Estradiol increases consumption of a chocolate cake mix in female rats

https://doi.org/10.1016/j.pbb.2006.04.010Get rights and content

Abstract

Female Sprague-Dawley rats were given an opportunity to eat chocolate cake mix (CCM) using a common brand of cake mix, while standard laboratory food was also available. They took large amounts of the CCM, often taking more than 20 g in 24 h. Some animals were given a single injection of 1 of 6 doses of estradiol valerate (ranging from 0.09 to 10.0 mg/kg) and others were given vehicle. Estradiol valerate provides for sustained release of estradiol. Those receiving estradiol ate more than those receiving vehicle at doses larger than 0.09 mg/kg. Further, with a dose of 10 mg/kg, greater intake among estradiol-treated females was apparent 2 months post-injection. Methodological issues of neophobia and conditioned avoidance were addressed in the study's design and may explain why increased intakes were observed here in contrast to the consensus that estradiol reduces food intake.

Introduction

Based on data from adults in the USA (20+ years old) and defining obesity as a BMI  30, it is estimated that 8 million plus more women are obese than men. The incidence of obesity for women is 33.4% compared to 27.5% for men (Flegal et al., 2002). Women are exposed to higher levels of both endogenous and exogenous estrogenic compounds. Perhaps this might account for the different rates of obesity.

The hypothesis that higher rates of exposure to estrogenic compounds might account for the difference in obesity is not supported by reports from the animal laboratory. An early example is a study by Wade (1975) showing that estradiol reduced the consumption of food among female rats. Following Wade's experiment, there were many demonstrations supporting the hypothesis that estrogenic compounds lead to a reduction in food intake. A literature search, involving a computer-generated list of papers citing Wade's 1975 paper, yields a list of hundreds of reports. The consensus is that estrogenic compounds reduce food intake (Eckel, 2004, Horvath et al., 2004).

A different perspective emerges from our recent research. We were interested in following the observations (Reid, 1996, Reid and Hunter, 1984) that small doses of morphine (e.g., 1.0 mg/kg, not sufficiently large to induce analgesia) enhanced the intake of alcoholic beverages among rats, and doses of opioid antagonists reduced intakes. There is considerable evidence that the opioidergic system modulates intake of alcoholic beverages and intake of palatable ingesta (Reid, 1985, Reid, 1990, for reviews). Brawer and colleagues (e.g., Brawer et al., 1993, Desjardins et al., 1990, Desjardins et al., 1993) showed that large doses of estradiol valerate (EV) (2 mg a rat or about 10 mg/kg) selectively disrupted the arcuate nucleus of the hypothalamus and hence selectively reduced (in terms of the endogenous opioids) the β-endorphin content of brain. In the interest of determining which of the endogenous opioids is salient to intake of alcoholic beverages, we gave 2 mg of EV to female rats that were having daily opportunities to take alcoholic beverages. This dose of EV led, initially, to a transitory reduction in bodyweight and a marked reduction in intakes that was sustained for days. However, with continued opportunity to take the beverage, the females' intakes increased until they were substantially larger than the control group's intakes (Reid et al., 2002). Once the increased intakes emerged, they were sustained for months (Reid et al., 2003b). The initial decrease in intakes was predictable based on the idea that decrements in opioidergic functioning (induced by the toxic effects of EV) would reduce appetite for alcohol much the same way opioid antagonists reduced intakes. The large increases in intakes manifest days after the injection of EV (Marinelli et al., 2003, Reid et al., 2002, Reid et al., 2003a, Reid et al., 2003b) were not anticipated. A hormonal manipulation that induces a large increment in intake of alcoholic beverages, which is sustained for months without further intervention, might have relevance to alcoholism; consequently, further research was initiated.

Recently, we (Boswell et al., 2005) addressed the issue of whether the increased appetite for alcoholic beverage, seen after large doses of EV, is peculiar to alcoholic beverage or is a general increase in appetite that might affect intakes of many kinds of ingesta. Given the conclusion that there is considerable overlap in mechanisms that control ingestion in general and ingestion of alcohol (Reid, 1985, Reid, 1990), there were reasons to suspect that EV might enhance intakes of substances other than alcoholic beverages, contrary to the consensus that estradiol decreased intakes of ingesta (Eckel, 2004, Horvath et al., 2004).

