Female mice and rats exhibit species-specific metabolic and behavioral responses to ovariectomy

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Abstract

Ovariectomy (OVX) leads to hyperphagia and weight gain in rats, which can be prevented by estradiol (E2) replacement; however, the role of endogenous E2 on feeding and energy homeostasis in female mice has not been well characterized. The primary goal of this study was to assess the relative contribution of increased energy intake and decreased energy expenditure to OVX-induced weight gain in female rats and mice. OVX led to hyperphagia in rats, but did not produce daily, nor cumulative, hyperphagia in mice. OVX decreased mass-specific metabolic rate in mice, but not in rats. OVX decreased home cage locomotor activity in both species. Pair-feeding attenuated OVX-induced weight gain in rats and produced both short- and long-term changes in expression of key hypothalamic genes involved in food intake and energy homeostasis, i.e., the anorexigenic neuropeptide pro-opiomelanocortin (POMC) and the orexigenic neuropeptides: melanin-concentrating hormone (MCH) and agouti-related peptide (AgRP). No differences in hypothalamic gene expression were observed between OVX’d and sham mice. The results suggest that OVX-induced weight gain is mediated by hyperphagia and reduced locomotor activity in rats, but that in mice, it is primarily mediated by reduced locomotor activity and metabolic rate.

Introduction

There is uncertainty regarding the evidence that estradiol (E2) influences energy homeostasis by regulating energy expenditure. Pair-feeding of ovariectomized (OVX’d) rats generally does not prevent weight gain (Roy and Wade, 1977); however, this finding is not universal (Liang et al., 2002). If OVX-induced weight gain is not prevented by restricting daily food intake of OVX’d rats, then a role for E2 in the regulation of energy expenditure is strongly suggested. Thus, the primary goal of this study was to assess the relative contribution of increased energy intake and decreased energy expenditure to OVX-induced weight gain in female mice and rats.

In addition, it is well established that E2 exerts both a tonic and a phasic inhibitory effect on food intake in female rats (reviewed in Eckel, 2004). While the hypophagia and hyperactivity that occur on estrus have been well characterized in the female rat (Wade, 1972) they have not been well characterized in the female mouse. In fact, exogenous E2 treatment has been found to increase locomotor activity in OVX’d female mice (Ogawa et al., 2003), yet surprisingly few studies have investigated the role of endogenous E2 on food intake and locomotor activity in the ovarian-intact female mouse. Of these studies, the following conclusive statements can be made: (1) an estrous rhythm of locomotor activity has not been established in ovarian-intact female mice and (2) an estrous-related decrease in food intake has not been observed in ovarian-intact female mice (in fact, the absence of these effects has been reported (Barnett and McEwan, 1973, Petersen, 1976)). In light of the increasing use of mice as the pre-clinical vertebrate model of choice, it is crucial to know how exactly endogenous E2 affects food intake and energy homeostasis in the normal ovarian-intact mouse. Experience tells us that we cannot simply extrapolate from what is already known about E2 in the ovarian-intact rat to the mouse. Furthermore, evidence involving exogenous, pharmacological doses of E2 does not necessarily indicate how endogenous, physiological levels of E2 affect the physiology of the ovarian-intact mouse. Therefore, the secondary goal of this study was to characterize the daily food intake and locomotor activity patterns of ovarian-intact mice. After observing hyperphagia in OVX’d rats (an effect that was clearly absent in OVX’d mice), we sought to measure changes in gene expression of key hypothalamic neuropeptides involved in feeding and energy homeostasis.

Section snippets

Animals and housing

Female C57BL/6 mice (14 wk old) and Long-Evans rats (14 wk old) were obtained from Charles River Laboratories (Charlotte, NC). Upon arrival, animals were housed individually in polycarbonate cages containing wood chip bedding and a red, translucent igloo niche (Bio-Serv, Frenchtown, NJ; niches were in mouse cages only). Animals were given 2 wk to fully recover from shipment stress and to acclimate to a reversed circadian cycle (11a–11p dark:11p–11a light). Pellet chow (4.5% fat, physiological

Mice

OVX’d mice gained weight (Fig. 1A) with no accompanying increase in food intake; neither daily (Fig. 1B), nor cumulative (shams = 93.4 +/− 6.6 g, OVX = 96.6 +/− 4.9 g; post-surgical days 1–21) food intake increases were observed in OVX’d mice. Other than on post-surgical days 1 and 2, daily energy expenditure and daily energy balance did not differ between OVX and sham mice (Fig. 1C and D, respectively, p > 0.05).

Ovarian-intact mice (n = 8) exhibited no difference in daily food intake on estrous- vs.

Discussion

The primary goal of this study was to assess the relative contribution of energy intake and expenditure to OVX-induced weight gain in female mice and rats. Three new findings were obtained. First, OVX-induced weight gain in rats is mediated by hyperphagia and reduced locomotor activity; while in mice, it is mediated by reduced locomotor activity and reduced metabolic rate. Second, pair-feeding of OVX’d rats attenuated, but did not prevent, OVX-induced weight gain. Lastly, ovarian-intact mice

Acknowledgments

This work was supported by a Ruth L. Kirschstein National Research Service Award (NRSA) Predoctoral Training Grant, National Institute for Neurological Disorders and Stroke, NIH F31 NS057856-01 (M.M. Witte).

We gratefully acknowledge Dr. James Olcese, Holly E. Sikes, Gelson J. Taube, Jr., and James Sharkey for their generous assistance with molecular techniques and Dr. Lisa A. Eckel for her always helpful assistance and feedback. We would also like to thank the Florida State University Program

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