Elsevier

Regulatory Peptides

Volume 151, Issues 1–3, 29 November 2008, Pages 71-74
Regulatory Peptides

Oxytocin stimulates glucose uptake in skeletal muscle cells through the calcium–CaMKK–AMPK pathway

https://doi.org/10.1016/j.regpep.2008.05.001Get rights and content

Abstract

Oxytocin is a mammalian hormone that is released mainly after distension of the uterine cervix. In this study, we report that oxytocin stimulates intracellular release of calcium, and also activates AMPK (AMP-activated protein kinase) in C2C12 myoblast cells in a time/dose-dependent manner. Oxytocin receptor mRNA was detected in C2C12 cells. In addition, oxytocin stimulated glucose uptake and, moreover, inhibition of either CaMKK (Ca2+/calmodulin-dependent protein kinase kinase) or AMPK blocked oxytocin-mediated AMPK activation and glucose uptake. Taken together, our findings suggest that oxytocin may serve a peripheral metabolic function in skeletal muscle cells through the calcium–CaMKK–AMPK pathway.

Introduction

Oxytocin, a nonapeptide produced in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus, exerts a wide variety of central and peripheral effects. It is mainly associated with uterine contraction during parturition and the milk ejection reflex during lactation. Oxytocin also influences cardiovascular regulation and various social behaviors and modulates the release of adenohypophyseal hormones [1], [2], [3], [4], [5].

An anorectic hypothalamic neuropeptide, oxytocin may play a key role in regulating energy intake in the central nervous system. Of the many neuropeptides now known to be involved in the complex regulation of food intake, only oxytocin has been associated with pregnancy, a natural state of hyperphagia, during which body weight and adipose increase dramatically [6]. Oxytocin neurons are located in the SON and PVN of the hypothalamus. The effects of oxytocin on feeding behavior have been noted [7], [8]. A role for oxytocin in appetite control is suggested by a report of decreased activity of PVN oxytocin neurons in Prader–Willi syndrome, which is characterized by hyperphagia [9]. In addition, appetite is altered in oxytocin knock-out mice [10], indicating that oxytocin may play an important role in the regulatory neuronal network that mediates satiety.

AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that promotes energy production and simultaneously limits energy utilization. AMPK, a heterotrimeric complex comprised of a catalytic subunit and two regulatory subunits, is activated when cellular energy is depleted [11]. Upon activation by allosteric binding of AMP or phosphorylation at Thr 172 of the catalytic subunit by AMPK kinase, AMPK accelerates ATP-generating catabolic pathways, including glucose and fatty acid oxidation [12], [13], [14], while reducing ATP-consuming anabolic pathways such as cholesterol, fatty acid, and triacylglycerol synthesis [15].

Oxytocin has been implicated in the regulation of appetite in the central nervous system, but little is known about its role in the peripheral skeletal muscle system. Moreover, the demonstration of oxytocin in glucose homeostasis [16], [17] suggests that oxytocin might act directly in metabolic function. To date, however, the underlying molecular mechanisms remain largely unknown. In this study, we determined that oxytocin activates AMPK and stimulates intracellular calcium in skeletal muscle cells, and demonstrated that the activities of AMPK and calcium affect oxytocin-mediated glucose uptake. These findings provide novel insights into the manner in which AMPK contributes to oxytocin-mediated skeletal function.

Section snippets

Reagents

Phospho-ACC (Ser79) and phospho-AMPK (Thr172) antibodies were purchased from Cell Signaling Technology (New England Biolabs, Beverly, MA) and horseradish peroxidase-conjugated secondary antibodies were obtained from Kirkegaard and Perry Lab (Gaithersburg, MD). AMPK and beta-actin antibodies were purchased from Sigma-Aldrich (St. Louis, MO). Oxytocin, AICAR (5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside), STO-609, BAPTA-AM and Compound C were obtained from Calbiochem (San Diego, CA).

Oxytocin stimulates an increase in intracellular calcium in mouse myoblast C2C12 cells

Intracellular calcium measurements were performed in order to determine the role of oxytocin in the skeletal system. Cells were initially starved of serum for 24 h to remove any stimulants from the media, then treated with various doses of oxytocin. In the experiment with Fluo-3 AM, the concentration of intracellular calcium increased after stimulation with 10 μM oxytocin (Fig. 1A). To prove the involvement of the oxytocin receptor, the effect of oxytocin on calcium increase at different doses

Discussion

The principal finding of this study is that oxytocin is involved in peripheral metabolic functions of skeletal muscle cells. We determined that AMPK and calcium play instrumental roles in oxytocin-mediated glucose uptake.

The primary assertion of this study is that AMPK mediates the peripheral effects of oxytocin. The physiological mechanisms that control the balance of energy in the central nervous system are reciprocally linked to those that control fluctuating conditions in the peripheral

Acknowledgments

This study was supported by a grant from Korea University and also supported by Kmep (T28021) to Jong-Soon Choi.

The authors declare no conflicts of interest.

References (20)

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1

These two authors contributed equally.

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