Estradiol Replacement Blocks GHRP-6's Appetite-Stimulating Effects in Ovariectomized Rats
Background
Menopause is often associated with increased central obesity and metabolic dysfunction, linked to the decline in estrogen. The hormone ghrelin, often called the 'hunger hormone', stimulates appetite by acting on the growth hormone secretagogue receptor (GHSR). The interaction between estrogen deficiency and the ghrelin system in the context of a high-fat diet (HFD) is a critical area of research for understanding and potentially treating postmenopausal weight gain. This study investigates whether estradiol replacement can counteract the appetite-stimulating (orexigenic) effects of a ghrelin system agonist, GHRP-6, in an animal model of menopause and diet-induced obesity, aiming to clarify the hormonal mechanisms that regulate energy balance.
Study Design
Wistar rats were ovariectomized (OVX) at 9 weeks of age to model menopause. After 4 weeks, they were subcutaneously implanted with either 17β-estradiol (E2) pellets or placebo pellets and started on a high-fat diet (HFD) for another 4 weeks. Following the HFD period, the orexigenic response to an intraperitoneal injection of GHRP-6 (a GHSR agonist) was measured by assessing HFD intake. Neuronal activation was quantified by counting c-Fos-positive neurons in the hypothalamic arcuate nucleus (ARC). Gastric ghrelin and GHSR protein levels were analyzed using Western blotting, and ghrelin mRNA was measured with real-time PCR.
Results
Rats in the placebo group on a high-fat diet showed increased energy intake and body weight. In contrast, the estradiol (E2) replacement group experienced a temporary reduction in these measures. The key intervention, an injection of the ghrelin agonist GHRP-6, significantly enhanced HFD intake and activated neurons in the hypothalamic arcuate nucleus (ARC), but only in the placebo group. The E2-treated rats showed no such response to GHRP-6.
Mechanistically, the study found that gastric ghrelin protein levels and
GHSRprotein levels were both lower in the E2 group compared to the placebo group.
This suggests that estradiol acts directly on the stomach to suppress the ghrelin system at both the ligand and receptor level. Interestingly, plasma acyl ghrelin levels were similar between the two groups, indicating a localized, gastric effect of estradiol rather than a systemic reduction in circulating ghrelin.
Key Findings
- GHRP-6 increased high-fat diet intake and activated hypothalamic ARC neurons only in placebo-treated rats, not in estradiol-treated rats.
- Estradiol (E2) replacement lowered gastric ghrelin protein levels compared to the placebo group.
- E2 replacement also reduced growth hormone secretagogue receptor (GHSR) protein levels in the stomach.
- Plasma acyl ghrelin levels were similar between the E2 and placebo groups, suggesting a localized gastric effect.
- E2 replacement temporarily reduced energy intake and body weight gain in rats fed a high-fat diet.
Why It Matters
This research provides a mechanism explaining how estradiol replacement therapy (ERT) may help manage weight gain after menopause. It suggests that E2's benefits are not just metabolic but also behavioral, by directly blunting the a_ppetite-stimulating signals_ originating from the stomach's ghrelin system in response to a high-fat diet. For individuals considering or using ERT, this highlights an additional benefit related to appetite control and resistance to obesogenic foods. The key takeaway is that estradiol's protective effect against obesity involves suppressing the ghrelin pathway at the gastric level, making the body less responsive to hunger signals amplified by GHSR agonists like GHRP-6. This finding reinforces the importance of hormonal balance in regulating feeding behavior and could inform more targeted strategies for managing postmenopausal metabolic health.
ghrelin
estradiol
obesity
menopause
animal study
ghsr
