Sex and estrogens alter the action of glucagon-like peptide-1 on reward

Abstract

BackgroundFeeding behavior is regulated through an intricate array of anorexic and orexigenic hormones acting on the central nervous system (CNS). Some of these hormones may have differential effects in males and females, effects potentially attributed to actions of gonadal steroids, especially estrogens. Central stimulation of the glucagon-like peptide-1 (GLP-1) receptors reduces feeding and food-reward behavior by acting on CNS regions important for the anorexic actions of estrogens. Thus, we propose that the action of GLP-1 on food intake and reward may differ between sexes.MethodsMale and female rats were centrally injected with the GLP-1 analog exendin-4 (Ex4) in a non-deprived or food-restricted state; reward behavior was measured in a progressive ratio operant conditioning task. Intake of chow and palatable food were also measured. To determine if sex differences in the actions of Ex4 are due to interactions with estrogens, Ex4 treatment was preceded by treatment with a nonselective estrogen receptor-α (ERα) and ERβ or ERα-selective antagonist.ResultsCentral injection of Ex4 revealed increased reward behavior suppression in females, compared to males, in the operant conditioning task. This increase was present in both non-deprived and food-restricted animals with larger differences in the fed state. Intake of chow and palatable food, after Ex4, were similar in males and females. Food reward, but not food intake, effect of Ex4 was attenuated by pretreatment with ER antagonist in both sexes, suggesting that estrogens may modulate effects of Ex4 in both sexes. Furthermore, central pretreatment with ERα-selective antagonist was sufficient to attenuate effects of Ex4 on reward.ConclusionsCollectively, these data reveal that females display much higher sensitivity to the food reward impact of central GLP-1 receptor activation. Surprisingly, they also demonstrate that central ERα signaling is necessary for the actions of GLP-1 on food-reward behavior in both sexes.

Estradiol modulates the anorexic response to central glucagon-like peptide 1

“…A previous LV GLP-1 dose response study performed in our laboratory in male rats found smaller effects at 2 h into the dark phase, and no effect on overnight intake (Dossat et al, 2011). Although we did not perform a direct male-female comparison in the current study, these and other data (Richard et al, 2016) suggest that sizable sex differences in GLP-1 responsiveness exists. This effect may require the presence of ovarian hormones at the time of treatment, because OVX oil-treated female rats in the present study did not show the long-lasting intake suppression after GLP-1 (Figure 1E).…”

“…Previous findings demonstrate that a novel estradiol/GLP-1 conjugate molecule was more effective at suppressing food intake in rodents than both GLP-1 in its native form and a dissociated conjugate mixture of estradiol and GLP-1, an effect hypothesized to be due to estrogens guiding GLP-1 to certain cell populations (Finan et al, 2012; Vogel et al, 2016). A recent examination of sex differences in the effect of GLP-1R activation on food reward-motivated behavior suggest an interaction with estrogens (Richard et al, 2016). Our data indicate that estrogens, specifically EB, enhance sensitivity to the anorexic effects of central GLP-1R activation.…”

“…In another recent study, Finan and colleagues found that in gonadally intact male and female mice, an estradiol/GLP-1 conjugate molecule was more effective at suppressing food intake and body weight than both GLP-1 in its native form and a dissociated conjugate mixture of estradiol and GLP-1 (2012). Furthermore, new evidence has emerged suggesting that estrogens may be involved in the effect of central GLP-1R activation on food-motivated behavior (Richard et al, 2016). However, given that these studies were not designed to control for estrous cycle stage when testing females, and utilized the GLP-1R agonist Ex4, rather than GLP-1 itself, the conclusions that can be drawn regarding an interaction between estrogens and GLP-1 are limited.…”

Exenatide Improves Bone Quality in a Murine Model of Genetically Inherited Type 2 Diabetes Mellitus

“…Our experiments were performed in male db/db mice that exhibit more severe clinical symptoms and we cannot exclude potential gender differences regarding the skeletal effects of Exenatide in db/db mice. T2DM women treated with Exenatide presented more benefit in terms of cardiovascular risk factor and body weight ( 64 ) that can be attributed to interaction of Exenatide with estrogen signaling ( 65 ). As there is increased fracture risk among T2DM women compared with men, it would be of interest to verify our findings in female T2DM models in order to have sex-specific treatment guidelines.…”

Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons

“…For example, female rats have higher levels of LHA ghrelin receptor expression than males, and acute blockade of LHA ghrelin receptors in females, but not males, reduces food intake, body weight, and food seeking behaviors ( 88 ). Central GLP-1R activity also reveals sex dimorphism, where broad activation of GLP-1Rs results in greater suppression in food motivated behaviors in female compared to male rats along with interactions with estrogen signaling ( 247 ). Interestingly, these results appear to vary depending on brain region, as LHA GLP-1R knockdown or blockade increases food motivation only in male rats ( 85 ).…”