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

Abstract

Exposure to stress early in life has been associated with adult-onset co-morbidities 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 pre-clinical 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 weeks of age. Robust increases in body weight and fat were observed in HFS-fed NMS mice during the first 10 weeks on the diet, driven partly by increased food intake. Female NMS mice on a HFS diet showed widespread mechanical hypersensitivity compared to either naïve mice on a 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 a 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 pro-inflammatory 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.

VCD-induced menopause mouse model reveals reprogramming of hepatic metabolism

“…Interestingly, fat mass, and not fat-free mass, was found to be a powerful co-variate impacting systemic energy metabolism. We have previously observed this in another unrelated experiment involving chronic HFHS feeding of normally cycling female mice 66 . Combined, these findings are interesting considering the low metabolic rate of adipose tissue and the numerous observations of a high correlation of FFM with energy expenditure, particularly resting EE 67 .…”

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

“…It was somewhat surprising that early life stress affected female mice to a greater degree than male mice. Our prior work has shown adverse metabolic effects in both male and female mice after NMS [23,27], although sex differences were not directly tested, as was done in this study. The present study necessitated singly-housing the mice at 10 weeks of age, which we had not previously employed.…”

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

“…It was somewhat surprising that ELS affected female mice to a greater degree than male mice. Our prior work has shown adverse metabolic effects in both male and female mice after NMS [24, 25], although sex differences were not directly tested, as was done in this study. The present study necessitated singly housing the mice at 10 weeks of age, which we had not previously employed.…”

“…Additionally, pregnant dams were shipped to our facility during the last week of gestation for both naïve and NMS mice. Although we have successfully employed this methodology in previous studies using both male and female mice [24,25,[29][30][31][32], it is possible that there were sex-specific differences in the effects of this prenatal stressor that affected later results within the current study.…”