Modulation of appetite by gonadal steroid hormones

1. Introduction

Gonadal steroid hormones (GSH; abbreviations are listed in the glossary), i.e. the androgens, estrogens and progestins, are pluripotent signalling molecules with a diverse variety of biological actions, many of which bear no clear relationship to their primary reproductive functions within the HPG axis (Pfaff et al. 2002). This article reviews one such ancillary action, the modulation of eating by GSH. As is the case for most GSH functions, the effects of GSH on eating are species specific. Therefore, we focus our review on rats and mice, the animals for which the most data are available, and discuss human data wherever possible.

Especially in rodents, GSH have many actions that may affect body weight and adiposity independent of eating, including effects on energy expenditure, gastrointestinal function, metabolism, growth and body composition (Chen et al. 1995; Tarnopolsky 1999; Cortwright & Koves 2000; Wajchenberg 2000; Blaak 2001; Heymsfeld et al. 2002; Clegg et al. 2003; Bruns & Kemnitz 2004; Williams 2004). The mechanisms underlying these effects and their relations to eating are not well understood (Woods et al. 2003; Geary 2004a,b). Therefore, we limit our review to GSH effects on eating per se.

The review has three sections. First, we describe the major sex differences in eating in adults and their dependence on secretion of GSH. This section begins with a brief overview of some relevant aspects of HPG axis function. Second, we review progress in understanding how E2 interacts with the controls of normal eating behaviour to produce sex differences in eating. We do not consider the mechanisms through which T increases eating because almost nothing is known about them. Finally, we describe some developmental aspects of sex differences in eating.

(iii) Cholecystokinin

CCK released from the small intestine during meals acts on abdominal CCK-1 (or CCK-A) receptors to produce a vagally mediated satiating effect in animals and humans (Cox 1998; Smith 1998; Beglinger et al. 2001; Geary 2001, 2004a,b). Three results following manipulation of endogenous CCK indicate convincingly that CCK plays a major role in the peri-ovulatory decrease in eating in rats: (i) in intact rats, the de-satiating effect of CCK-1 receptor antagonism was much larger during estrus than during diestrus; (ii) in ovariectomized rats, the de-satiating effect of CCK-1 receptor antagonism was larger on the day that modelled estrus than on the day that modelled diestrus; and (iii) in ovariectomized rats, the CCK-dependent satiating potency of intraduodenal lipid infusions was increased on the day that modelled estrus (Huang et al. 1993; Asarian & Geary 1999, submitted; Eckel & Geary 1999). These effects appear to involve an increase in the potency of CCK rather than increased CCK secretion, because E2 also increased the satiating potency of exogenous CCK in ovariectomized rats (Lindén et al. 1990; Butera et al. 1993; Geary et al. 1994). The increase in CCK's satiating potency appears not to involve changes in vagal CCK-1 receptor function, because E2 failed to affect the number or affinity of CCK-1 receptors in the NTS, which includes the terminal fields of vagal afferent neurons (Geary et al. 1996). Finally, the effect of E2 on the satiating potency of intestinal food stimuli is apparently selective. This is because the satiating potency of intraintestinal infusions of l-phenylalanine, which do not elicit CCK secretion in the rat (Brenner et al. 1993), was not increased by E2 treatment in ovariectomized rats (Asarian & Geary submitted).

Experiments mapping brain activity with c-fos immunocytochemistry indicate that E2 can affect eating-induced neuronal activation in a widespread neuronal network. Thus, E2 increased c-fos expression in the NTS, the paraventricular nucleus and the central nucleus of the amygdala after either eating or CCK injection (Eckel & Geary 2001; Eckel et al. 2002). The effect of CCK on c-fos in the NTS was shown to depend on ERα in mice (Geary et al. 2001). More recently, we have obtained results indicating that E2 acts specifically in the NTS to increase CCK's satiating potency: (i) the c-fos expression that was associated with CCK- and E2-dependent increases in the satiating potency of intraduodenal lipid infusions occurred only in a circumscribed part of the NTS, just caudal to the area postrema; (ii) many of these c-fos positive cells also expressed ERα; and (iii) local administration of E2 to the surface of the brainstem, just caudal to the area postrema, was sufficient both to decrease eating and to increase CCK-induced c-fos in the caudal NTS of ovariectomized rats (Asarian & Geary submitted; Thammacharoen et al. in press). The neurotransmitter phenotype of these neurons is not known, although they did not express either GLP-1 or tyrosine hydroxylase, each of which is expressed by many neurons in this area (Asarian & Geary submitted). The lack of co-localization with tyrosine hydroxylase is surprising, given previous indications that NTS catecholaminergic neurons might be involved in the effect of CCK on eating (Rinaman et al. 1995).

In summary, one mechanism through which E2 decreases eating, at least in rats, is by increasing the satiating action of CCK. The interaction of E2 and CCK is the only mechanism discovered so far that can be linked to both the endogenous feedback control signal and endogenous E2. Furthermore, its likely site, the caudal NTS, is known. It would seem important to determine the significance of this interaction in normal and disordered eating in women.