Type of Document	Dissertation
Author	Messina, Michelina Marie
URN	etd-07092008-141324
Title	Estradiol's Regulation of Energy Homeostasis.
Degree	Doctor of Philosophy
Department	Program in Neuroscience
Advisory Committee	Advisor Name Title J. Michael Overton Committee Chair James Olcese Committee Member Jasminka Ilich-Ernst Committee Member Joyce Carbonell Committee Member Lisa A. Eckel Committee Member Robert J. Contreras Committee Member
Keywords	Estrogen Metabolism RT-PCR Estrogen Receptor Knock-Out Mice Amylin Food Intake Body Weight
Date of Defense	2008-06-17
Availability	unrestricted
Abstract OVX leads to hyperphagia and weight gain in female rats, which can be prevented by E2; however, the role of endogenous E2 on feeding and energy homeostasis in female mice has not been well characterized. The 2-part goal of this study was to: 1.) investigate the mechanisms by which lack of gonadal steroids produces weight gain in female mice vs. rats and 2.) determine the contribution of energy intake to OVX-induced obesity. By 3 wk post-surgery, both OVX’d mice and rats had increased weight gain compared to shams. OVX produced hyperphagia in rats (pre-OVX = 68.4 +/- 1.8, post-OVX = 78.6 +/- 0.7 kcal/d), but did not produce daily (pre-OVX = 14.2 +/- 1.1, post-OVX = 14.7 +/- 0.1 kcal/d), nor cumulative (sham = 294.1 +/- 1.2, OVX = 294.4 +/- 0.9 kcal) hyperphagia in mice. OVX decreased locomotor activity (LA; mice: pre-OVX = 411 +/- 9 vs. post-OVX = 216 +/- 2 m; rats: pre-OVX = 85 +/- 3 vs. post-OVX = 68 +/- 1 m) in both species and it decreased mass-specific metabolic rate in mice only (VO2: pre-OVX = 33.1 +/- 0.1 vs. post-OVX = 31.9 +/- 0.1 ml/min/kg0.75). Pair-feeding of OVX’d rats to the amount of food consumed on non-estrous days attenuated OVX-induced obesity (final weights: OVX ad libitum fed= 420.5 +/- 7.3, OVX pair-fed = 385.8 +/- 6.9, sham = 348.8 +/- 4.5 g). The results suggest that OVX-induced weight gain is mediated by hyperphagia and reduced LA in rats, but that in mice, it is mediated primarily by reduced LA and suppressed metabolism. The distinct contributions of the two known nuclear ERs (ER alphaand ER beta to endogenous E2’s regulation of energy homeostasis have yet to be determined. The goal of chapter two of this report was to delineate the respective roles of ER alpha and ER beta in E2’s modulation of energy homeostasis. The results indicate that ER alpha is critical for E2’s modulation of body weight, locomotor activity, and VO2, as deletion of this receptor led to an obese, hypoactive phenotype (baseline body weight = 27.2 +/- 0.1g (aERKO), 22.7 +/- 0.1 g (WT); dark-phase LA = 102.7 +/- 3.6m (aERKO), 439.9 +/- 9.9m (WT); dark-phase VO2 = 23.6 +/- 0.2 ml/min/kg2 (aERKO), 29.9 +/- 0.3 ml/min/kg2 (WT)) that was not altered by OVX. Surprisingly, ER beta gene deletion led to an intermediate phenotype characterized by moderate hypoactivity (dark-phase LA = 246.9 +/- 12.3 m), body weight that was lower than aERKO, but higher than WT mice of the same age (25.0 +/- 0.1 g), and moderately suppressed VO2 (27.6 +/- 0.2 ml/min/kg2). Similar to WT mice, OVX led to a greater decrease in LA and an increase in body weight in this mutant, suggesting that ER beta plays an ancillary role in E2’s modulation of energy homeostasis. It is well-documented that housing rodents at a thermoneutral ambient temperature (Ta; ~28-32°C) markedly reduces food intake and energy expenditure. Nonetheless, whether Ta affects the capacity of E2 to modulate food intake and energy expenditure in rodents is unknown. The goal of chapter three of this report was to determine the role of Ta in E2’s capacity to modulate energy homeostasis. The results indicate that thermoneutrality attenuated OVX-induced changes in body weight (OVX mice housed at standard Ta (23°C) gained 3.2 +/- 0.2 g, while OVX-thermoneutral (TMN) mice gained only 0.8 +/- 0.4 g) and LA (OVX decreased LA in 23°C mice by 201 +/- 3 m, while it decreased LA in TMN mice by 98 +/- 4 m), suggesting that OVX-induced weight gain may be mediated, at least in part, by suppression of non-shivering thermogenesis. Finally, the hypophagic effect of E2 appears to be mediated by its ability to interact with multiple hormone, neuropeptide, and neurotransmitter systems implicated in the direct control of food intake. Nonetheless, the extent to which each individual compound contributes to the hypophagic effect of E2 is not known. The goal of chapter four of this report was to examine the extent to which estradiol modulates the anorectic effect of the pancreatic beta-cell hormone, amylin. Two major new findings were obtained: 1.) acute i.p. amylin, at 5 and 10 micrograms/kg doses, does not reduce food intake in OVX’d female rats, with or without hormone replacement and 2.) ER alpha and amylin-positive cell bodies are co-localized in various regions of the brain, most abundantly in hindbrain regions. Whether this neuroanatomical evidence has any behavioral significance remains to be elucidated.
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