Boswell et al. (2005) provided female rats with two different saccharin solutions, one (0.025%) that rats consume in large amounts and another (2.0%) that is taken in only small amounts (bittersweet to the human taste). EV-treated rats consumed more of the 0.025% solution and less of the 2.0% solution than vehicle-treated females. The effects on intake remained measurable for 3 months post-injection. It was also noted that the EV-treated rats did not show an enhanced appetite for laboratory food, as their rate of weight gain paralleled that of the vehicle-control animals once the acute effects of EV subsided. Large doses of EV can induce circumstances enhancing appetite for alcoholic beverages and some other ingesta (e.g., palatable saccharin solutions), but not all ingesta (e.g., bittersweet saccharin solution and ordinary laboratory food).

Procedural differences may provide an explanation for the discrepancy in our findings that estrogenic injections enhance intakes, compared with other published findings that they suppress intakes. After an injection of EV, female rats either lose weight or do not gain weight across a number of days. Vehicle-injected rats gain weight nearly daily (Flanagan-Cato et al., 2001, Reid et al., 2002). The acute effects of EV on weight may reflect a malaise caused by the initial effects of the drug. Supporting such a contention, de Beun et al. (1991) and Flanagan-Cato et al. (2001) have found that injections of estradiol induce taste and place aversions. The initial effects of the continuous estrogenic stimulation are probably related to a malaise, manifest as weight loss, resulting in reduced food intake. After the rats have adapted to continuous estrogenic stimulation, they gain weight at the rate of controls and an increase in appetite (relative to control group animals) for certain ingesta may emerge.

The following experiments extend the study of EV's effects to appetite for a complex palatable food. We chose chocolate cake mix batter (CCM), which had been used by Koch and Matthews (2001) and shown to be sensitive to drug effects. We took into account the possibility that the initial effects of EV might induce a conditional taste aversion and, therefore, did not pair the initial effects of EV with presentation of CCM.

Section snippets

General methods

There were four experiments. They shared a number of common features summarized in this part of the report.

Experiment 1: large doses of EV and intake of CCM

The dose of EV used in the initial experiments assessing intake of alcoholic beverages was 2 mg per female or 10 mg of EV per kg of rat (mg/kg). Since the interest was in seeing if this same dose would affect ingestion of CCM, the dose used in this experiment was 10 mg/kg.

Experiment 2: changes in bodyweight following removal of access to chocolate and white cake mix

In Experiment 1, the weight loss associated with ending availability of CCM was unanticipated. We were curious to see if it would occur with a substance of similar complexity, but lacking cocoa. Consequently, in the next study, some female rats were given access to CCM while others were provided access to white cake mix (WCM).

In Experiment 1, reliable reductions in bodyweight occurred within 24 h after removal of rats' access to CCM. This phenomenon occurred on each of 10 occasions when CCM was

Experiment 3: 1.5 mg/kg doses of EV and intake of CCM

The 10 mg/kg dose of EV provides supraphysiological doses of estradiol for a period of as many as 20 days and is apt to be toxic to the neurons of the arcuate nucleus of the hypothalamus (Desjardins et al., 1993). The next two experiments are explorations of considerably smaller doses that may not be toxic to the arcuate nucleus, but do provide continuous estradiol for a period of a number of days. This experiment assesses the dose of 1.5 mg/kg of EV, 11 to 19 days after it was administered.

Experiment 4: dose–response assessment, EV and intake of CCM

The 1.5 mg/kg dose of EV is very large compared to the doses of estradiol that affect events of the estrous cycle. The question of whether considerably smaller doses might also enhance intakes is addressed by testing four doses of EV, repeatedly halving the 1.5 mg/kg dose used in Experiment 3: the doses assessed were 0.75, 0.38, 0.19 and 0.09 mg/kg of bodyweight, plus a vehicle control.

A methodological change was made here in comparison with Experiment 1, to reduce the possibility of neophobic

Discussion

A recently published, comprehensive review of the literature on regulation of energy homeostasis stated “Gonadal steroids, including estradiol and testosterone, have also been long known to reduce appetite, increase energy expenditure, and decrease adiposity” (Horvath et al., 2004, p. 236). In addition, it has been long known that ovariectomy leads to weight gains (see, Eckel, 2004, for another review). There is a nice symmetry to these long known generalizations (applications of estradiol

References (31)

Cited by (0)

View full text