Metabolic adaptations occur with weight loss that result in increased hunger with discordant simultaneous reductions in energy requirements—producing the so-called energy gap in which more energy is desired than is required. The increased hunger is associated with elevation of the orexigenic hormone ghrelin and decrements in anorexigenic hormones. The lower total daily energy expenditure with diet-induced weight loss results from (1) a disproportionately greater decrease in circulating leptin and resting metabolic rate (RMR) than would be predicted based on the decline in body mass, (2) decreased thermic effect of food (TEF), and (3) increased energy efficiency at work intensities characteristic of activities of daily living. These metabolic adaptations can readily promote weight regain. While more experimental research is needed to identify effective strategies to narrow the energy gap and attenuate weight regain, some factors contributing to long-term weight loss maintenance have been identified. Less hunger and greater satiation have been associated with higher intakes of protein and dietary fiber, and lower glycemic load diets. High levels of physical activity are characteristic of most successful weight maintainers. A high energy flux state characterized by high daily energy expenditure and matching energy intake may attenuate the declines in RMR and TEF, and may also result in more accurate regulation of energy intake to match daily energy expenditure.

Fear extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear extinction memories are labile and fear tends to return even after successful extinction. The relapse of fear contributes to the poor long-term efficacy of exposure therapy. A single session of voluntary exercise can enhance the acquisition and consolidation of fear extinction in male rats, but the effects of exercise on relapse of fear after extinction are not well understood. Here, we characterized the effects of 2 h of voluntary exercise during the consolidation phase of contextual or auditory fear extinction learning on long-term fear extinction memory and renewal in adult, male and female, Long-Evans rats. Results indicate that exercise enhances consolidation of fear extinction memory and reduces fear relapse after extinction in a sex-dependent manner. These data suggest that brief bouts of exercise could be used as an augmentation strategy for exposure therapy, even in previously sedentary subjects. Fear memories of discrete cues, rather than of contextual ones, may be most susceptible to exercise-augmented extinction, especially in males. Additionally, exercise seems to have the biggest impact on fear relapse phenomena, even if fear extinction memories themselves are only minimally enhanced.

Exercise is often used as a strategy for weight loss maintenance. In preclinical models, we have shown that exercise may be beneficial because it counters the biological drive to regain weight. However, our studies have demonstrated sex differences in the response to exercise in this context. In the present study, we sought to better understand why females and males exhibit different compensatory food eating behaviors in response to regular exercise. Using a forced treadmill exercise paradigm, we measured weight gain, energy expenditure, food intake in real time, and the anorectic effects of leptin. The 4-wk exercise training resulted in reduced weight gain in males and sustained weight gain in females. In male rats, exercise decreased intake, whereas it increased food intake in females. Our results suggest that the anorectic effects of leptin were not responsible for these sex differences in appetite in response to exercise. If these results translate to the human condition, they may reveal important information for the use and application of regular exercise programs.

Exposure to stress early in life has been associated with adult-onset comorbidities such as chronic pain, metabolic dysregulation, obesity, and inactivity. We have established an early-life stress model using neonatal maternal separation (NMS) in mice, which displays evidence of increased body weight and adiposity, widespread mechanical allodynia, and hypothalamic-pituitary-adrenal axis dysregulation in male mice. Early-life stress and consumption of a Western-style diet contribute to the development of obesity; however, relatively few preclinical studies have been performed in female rodents, which are known to be protected against diet-induced obesity and metabolic dysfunction. In this study, we gave naïve and NMS female mice access to a high-fat/high-sucrose (HFS) diet beginning at 4 wk of age. Robust increases in body weight and fat were observed in HFS-fed NMS mice during the first 10 wk on the diet, driven partly by increased food intake. Female NMS mice on an HFS diet showed widespread mechanical hypersensitivity compared with either naïve mice on an HFS diet or NMS mice on a control diet. HFS diet-fed NMS mice also had impaired glucose tolerance and fasting hyperinsulinemia. Strikingly, female NMS mice on an HFS diet showed evidence of hepatic steatosis with increased triglyceride levels and altered glucocorticoid receptor levels and phosphorylation state. They also exhibited increased energy expenditure as observed via indirect calorimetry and expression of proinflammatory markers in perigonadal adipose. Altogether, our data suggest that early-life stress exposure increased the susceptibility of female mice to develop diet-induced metabolic dysfunction and pain-like behaviors.