Role of the Oxytocin Receptor Expressed in the Rostral Medullary Raphe in Thermoregulation During Cold Conditions

Abstract

Recent papers have reported that oxytocin (Oxt) and the oxytocin receptor (Oxtr) may be involved in the regulation of food intake in mammals. We therefore suspected the Oxt/Oxtr system to be involved in energy homeostasis. In previous studies, we found a tendency toward obesity in Oxtr-deficient (Oxtr−/−) mice, as well as impaired thermoregulation when these mice were exposed to cold conditions. In the present study, we observed the expression of Oxtr in the rostral medullary raphe (RMR), the brain region known to control thermogenesis in brown adipose tissue (BAT). Through immunohistochemistry, we detected neurons expressing Oxtr and c-Fos in the RMR of mice exposed to cold conditions. Up to 40% of Oxtr-positive neurons in RMR were classified as glutamatergic neurons, as shown by immunostaining using anti-VGLUT3 antibody. In addition, mice with exclusive expression of Oxtr in the RMR were generated by injecting an AAV-Oxtr vector into the RMR region of Oxtr−/− mice. We confirmed the recovery of thermoregulatory ability in the manipulated mice during exposure to cold conditions. Moreover, mice with RMR-specific expression of Oxtr lost the typical morphological change in BAT observed in Oxtr−/− mice. Additionally, increased expression of the β3-adrenergic receptor gene, Adrb3, was observed in BAT. These results are the first to show the critical role of RMR Oxtr expression in thermoregulation during cold conditions.

Chronic hindbrain administration of oxytocin is sufficient to elicit weight loss in diet-induced obese rats

“…Conversely, reduced OT signaling is associated with obesity (11,54,58,60), despite the absence of hyperphagia (11,54), suggesting that EE must also be reduced in this setting (29, 58 -60). Indeed, defects in BAT thermogenesis are reported in such models (29,30). Collectively, these findings support a role for increased BAT thermogenesis in OT-elicited weight loss.…”

“…Neurons in the RPa regulate SNS control of BAT via projections to sympathetic preganglionic neurons in the spinal cord in a circuit that is essential for normal thermoregulation (13,36,38). Since neurons in this brain area also express OTRs that are activated by cold exposure (30), OT-mediated BAT thermogenesis may also involve activation of OTRs within the RPa. Consistent with this hypothesis is evidence that, in mice that lack OTRs, virally mediated rescue of OTRs, specifically in the rostral RPa, is sufficient to rescue impairments of thermogenesis and IBAT activation by cold exposure (30).…”

“…Since neurons in this brain area also express OTRs that are activated by cold exposure (30), OT-mediated BAT thermogenesis may also involve activation of OTRs within the RPa. Consistent with this hypothesis is evidence that, in mice that lack OTRs, virally mediated rescue of OTRs, specifically in the rostral RPa, is sufficient to rescue impairments of thermogenesis and IBAT activation by cold exposure (30). Histological analysis revealed that these effects coincided with "scarce" accumulation of lipid droplets in IBAT (30) compared with the excessive number of lipid droplets in IBAT of OTR-null mice (consistent with hypoactivity of BAT and impaired thermogenesis) (54).…”

Intranasal oxytocin administration rescues neonatal thermo-sensory deficit in mouse model of Autism

“…Importantly, OT has been found to be a modulator of adult sensory functions (Grinevich and Stoop, 2018). Both adult and young mice lacking a functional OT system have thermogenesis difficulties ((Harshaw et al, 2018; Kasahara et al, 2013; Kasahara et al, 2007; Kasahara et al, 2015; Xi et al, 2017) which affect in response to cold challenge huddling and thermotaxis behavior in the litter (Harshaw et al, 2018)…”

Localization of oxytocin receptors in the prairie vole (Microtus ochrogaster) neocortex

“…But in the past few decades, it was discovered that OT and its analogs, including vasopressin and vasotocin, also have central effects and contribute to a wide variety of behaviors in many vertebrate species (Kelly and Goodson 2014), including food intake (Arletti, et al 1990, Chaves, et al 2013), stress response (Jezova, et al 1995, Gibbs 1984, Williams, et al 1985), temperature regulation (Chaves, et al 2013, Young 2013, Kasahara, et al 2015), grooming (Carter and Wilkinson 2015, Burkett, et al 2016), and social and reproductive behaviors, including sexual behavior, parental behavior, infant attachment and social bonding (Insel and Shapiro 1992, Insel, et al 1997, Bales, et al 2013, Ross, et al 2009, Bales, et al 2007). Indeed, the OT system is an integral component to the development and expression of species-typical social behaviors.…”