The Impact of Long-term High-fat Diet on Co-morbid Disorders in an Early Life Stress Mouse Model

Abstract

Exposure to stress early in life has been associated with adult-onset co-morbidities such as chronic pain, obesity, and metabolic disorders. We have established a mouse model of early life stress using neonatal maternal separation (NMS) that results in urogenital hypersensitivity and increased body weight and adiposity compared to naive (non-separated) mice. In this study we tested the hypothesis that consumption of a high fat/high sucrose (HFS) diet will worsen NMS-related outcomes. Male and female naive and NMS mice were pair-housed with a sex matched littermate. At 4-weeks of age mice were assigned to either control diet or HFS diet and weight gain and food intake were measured weekly. Mechanical sensitivity and body composition were measured at 22-weeks of age. At 25-29 weeks of age mice were subject to a glucose tolerance test. Mice were then sacrificed, and tissues were fixed and frozen. Adipose tissue was analyzed via RT-PCR and fixed liver tissue was stained and analyzed for steatosis. NMS mice on a HFS diet were found to have increased body weight and percent body fat compared to naive mice on a HFS diet and to NMS mice on a control diet. Additionally, both NMS and the HFS diet resulted in significantly lower hind paw mechanical withdrawal thresholds indicative of hypersensitivity. Both NMS and HFS diet consumption were found to result in impaired glucose homeostasis. Upon histological examination of the liver, HFS diet fed NMS mice were observed to have increased steatosis and hepatocyte ballooning. Our results suggest that HFS diet exacerbates the outcomes of NMS in both males and females, resulting in widespread hypersensitivity, weight gain, glucose intolerance, and steatosis. Future work will explore possible underlying mechanisms for the increased weight gain and sensitivity associated with stress and diet. Grant support from RO1DK099611 (JAC), RO1DK103872 (JAC), T32HD057850 (OCE), COBRE grant P20GM104936, IDeA grant P20GM103418, core support from IDDRC grant P30HD002528.