Oxyntomodulin induces satiety and activates the arcuate nucleus of the hypothalamus in Japanese quail

Highlights

• Centrally injected oxyntomodulin (OXM) caused reduced food and water intake in Japanese quail.

• There was an increase in c-Fos immunoreactivity in the arcuate nucleus and dorsomedial nucleus of the hypothalamus.

• Results suggest that quail are more sensitive than chickens to the satiety-inducing effects of OXM.

Abstract

Oxyntomodulin (OXM) is a proglucagon-derived peptide that suppresses hunger in humans. There are some differences in its food intake-inhibitory effects among species. The central mechanisms are unclear and it is unknown if OXM is more efficacious in a gallinaceous species that has not undergone as much selection for growth as the chicken. The objective was thus to determine the effects of OXM on food and water intake and hypothalamic physiology in Japanese quail. At 7 days post-hatch, 6-h-fasted quail were injected intracerebroventricularly (ICV) or intraperitoneally (IP) with 0.32, 0.65, or 1.3 nmol of OXM. All doses decreased food intake for 180 min post-ICV injection. On a cumulative basis, water intake was not affected until 120 min, with the lowest and highest doses decreasing water intake after ICV injection. The two highest doses were anorexigenic when administered via the IP route, whereas all doses were anti-dipsogenic starting at 30 min post-injection. In hypothalamic samples collected at 1-h post-ICV injection, there was an increase in c-Fos immunoreactivity, an indicator of recent neuronal activation, in the arcuate nucleus (ARC) and dorsomedial nucleus (DMN) of the hypothalamus in OXM-injected individuals. Results suggest that quail are more sensitive than chickens to the satiety-inducing effects of OXM. The central mechanism is likely mediated through a pathway in the ARC that is conserved among species, and through activation of the DMN, an effect that is unique to quail. Such knowledge is critical for facilitating the development of novel, side effect-free anti-eating strategies to promote weight-loss in obesity.

Introduction

Proglucagon-like peptides are produced in the gastrointestinal (GI) tract and pancreas in response to digestion products, and include glucagon, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), and oxyntomodulin (OXM) (Drucker, 2001). OXM, a 37 amino acid peptide, is released with GLP-1 from the GI tract in response to nutrient intake and activates both the glucagon and GLP-1 receptors (GLP-1Rs) (Pocai, 2014). The amino acid sequence of OXM contains the entirety of glucagon's sequence, as well as 8 additional residues at the C-terminus. Prohormone convertase 1/3 processes proglucagon into glicentin within the enteroendocrine L-cells, in which it is then cleaved into OXM (Drucker, 2005; Holst et al., 2018). Thereafter, OXM, as the name implies, targets oxyntic glands (Bataille et al., 1981) and reduces gastric acid secretions (Dubrasquet et al., 1982; Jarrousse et al., 1986; Jarrousse et al., 1985). The enzyme dipeptidyl-peptidase IV inactivates OXM, an interaction that can be exploited in the design of structural analogs that have an extended half-life (Druce et al., 2008; Druce and Bloom, 2006).

As reviewed, OXM potently induces satiety in humans and promotes weight loss, and appetite-related effects are mediated via the hypothalamus, in particular the arcuate nucleus (ARC) through GLP-1Rs (Wynne and Bloom, 2006). However, there are some conflicting behavioral effects reported among studies and species. For instance, in rats, both intracerebroventricular (ICV) (Dakin et al., 2001) and intraperitoneal (IP) (Dakin et al., 2004) injection of OXM reduce food intake, whereas in mice, the IP route of administration did not influence food intake (Baggio et al., 2004). In broiler (meat-type) chicks, ICV (Honda et al., 2014) but not IP or intravenous (IV) injection of OXM inhibited food intake (Cline et al., 2008). Water intake was also reduced in ICV-injected broiler chicks (Cline et al., 2008) and IP-injected rats (Dakin et al., 2004), but not IV-infused humans (Cohen et al., 2003). It is unclear if the effects in chickens are species-specific or influenced by the fact that chickens have been intensely selected for growth-related traits that have led to correlated responses in food intake. Thus, it would not be surprising that selection for growth and consequently the increase in inherent appetite would alter anorexigenic tone and influence the sensitivity to appetite-suppressants. Japanese quail (Coturnix japonica) are also gallinaceous and well-adapted to a captive environment, but are not as extensively selected and may thus better resemble a more “wild-type” bird. Thus, the objective of the present study was to characterize responses in food and water intake to centrally and peripherally administered OXM in quail, and to identify associated activations in hypothalamic nuclei.