High-fat/high-sucrose diet worsens metabolic outcomes and widespread hypersensitivity following early-life stress exposure in female mice.

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.

Early-life stress perturbs the epigenetics of Cd36 concurrent with adult onset of NAFLD in mice.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the U.S. and worldwide. The roles of early postnatal life stress (EPLS) and the fatty acid translocase (CD36) on the pathogenesis of adult-onset NAFLD remain unknown. We hypothesized that EPLS, in the form of neonatal maternal separation (NMS), would predispose mice towards developing adult NAFLD, increase hepatic CD36 expression, and differentially methylate Cd36 promoter concurrently. METHODS: NMS was performed on mice from postnatal day 1 to 21 and a high-fat/high-sucrose (HFS) diet was started at 4 weeks of age to generate four experimental groups: Naive-control diet (CD), Naive-HFS, NMS-CD, and NMS-HFS. RESULTS: NMS alone caused NAFLD in adult male mice at 25 weeks of age. The effects of NMS and HFS were generally additive in terms of NAFLD, hepatic Cd36 mRNA levels, and hepatic Cd36 promoter DNA hypomethylation. Cd36 promoter methylation negatively correlated with Cd36 mRNA levels. Two differentially methylated regions (DMRs) within Cd36 promoter regions appeared to be vulnerable to NMS in the mouse. CONCLUSIONS: Our findings suggest that NMS increases the risk of an individual, particularly male, towards NAFLD when faced with a HFS diet later in life. IMPACT: The key message of this article is that neonatal maternal separation and a postweaning high-fat/high-sucrose diet increased the risk of an individual, particularly male, towards NAFLD in adult life. What this study adds to the existing literature includes the identification of two vulnerable differentially methylated regions in hepatic Cd36 promoters whose methylation levels very strongly negatively correlated with Cd36 mRNA. The impact of this article is that it provides an early-life environment-responsive gene/promoter methylation model and an animal model for furthering the mechanistic study on how the insults in early-life environment are "transmitted" into adulthood and caused NAFLD.

Exposure to early-life stress impairs weight-loss maintenance success in mice.

OBJECTIVE: The impact of early-life stress on weight-loss maintenance is unknown. METHODS: Mice underwent neonatal maternal separation (NMS) from 0 to 3 weeks and were weaned onto a high-fat sucrose diet (HFSD) from 3 to 20 weeks. Calorie-restricted weight loss on a low-fat sucrose diet (LFSD) occurred over 2 weeks to induce a 20% loss in body weight, which was maintained for 6 weeks. After weight loss, half of the mice received running wheels, and the other half remained sedentary. Mice were then fed ad libitum on an HFSD or LFSD for 10 weeks and were allowed to regain body weight. RESULTS: NMS mice had greater weight regain, total body weight, and adiposity compared with naïve mice. During the first week of refeeding, NMS mice had increased food intake and were in a greater positive energy balance than naïve mice. Female mice were more susceptible to NMS-induced effects, including increases in adiposity. NMS and naïve females were more susceptible to HFSD-induced weight regain. Exercise was beneficial in the first week of regain in male mice, but, long-term, only those on the LFSD benefited from exercise. As expected, HFSD led to greater weight regain than LFSD. CONCLUSIONS: Early-life stress increases weight regain in mice.

Exposure to early life stress impairs weight loss maintenance success in mice.

Early life stress increases obesity risk, but its impact on weight loss maintenance is unknown. Mice underwent neonatal maternal separation (NMS) from 0-3 weeks and were weaned onto high fat sucrose diet (HFSD) from 3-20 weeks. Calorie-restricted weight loss on a low fat sucrose diet (LFSD) occurred over 2 weeks to induce a 20% loss in body weight, which was maintained for 6 weeks. After weight loss, half the mice received running wheels (EX) the other half remained sedentary (SED). Mice were then fed ad libitum on HFSD or LFSD for 10 weeks and allowed to regain body weight. NMS mice had greater weight regain, total body weight and adiposity compared to naïve mice. During the first week of refeeding, NMS mice had increased food intake and were in a greater positive energy balance than naïve mice, but total energy expenditure was not affected by NMS. Female mice were more susceptible to NMS-induced effects, including increases in adiposity. NMS and naïve females were more susceptible to HFSD-induce weight regain. Exercise was beneficial in the first week of regain in male mice, but long-term only those on LFSD benefited from EX. As expected, HFSD led to greater weight regain than LFSD.