Effects of voluntary wheel running on appetite-regulating peptides and neuroinflammation in the hypothalamus of ovariectomized middle-aged mice

Abstract

The postmenopausal period is associated with an increased tendency to gain weight. This may be due to disturbances in appetite regulation, mainly in the hypothalamus and nutritional behaviors, as well as persistent neuroinflammation resulting from estrogen deficiency. Research indicates that physical activity may counteract estrogen deficiency by improving hypothalamic regulation of appetite and inflammation, thereby promoting better energy balance and decreasing the risk of weight gain after menopause. We investigated whether voluntary wheel running (VWR) impacts factors related to appetite, energy homeostasis, and neuroinflammatory changes induced by ovariectomy (OVX). Thus, 13-month-old female mice underwent OVX, creating a comprehensive model of reproductive aging in females. Ovariectomized (OVX-VWR) and sham-operated (SHAM-VWR) mice were subjected to 6 weeks of VWR. The control sedentary groups (SHAM-SED, OVX-SED) were housed with immobilized wheels. The body mass, food and water intake, and daily running activity were recorded. Hypothalamic and serum samples were collected to examine the expression levels of genes, proteins, and hormones related to appetite regulation and neuroinflammation processes. OVX mice gained weight most excessively and showed reduced running activity. OVX downregulated the ERα/ERβ ratio, and VWR increased ERβ expression. VWR increased Lepr and Cckar expression in the sham-operated group. VWR has an impact on hypothalamic neuroinflammation regardless of ovarian status, through changes in expression of NLRP3, pro-IL-18, TLR4, pro-caspase 1, Il-1b, and Il-18. OVX in middle-aged mice altered body weight and energy metabolism, but did not affect food intake. VWR modulated hypothalamic appetite-regulating factors—changes not seen in OVX females—and elicited a comparable neuroinflammatory response in the hypothalamus of both SHAM- and OVX-operated mice.