Estradiol treatment attenuates high fat diet-induced microgliosis in ovariectomized rats.

Consumption of a high fat diet (HFD) increases circulating free fatty acids, which can enter the brain and promote a state of microgliosis, as defined by a change in microglia number and/or morphology. Most studies investigating diet-induced microgliosis have been conducted in male rodents despite well-documented sex differences in the neural control of food intake and neuroimmune signaling. This highlights the need to investigate how sex hormones may modulate the behavioral and cellular response to HFD consumption. Estradiol is of particular interest since it exerts a potent anorexigenic effect and has both anti-inflammatory and neuroprotective effects in the brain. As such, the aim of the current study was to investigate whether estradiol attenuates the development of HFD-induced microgliosis in female rats. Estradiol- and vehicle-treated ovariectomized rats were fed either a low-fat chow diet or a 60% HFD for 4 days, after which they were perfused and brain sections were processed via immunohistochemistry for microglia-specific Iba1 protein. Four days of HFD consumption promoted microgliosis, as measured via an increase in the number of microglia in the arcuate nucleus (ARC) of the hypothalamus and nucleus of the solitary tract (NTS), and a decrease in microglial branching in the ARC, NTS, lateral hypothalamus (LH), and ventromedial hypothalamus. Estradiol replacement attenuated the HFD-induced changes in microglia accumulation and morphology in the ARC, LH, and NTS. We conclude that estradiol has protective effects against HFD-induced microgliosis in a region-specific manner in hypothalamic and hindbrain areas implicated in the neural control of food intake.

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

Estrogens suppress feeding in part by enhancing the response to satiation signals. Glucagon-like peptide 1 (GLP-1) acts on receptor populations both peripherally and centrally to affect food intake. We hypothesized that modulation of the central GLP-1 system is one of the mechanisms underlying the effects of estrogens on feeding. We assessed the anorexic effect of 0, 1, and 10µg doses of GLP-1 administered into the lateral ventricle of bilaterally ovariectomized (OVX) female rats on a cyclic regimen of either 2µg ß-estradiol-3-benzoate (EB) or oil vehicle 30min prior to dark onset on the day following hormone treatment. Central GLP-1 treatment significantly suppressed food intake in EB-treated rats at both doses compared to vehicle, whereas only the 10µg GLP-1 dose was effective in oil-treated rats. To follow up, we examined whether physiologic-dose cyclic estradiol treatment influences GLP-1-induced c-Fos in feeding-relevant brain areas of OVX females. GLP-1 significantly increased c-Fos expression in the area postrema (AP) and nucleus of the solitary tract (NTS), and the presence of estrogens may be required for this effect in the paraventricular nucleus of the hypothalamus (PVN). Together, these data suggest that modulation of the central GLP-1 system may be one of the mechanisms by which estrogens suppress food intake, and highlight the PVN as a region of interest for future investigation.

Activation of ERα is necessary for estradiol's anorexigenic effect in female rats.

While there is considerable evidence that the ovarian hormone estradiol reduces food intake in female rats, it is unclear which estrogen receptor (ER) subtype, ERα or ERß, mediates this effect. While several studies have demonstrated that activation of ERα, but not ERß, is sufficient to reduce food intake in ovariectomized (OVX) rats, there are limited data regarding which receptor subtype is necessary. Here we used the selective ERα and ERß antagonists, MPrP and PHTPP, respectively, to investigate this question. We found that antagonism of ERα, but not ERß, prevented the decrease in food intake following acute administration of estradiol in OVX rats. In addition, antagonism of ERα prevented the estrous-related, phasic reduction in food intake that occurs in response to the rise in circulating levels of estradiol in cycling rats. We conclude that activation of ERα is necessary for the anorexigenic effects of exogenous and endogenous estradiol in female rats.