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Neuropeptides

Volume 87, June 2021, 102149
Neuropeptides

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Ninjin'yoeito modulates feeding and activity under negative energy balance conditions via the NPY system

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Abstract

The central and peripheral neuropeptide Y (NPY) system is critically involved in feeding and energy homeostasis control. Disease conditions as well as aging can lead to reduced functionality of the NPY system and boosting it represents a promising option to improve health outcomes in these situations. Here we show that Ninjin-yoeito (NYT), a Japanese kampo medicine comprising twelve herbs, and known to be effective to treat anorexia and frailty, mediates part of its action via NPY/peptide YY (PYY) related pathways. Especially under negative energy homeostasis conditions NYT is able to promote feeding and reduces activity to conserve energy. These effects are in part mediated via signalling through the NPY system since lack of Y4 receptors or PYY leading to modification in these responses highlighting the possibility for combination treatment to improve aging related conditions on energy homeostasis control.

Introduction

Maintaining a balanced energy homeostasis is essential for survival with short and long term variations in energy supply needed to be responded to with adaptations in energy expenditure mostly physical activity as well as thermo-regulation to ensure this (Zhang et al., 2019). While fluctuation in food availability is the most common cause for challenges to energy balance, conditions such as stress, illness, fatigue and general aging can also strongly influence this regulation (Zhang et al., 2011). The brain has developed a complex neuronal regulatory network to coordinate the control of feeding and energy homeostasis (Loh et al., 2015). This system has the capacity to sense the amount of energy stored in the body and adjust food intake and fuel consumption so that body temperature and bodyweight stay reasonably constant over time. Under conditions of negative energy balance, a variety of actions are initiated through brain circuits that turn on energy conserving pathways thereby reducing energy expenditure. Similarly, foraging and food intake pathways are strongly stimulated.

The first and foremost regulators of these processes are neuropeptide Y (NPY) neurons within the hypothalamus (Nguyen et al., 2011). Specifically, NPY in the arcuate nucleus (Arc) is strongly upregulated by a negative energy balance and chronically administering NPY into the Arc in combination with free access to food triggers a strong increase in feeding and a reduction in energy expenditure. However, hypothalamic NPY function has also been linked to the control of several other physiological processes including altering physical activity, fertility, the central control of bone mass, glucose homeostasis, and importantly also a variety of mood related behaviors (Loh et al., 2015).

In addition to its central actions on energy homeostasis, NPY and its related family members peptide YY (PYY) and pancreatic polypeptide (PP) produced in endocrine cells of the intestinal tract and pancreas, also play an important role in controlling peripheral aspects of glucose and energy homeostasis via para- as well as endocrine pathways (Boey et al., 2007). Thus, the NPY system is perfectly placed to have an integrating role in coordinating all aspects of energy homeostasis regulation.

The critical role of NPY in energy homeostasis control is further highlighted by the fact that it gets strongly dys-regultated under conditions of stress as well as by certain cancers, fatigue and its expression levels reduce considerably during aging (Comeras et al., 2019). Total lack of NPY expression in mice leads to a reduction in life span, which is significantly further diminished upon dietary restriction (Chiba et al., 2014). The reduced levels of NPY during aging can severely affect mitochondrial functions, cellular senescence and leads to stem cell exhaustion (Aveleira et al., 2015), all suggestive that boosting its levels could have beneficial effects in slowing the aging process.

NPY and its family members mediate their actions via signalling through a set of 4 major Y-receptors in humans (Y1, Y2, Y4 and Y5) (Lin et al., 2004). While several selective antagonist have been developed for these Y-receptors, non-peptidic agonists are not available. As such to promote the function of NPY, finding ways to increase its endogenous production might present an alternative. Not much is known about this possibility but recently evidence has emerged that certain herbal medicines could be beneficial in this process (Goswami et al., 2019). One such herbal medicine is Ninjin'yoeito (NYT), which is composed of 12 crude herbs; rehmannia root, Japanese angelica root, atractylodes rhizome, poria sclerotium, ginseng, cinnamon bark, polygala root, peony root, citrus unshiu peel, astragalus root, glycyrrhiza, and Schisandra fruit. NYT is used in Japanese Kambo traditional medicines for improving various types of symptoms, including fatigue, anemia, anorexia, night sweats, cold limbs, slight fever, chills, persistent cough, malaise, mental disequilibrium, and insomnia (Uto et al., 2018). NYT is also used in human for treating frailty-related symptoms such as lack of appetite (Morinaga et al., 2020). There are also reports on its effectiveness to improve appetite in patients with anorexia nervosa (Ohsawa et al., 2017). A large proportion of anorexia nervosa patients also display paradoxical hyperactivity, which correlates with disease severity and jeopardises the treatment effort. There are reports that some of the herbal components in NYT have effects on physical activity (Kuniaki et al., 2018). However, whether this effect on activity contributes to the therapeutic benefits of NYT on anorexia patients and if so, what the underlying mechanisms are is unknown. Furthermore, whether these effects of NYT involve changing responses of the NPY system, which is also known to control activity, is also unknown.

Thus we set out to investigate the effect of NYT on food intake, energy metabolism and activity in Drosophila and mice and then also used various NPY system related mouse models to get more insight into the interaction between NPY and NYT.

Section snippets

Drosophila culture

Fly stocks were maintained on a standard diet containing 2% agar, 5% sugar and 5% yeast and were raised at 25 °C with a 12 h/12 h light/dark cycle. Flies used in these experiments were Canton S originally purchased from Bloomington stock centre (64349). To generate experimental flies 10 virgin females were housed with 4 males and the flies were left for 24 h to mate before being removed. The eggs laid during this time were left to develop and once the flies hatched, they were collected into

NYT increases fasting induced food intake and reduces activity levels in Fly

Feeding and energy homeostasis regulation are controlled by evolutionarily conserved processes, which are largely unchanged between Drosophila and humans. Therefore to establish a role for NYT in influencing these critical physiological parameters in a simpler organism we first tested its effect on feeding and activity in Drosophila.

To determine whether NYT influences food consumption both, under fed as well as following starvation, we utilised the standard capillary feeding assay in flies. In

Discussions

Conditions that impact on energy balance can severely affect human health and preventing them or at least reducing its impact will be of great benefit for patients with certain cancers, anorexia, fatigue as well as being generally helpful for improving reduced functions during the aging process. Here we have shown that the herbal medicine NYT can influence various aspects of the energy balance and its effects are most prominent under a negative energy balance acting towards the restoration of

Declaration of Competing Interest

Part of the research was financially supported by Kracie Pharma Ltd. JAPAN.

Acknowledgements

This research is supported by the National Health and Medical Research Council of Australia (NHMRC) with project grant #1156381. We are grateful for the contribution from Ryuji Takahashi of Kampo Research Laboratories, Kracie Pharma Ltd. We thank the staff of the Garvan Institute Biological Testing Facility, staff of the Australian BioResources for facilitation of these experiments and taking care of our test mice.

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