The prevalence of overweight and obesity has increased dramatically in the US population [
1]. It is predicted that by 2030, 86% adults will be overweight or obese, and by 2048, all American adults will become overweight or obese [
1]. The role gender plays in the susceptibility to obesity is not fully understood, specifically the role ovarian hormones play. Epidemiological studies that focus on determining the role gender has on the susceptibility to obesity have provided valuable information, showing that "women generally have a larger proportion of body mass as fat, and are more likely to deposit fat subcutaneously and on their lower extremities; men are more likely to deposit fat in the abdominal region" [
2]. However, epidemiological studies have been limited by confounding factors (e.g., occupational differences between males and females) in determining the role gender and ovarian hormones play in the susceptibility to obesity. Confounding factors that can alter the effects of gender and ovarian hormones on the susceptibility to obesity include: 1) occupation differences between males and females (some jobs require more physical activity than others), 2) recreational physical activity differences between males and females, 3) differences in initial body composition at the beginning of the study between the sexes, 4) concomitant food intake pattern differences between males and females, and 5) reproductive differences (e.g., weight fluctuations during and after pregnancy). In animal studies, however, many of these confounding factors and others, such as age and genetics, can be controlled for; moreover, experimental animals can be closely monitored throughout the study to measure factors that affect body weight gain (e.g., initial body weight, diet, calorie intake, and physical activity). Review of the animal literature investigating the predisposition to obesity between males, females and ovarian hormones, revealed a lack of studies in this area. In fact, a direct comparison in the predisposition to obesity between males, females, and ovariectomized females on various diet regimens has not been made. We and others have shown that male mice have a higher susceptibility to become obese compared to female mice [
3,
4]. Moreover, we have shown that removal of ovarian hormones (surgical removal of the ovaries by ovariectomy) increased the susceptibility of female mice to become obese [
5,
6]. However, we have not simultaneously compared the predisposition to obesity between male, female and ovariectomized female mice receiving different diets. We conducted studies in mice to eliminate confounding factors that affect susceptibility to obesity, such as age, genetics, calorie intake and diet. Our results show that male mice are more susceptible to obesity than female mice, and that ovariectomy eliminates the protection against weight gain in female mice; in fact, ovariectomized female mice appear to mimic the male mice in their susceptibility to weight gain and percent body fat levels.