Oxytocin stimulates glucose uptake 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)
- et al.
The cardiovascular effects of oxytocin in conscious male rats
Eur J Pharmacol
(1985) - et al.
Pregnancy-induced hyperphagia is associated with increased gene expression of hypothalamic agouti-related peptide in rats
Reg Pept
(2003) - et al.
Influence of oxytocin on feeding behavior in the rat
Peptides
(1989) - et al.
Oxytocin-induced inhibition of feeding and drinking: no sexual dimorphism in rats
Neuropeptides
(1991) Neuropeptides in hypothalamic neuronal disorders
Int Rev Cytol
(2004)- et al.
Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase
Cell Metab
(2005) - et al.
The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases
J Biol Chem
(2005) - et al.
Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells
Cell Metab
(2005) - et al.
Natriuretic role of endogenous oxytocin in male rats infused with hypertonic NaCl
Am J Physiol
(1995) - et al.
Short-term increase and long-term decrease of blood pressure in response to oxytocin-potentiating effect of female steroid hormones
J Cardiovasc Pharmacol
(1999)
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- 1
These two authors contributed equally.