Hypothermia induced by central injection of sucralose potentially occurs via monoaminergic pathways in the hypothalamus of chicks

https://doi.org/10.1016/j.cbpa.2020.110752Get rights and content

Highlights

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    Central injection of sucralose could lower body temperature.

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    Central injection of sucralose reduced brain DA and 5-HT concentrations.

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    Central sucralose may mediate its hypothermic action via the DA metabolite pathway.

Abstract

Oral administration of sucralose has been reported to stimulate food intake through inducing hypothalamic neuropeptide Y (NPY) in mice and fruit flies. However, the underlying mechanisms of action of sucralose in hypothermia and NPY and monoamine regulation remain unknown. The aim of the present study was to investigate central effects of sucralose on body temperature, NPY, and monoamine regulation, as well as its peripheral effects, in chicks. In Experiment 1, 5-day-old chicks were centrally injected with 1 μmol of sucralose, other sweeteners (erythritol and glucose), or saline. In Experiment 2, chicks were centrally injected with 0.2, 0.4, and 1.6 μmol of sucralose or saline. In Experiment 3, chicks were centrally injected with 0.8 μmol of sucralose or saline, with a co-injection of 100 μg fusaric acid (FA), an inhibitor of dopamine-β-hydroxylase, to examine the role dopamine in sucralose induced hypothermia. In Experiment 4, 7–16-day-old chicks were orally administered with 75, 150, and 300 mg/2 ml distilled water or sucralose, daily. We observed that the central injection of sucralose, but not other sweeteners, decreased body temperature (P < .05) in chicks; however, the oral injection did not influence body temperature, food intake, and body weight gain. Central sucralose administration decreased dopamine and serotonin and stimulated dopamine turnover rate in the hypothalamus significantly (P < .05). Notably, sucralose co-injection with FA impeded sucralose-induced hypothermia. Sucralose decreases body temperature potentially via central monoaminergic pathways in the hypothalamus.

Introduction

Body temperature is a key parameter that is regulated precisely in all homoeothermic animals. Recently, we observed that central neuropeptide Y (NPY) caused hypothermia in chicks (Bahry et al., 2017; Eltahan et al., 2017). In addition, it has been demonstrated that oral sucralose stimulates central NPY functions in mice and fruit flies to induce hyperphagia (Wang et al., 2016, Wang et al., 2017). Sucralose is one of the most popular artificial sweeteners (Index, 2006). The P-glycoprotein transporter (P-gp) reduces the rate of absorption of ingested sucralose from the guts of rodents (Abou-Donia et al., 2008). P-gp is found in the blood-brain barrier as well as in the intestines in mice, with higher concentrations in adults than in neonates (Abu-Qare et al., 2003). The potential of sucralose entering the central nervous system in neonates is higher in than adults due to the low levels of expression of P-gp in the blood-brain barrier in neonates in mammals (Rother et al., 2015). However, no study has demonstrated the direct central effect of sucralose in any species.

Erythritol, a low-calorie bulk sweetener, does not influence blood glucose levels (Moon et al., 2010). Glucose is a major simple sugar that circulates in the blood of animals as an energy source and central injection of glucose could ameliorate stress responses in neonatal chicks (Asechi et al., 2008). Conversely, in another study, the oral administration of glucose increased the body temperature in neonatal chicks (Thaxton et al., 1974). Therefore, investigating the central effects of sweeteners, namely, sucralose, erythritol, and glucose, could provide critical insights on thermoregulation mechanisms.

Monoamines participate in the regulation of stress responses. Central injection of norepinephrine (NE) or serotonin (5-HT) can reduce stressful behavior induced by acute stress, but the former attenuates and the latter stimulates corticosterone release (Zhang et al., 2003, Zhang et al., 2004). Dopamine (DA) has an ergogenic effect of mediating psychological responses and increases heat storage and tolerance to hyperthermia (Zheng and Hasegawa, 2016). Aspartame, an artificial sweetener, can inhibit the synthesis and release of neurotransmitters, NE, DA, and 5-HT, and regulate neurophysiological activity (Choudhary and Lee, 2018). Therefore, it is critical to investigate the roles of some monoamines in thermoregulation. FA inhibits dopamine-β-hydroxylase (DBH), which catalyzes the conversion of DA into NE (Nagatsu et al., 1970).

