Increased hepatic lipogenic gene expression correlates with enhanced central and ectopic adiposity in female C57BL/6 mice exposed to maternal separation

Abstract

We previously reported that maternal separation (MatSep), a model of early life stress, in combination with high fat (HF) diet leads to exaggerated weight gain; however, female mice present with significantly greater levels of adiposity compared to male mice. The objective of this study was to investigate the sex‐specific differences within MatSep mice in driving fat tissue expansion by measuring 1) food intake and energy expenditure (EE), 2) body fat distribution using MRI, 3) ectopic lipid deposition, 4) systemic and local production of CORT, and 5) liver and white adipose tissue (WAT) gene expression in response to HF diet. MatSep was performed in male and female C57Bl/6 mice with early weaning at PND17 and mice were weaned onto a HF diet for 16 weeks. Normally reared mice served as controls (C). A group of mice (n=6–10) were placed into TSE metabolic chambers to obtain net food intake and EE normalized to lean body mass. In female mice, food intake was significantly higher in MatSep compared to C mice (slope: 0.522±0.59 vs −2.67±1.79, p<0.05) with no differences observed between groups in male mice. MatSep had no effect on EE in both male and female mice. MRI analysis revealed elevated levels of visceral fat in MatSep female mice compared to C (1550.7 ± 233.5 vs 904.1 ± 104.5 mm3 p=0.08, n=4). In addition, oil Red O staining within the liver and kidney revealed an elevated accumulation of neutral lipids suggesting that MatSep increases both central and ectopic adiposity. In response to HF diet, plasma levels of CORT were not different between MatSep and C in male (145.8 ± 38.6 vs. 111.04 ± 35 ng/ml, respectively) and female mice (193.8 ±36.3 vs. 176.5 ± 31 ng/ml, respectively, 2‐way ANOVA: NS, n=6). RT‐PCR analysis revealed that MatSep upregulated 11β‐HSD1 in subcutaneous WAT in both genders; however, only female MatSep mice showed upregulation of 11β‐HSD1 in liver (3.71±0.61 vs 0.82±0.37 2^ddCt, p<0.05, n=6–8) suggesting an elevated local CORT regeneration. In addition, we found a significant upregulation of several hepatic lipogenic genes including PPARγ, ACC‐1, FAS, SCD‐1, and CREB in MatSep females compared to C. No differences between MatSep and C were found in hepatic lipogenic genes from male mice. Interestingly, obese MatSep female mice showed increased ER β expression compared to C in gonadal WAT (113.91±22.63 vs. 1.41±0.43 2^ddCt, p<0.05) and SQ WAT (56.34±11.19 vs 1.05±0.23 2^ddCt, p<0.05) which may have diabetogenic effects. No differences in ER β expression were observed in male mice. We propose that excessive glucocorticoid signaling at the tissue level may contribute to the exacerbated lipogenesis and fat expansion in female mice exposed to MatSep, suggesting a potential mechanism by which female mice exposed to early life stress develop metabolic dysfunction.Support or Funding InformationNIH R00 HL111354 COBRE P20 GM103527‐06