Identification of peripheral oxytocin‐expressing cells using systemically applied cell‐type specific adeno‐associated viral vector

Abstract

The pituitary hormone oxytocin is best known for its role in smooth muscle contraction after secretion from the pituitary gland into the bloodstream. In addition to its classical roles in parturition and milk ejection and its role in electrolyte homeostasis in rodents, 1 oxytocin has emerged as a regulator of the brain-gut axis. Oxytocin is involved in energy homeostasis, 2,3 and hormonal signals released by the gastrointestinal tract in response to food intake, 4 including cholecystokinin , secretin 5 and insulin, 6 modulate the activity of oxytocin neurones.Conversely, there is evidence that oxytocin is involved in regulating gut motility, enteric neuronal activity, mucosal homeostasis, intestinal permeability and inflammation. 7 Oxytocin receptors are expressed in several cell types of the rat intestine, including villi enterocytes and neurones of the myenteric and submucosal plexuses. 8,9 Oxytocin given systemically stimulates gastric emptying 10 and colon motility, and exogenous oxytocin can restore peristaltic movements in patients with gastric atony. 11 Disruption of oxytocin signalling in oxytocin receptor-deficient mice results in increased excretion of faeces and faecal water content, as well as increased total bowel transit time. 7 Finally, administration of the oxytocin receptor antagonist atosiban decreases gastric emptying in humans. 12 Oxytocin is also synthesised locally in peripheral organs including the gut. The enteric nervous system (ENS) contains more than 400 million neurones in humans. These neurones are organised in networks of interconnected ganglia located in the walls of the gastrointestinal tract, constituting both the myenteric (Auerbach) and submucosal (Meissner) plexuses. Immunohistochemical studies have reported oxytocin immunoreactivity throughout the rat

Oxytocin signaling in the posterior hypothalamus prevents hyperphagic obesity in mice

“…The phenotypic discrepancy between our data and diphtheria toxin-induced ablation of OT cells (Wu et al, 2012b) might be due to the loss of OT cells outside the PVH (maybe even outside the brain (Paiva et al, 2021)) that somehow elicited appetite suppression, and therefore counterbalanced the overeating phenotype caused by the loss of OT in the PVH. Alternatively, neuropeptides or neurotransmitters other than OT expressed in the PVH OT neurons might have conveyed appetite-stimulating signals, which remained intact in our OT -selective cKO model, but were disrupted in the cell-based ablation, resulting in only the overeating phenotype to appear in our case.…”

Oxytocin as an Anti-obesity Treatment

“…Oxytocin is also expressed in peripheral tissues including the heart (rats; Jankowski et al, 1998 ) and rat and human gastrointestinal (GI) tract ( Ohlsson et al, 2006 ; Welch et al, 2009 ; Paiva et al, 2021 ) (including neurons of myenteric and submucosal plexus of enteric nervous system) ( Paiva et al, 2021 ) as well as the islets of Langerhans of the pancreas and Leydig cells of the testes in rats ( Paiva et al, 2021 ), although the stimuli that impact the release of OT within these areas, where it is released and extent to which these peripheral sources of OT contribute to energy balance is not clear.…”

Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies

“…In addition, more comprehensive anatomical studies are needed assessing OT cell numbers, OTergic projections, and OTR levels in murine models and brains from patients with SYS and PWS. Technical advances such as the uDISCO tissue clearing method [ 137 , 138 ] in combination with the new generation of OT promoter-driven, BBB-penetrating AAVs expressing GFP [ 139 , 140 ] would be a suitable tool to map and study the entirety of OTergic projections in murine models of PWS and SYS. While the uDISCO approach is applicable for post-mortem assessment of human brains [ 138 ], novel techniques allowing the labeling and discrimination of parvOT and magnOT neurons in human brains are desperately needed [ 41 ].…”

“…The drug caused selective reduction of histone methylation without changing DNA methylation, making it a promising candidate for the treatment of PWS patients [ 145 ]. In addition, the latest generation of BBB-crossing AAVs equipped with an OT promoter could serve as transport vehicles of genes and proteins for targeted gene therapy [ 139 , 140 ]. In fact, several studies using gene therapy approaches to treat various aspects of PWS are currently underway and funded by the Foundation for Prader-Willi Research ( https://www.fpwr.org/genetic-therapy-for-prader-willi-syndrome#what_is_it ).…”