in the paraventricular nucleus (PVN) receive neural projections from the arcuate nucleus (ARC), which is an important center for feeding regulation. On the other hand, these neurons in the PVN and supraoptic nucleus project to the ARC. PVN oxytocin neurons also project to the brain stem and the reward-related limbic system. In addition to this, oxytocin induces lipolysis and decreases fat mass. However, these effects in feeding and adipose tissue are known to be dependent on body weight (BW). Oxytocin treatment is more effective in food intake regulation and fat mass decline for individuals with leptin resistance and higher BW, but is known to be less effective in individuals with normal BW. In this review, we present in detail the recent findings on the physiological role of oxytocin in feeding regulation and the anorexigenic neural pathway of oxytocin neurons, as well as the advantage of oxytocin usage for anti-obesity treatment.

show abstract

“…CD38 and/or CD157 can be referred to as a neuro-entero-immunological regulator [6,18]. Interestingly, even for CD38, it is reported that the specific SNP (rs3796863) of CD38 was originally documented as an association with ASD [21], with close relation to gastrointestinal dysfunction, one of the typical symptoms of ASD [95].…”

Section: Conclusion and Perspectivementioning

confidence: 99%

CD38, CD157, and RAGE as Molecular Determinants for Social Behavior

Higashida

Hashii

Tanaka

et al. 2019

Cells

Self Cite

View full text Add to dashboard Cite

Recent studies provide evidence to support that cluster of differentiation 38 (CD38) and CD157 meaningfully act in the brain as neuroregulators. They primarily affect social behaviors. Social behaviors are impaired in Cd38 and Cd157 knockout mice. Single-nucleotide polymorphisms of the CD38 and CD157/BST1 genes are associated with multiple neurological and psychiatric conditions, including autism spectrum disorder, Parkinson’s disease, and schizophrenia. In addition, both antigens are related to infectious and immunoregulational processes. The most important clues to demonstrate how these molecules play a role in the brain are oxytocin (OT) and the OT system. OT is axo-dendritically secreted into the brain from OT-containing neurons and causes activation of OT receptors mainly on hypothalamic neurons. Here, we overview the CD38/CD157-dependent OT release mechanism as the initiation step for social behavior. The receptor for advanced glycation end-products (RAGE) is a newly identified molecule as an OT binding protein and serves as a transporter of OT to the brain, crossing over the blood–brain barrier, resulting in the regulation of brain OT levels. We point out new roles of CD38 and CD157 during neuronal development and aging in relation to nicotinamide adenine dinucleotide+ levels in embryonic and adult nervous systems. Finally, we discuss how CD38, CD157, and RAGE are crucial for social recognition and behavior in daily life.

show abstract

Intestinal transepithelial permeability of oxytocin into the blood is dependent on the receptor for advanced glycation end products in mice

Cited by 37 publications

References 69 publications

RAGE regulates oxytocin transport into the brain

RAGE regulates oxytocin transport into the brain

The Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication

CD38, CD157, and RAGE as Molecular Determinants for Social Behavior

Contact Info

Product

Resources

About