Central insulin action induces activation of paraventricular oxytocin neurons to release oxytocin into circulation

Boyang Zhang,Masanori Nakata,Toshihiko Yada,Jun Nakae,Wataru Ogawa

doi:10.1038/s41598-018-28816-w

Boyang Zhang, Masanori Nakata + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-28816-w

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Abstract

Oxytocin neurons in the paraventricular nucleus (PVN) of hypothalamus regulate energy metabolism and reproduction. Plasma oxytocin concentration is reduced in obese subjects with insulin resistance. These findings prompted us to hypothesize that insulin serves to promote oxytocin release. This study examined whether insulin activates oxytocin neurons in the PVN, and explored the underlying signaling. We generated the mice deficient of 3-phosphoinositide-dependent protein kinase-1 (PDK1), a major signaling molecule particularly for insulin, specifically in oxytocin neurons (Oxy Pdk1 KO). Insulin increased cytosolic calcium concentration ([Ca2+]i) in oxytocin neurons with larger (≧25 μm) and smaller (<25 μm) diameters isolated from PVN in C57BL/6 mice. In PDK1 Oxy Pdk1 KO mice, in contrast, this effect of insulin to increase [Ca2+]i was markedly diminished in the larger-sized oxytocin neurons, while it was intact in the smaller-sized oxytocin neurons. Furthermore, intracerebroventricular insulin administration induced oxytocin release into plasma in Oxy Cre but not Oxy Pdk1 KO mice. These results demonstrate that insulin PDK1-dependently preferentially activates PVN magnocellular oxytocin neurons to release oxytocin into circulation, possibly serving as a mechanism for the interaction between metabolism and perinatal functions.

Highlights

Insulin has various effects in multiple tissues, including stimulation of glucose uptake in skeletal muscle and adipose tissue and suppression of gluconeogenesis and glycogenolysis in the liver, thereby lowering the blood glucose level
ICV insulin administration doubled the plasma oxytocin concentration (Fig. 3). These results indicated that insulin activates paraventricular nucleus (PVN) oxytocin neurons in vivo
We found that insulin directly interacts with the larger-sized PVN oxytocin neurons to increase [Ca2+]i via signaling involving PDK1 and that this neuronal activation is relayed to oxytocin release in circulation

Summary

Introduction

Insulin has various effects in multiple tissues, including stimulation of glucose uptake in skeletal muscle and adipose tissue and suppression of gluconeogenesis and glycogenolysis in the liver, thereby lowering the blood glucose level. A knockout of insulin receptor in neuronal tissue (NIRKO) showed increases in body weight, white adipose tissue, and serum triglycerides, and these changes were more pronounced in females[4]. Diabetes mellitus is known to increase the frequency of maternal complications during perinatal periods in pregnancies. These findings have demonstrated the importance of insulin in maintaining reproduction and perinatal functions. Decreased plasma level of oxytocin in obese patients was reported[16]. These findings prompted us to hypothesize that insulin serves to promote oxytocin release. We aimed to clarify whether insulin activates oxytocin neurons in the PVN and, if so, to explore the underlying signaling pathway

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