In the present study, our aim was to examine the effect of the central injection of sucralose and other sweeteners on thermoregulatory functions. To explore the mechanisms of action of sucralose, we have further investigated NPY expression and monoamine concentrations in neonatal chicks. Subsequently, we investigate the role of DA in the central sucralose-induced thermoregulation. In addition, we investigated the effects of oral administration of sucralose on body temperature, food intake, and body weight gain.

Section snippets

Animals

One-day-old male layer chicks (Julia strain; Gallus Gallus domesticus) were purchased from a local hatchery (Murata Hatchery, Fukuoka, Japan) and maintained in a room with a constant temperature of 30 ± 1 °C under continuous light in metal wire-mesh cages (50 × 35 × 33 cm) in groups of 20–25 birds until they were 4 or 5-days-old. Food (Adjust diets [metabolizable energy: >12.55 MJ/kg, protein: >23%]); Toyohashi Feed and Mills Co. Ltd., Aichi, Japan) and water were provided ad libitum. The

Rectal temperature, blood glucose and diencephalic NPY mRNA abundance in chicks following intracerebroventricular administration of sucralose

Central sucralose decreased rectal temperature significantly (P < .05), but not other sweeteners (glucose or erythritol), as illustrated in Fig. 1 A. Furthermore, sucralose injection decreased rectal temperature in chicks in a dose-dependent manner as shown in Fig. 1 B (P < .05). Time influenced changes in rectal temperature significantly (P < .001). In addition, there was a significant interaction between treatment and time (P < .001), indicating that sucralose-dependent decreases in body

Discussion

In the present study, we performed i.c.v. injections of three sweeteners in chicks to examine their effects on body temperature. Afterward, we focused on sucralose since it exhibited hypothermic activity, to investigate its effect on plasma glucose, brain monoamine concentrations, and NPY mRNA expression in the diencephalon. Subsequently, FA was used to confirm the participation of DA under sucralose-induced hypothermia. Finally, we investigated the effect of oral administration of sucralose on

Conclusions

Central injection of sucralose could lower body temperature and brain DA and 5-HT concentrations. Although we did not apply a 5-HT antagonist in the present study, our results based on sucralose and FA co-injection suggest that the hypothermic activity of central sucralose may be mediated at least via the DA metabolic pathway.

The following is the supplementary data related to this article.

Authors' contributions

HME, MF and VSC designed the study; HME, LTNN, GH and HY conducted the study; HME, MNA, KAA, MF and VSC wrote the paper. All authors read and approved the final manuscript.

Declaration of Competing Interest

None.

Acknowledgments

We express our gratefulness to the Egyptian High Education Ministry for offering a scholarship to HME, who studies at Kyushu University and works for the Animal Production Research Institute, Agriculture Research Center, Egypt. This work funded in part by JSPS KAKENHI Grant Number JP18K19271, JP19H03110 as well as the Egyptian High Education Ministry to VSC. We would like to thank Editage (www.editage.com) for English language editing.

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      Rectal temperature was recorded at 0, 30, and 60 min after administration of the treatment, and food intake was recorded at 0 and 60 min after treatment. Rectal temperature was recorded using a digital thermometer with an accuracy of ±0.1 °C (Thermalert TH-5, Physitemp Instruments Inc., USA) by inserting the thermistor probe into the rectum through the cloaca to a depth of 2 cm, as previously reported (Chowdhury et al., 2015; Bahry et al., 2017; Eltahan et al., 2020). Chicks were anesthetized 1 h post ICV injection with isoflurane before collection of blood samples.

    1

    Visiting Researcher from Animal Production Research Institute, Agriculture Research Center, Agriculture Ministry, Egypt.

    2

    Present address: Department of Animal Science, College of Agriculture, Can Tho University, 3/2 Street, Ninh Kieu District, Can Tho City, Vietnam.

    3

    Present address: Department of Animal Nutrition and Food Science, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.

    4

    Present address: Research and Development Division, Toyo Shinyaku Co. Ltd., Saga 841-0005, Japan.

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