Exposure to Early Life Stress (ELS) is associated with behavioral-related alterations, increases in body mass index and higher systolic blood pressure in humans. Postnatal maternal separation and early weaning (MSEW) is a mouse model of neglect characterized by a long-term dysregulation of the neuroendocrine system. Objectives Given the contribution of adrenal-derived hormones to the development of obesity, we hypothesized that exposure to MSEW could contribute to worsen the cardiometabolic function in response to chronic high fat diet (HF) feeding by promoting adipose tissue expansion and insulin resistance. Subjects MSEW was performed in C57BL/6 mice from postnatal days 2–16 and weaned at postnatal day 17. Undisturbed litters weaned at postnatal day 21 served as the control (C) group. At the weaning day, mice were placed on a low fat diet (LF) or HF for 16 weeks. Results When fed a LF, male and female mice exposed to MSEW display similar body weight but increased fat mass compared to controls. However, when fed a HF, only female MSEW mice display increased body weight, fat mass and adipocyte hypertrophy compared with controls. Also, female MSEW mice display evidence of an early onset of cardiometabolic risk factors, including hyperinsulinemia, glucose intolerance and hypercholesterolemia. Yet, both male and female MSEW mice fed a HF show increased blood pressure compared with controls. Conclusions This study shows that MSEW promotes a sex-specific dysregulation of the adipose tissue expansion and glucose homeostasis that precedes the development of obesity-induced hypertension.
Experimental studies in rodents have shown that females are more susceptible to exhibiting fat expansion and metabolic disease compared with males in several models of fetal programming. This study tested the hypothesis that female rat pups exposed to maternal separation (MatSep), a model of early-life stress, display an exacerbated response to diet-induced obesity compared with male rats. Also, we tested whether the postnatal treatment with metyrapone (MTP), a corticosterone synthase inhibitor, would attenuate this phenotype. MatSep was performed in WKY offspring by separation from the dam (3 h/day, postnatal days 2-14). Upon weaning, male and female rats were placed on a normal (ND; 18% kcal fat) or high-fat diet (HFD; 60% kcal fat). Nondisturbed littermates served as controls. In male rats, no diet-induced differences in body weight (BW), glucose tolerance, and fat tissue weight and morphology were found between MatSep and control male rats. However, female MatSep rats displayed increased BW gain, fat pad weights, and glucose intolerance compared with control rats (P < 0.05). Also, HFD increased plasma corticosterone (196 ± 51 vs. 79 ± 18 pg/ml, P < 0.05) and leptin levels (1.8 ± 0.4 vs. 1.3 ± 0.1 ng/ml, P < 0.05) in female MatSep compared with control rats, whereas insulin and adiponectin levels were similar between groups. Female control and MatSep offspring were treated with MTP (50 µg/g ip) 30 min before the daily separation. MTP treatment significantly attenuated diet-induced obesity risk factors, including elevated adiposity, hyperleptinemia, and glucose intolerance. These findings show that exposure to stress hormones during early life could be a key event to enhance diet-induced obesity and metabolic disease in female rats. Thus, pharmacological and/or behavioral inflection of the stress levels is a potential therapeutic approach for prevention of early life stress-enhanced obesity and metabolic disease.
Exposure to early life stress or adverse childhood experiences is associated with a greater BMI and cardio‐metabolic disease risk. We have previously shown that maternal separation and early weaning (MSEW), a model of early life stress and neglect, exacerbates adipose tissue expansion and metabolic dysfunction during obesity‐induced hypertension in adult female MSEW mice compared with males. Thus, the goal of this study was to determine whether there are sex‐specific changes in fat mass and glucose homeostasis in juvenile and young adult male and female mice exposed to MSEW. We also investigated the status of adipose tissue transcription factors. MSEW was performed by separating the pups from the mother for periods of 4 to 8 hour during postnatal days 2–16. Mice were weaned at postnatal day 17 (P17). Control mice remained undisturbed in the home cage at all times and were weaned at P21. We used 4 control and 4 MSEW li‐‐‐‐tters. All observations were averaged within litters by sex, and analysis was performed with litters as experimental units. Body weight (BW) and fat mass measured by EcoMRI were similar between control and MSEW mice at P17, P21 and P56 when fed a regular chow in both sexes. At P60, one subset of littermates was placed on a low fat diet (LF, 10% kcal from fat) for one week. LF‐fed MSEW and control mice showed similar BW and fat mass; however, the number of pre‐adipocytes isolated from Gonadal white adipose tissue (gWAT) stromal vascular fraction were increased significantly in MSEW mice (p<0.05). The other subset of littermates was placed one week on a high fat diet (HF, 60% kcal from fat). MSEW increased BW and fat mass in HF‐fed mice. Six‐hour fasting glucose was higher in mice exposed to MSEW regardless sex or diet, although the oral glucose tolerance test was not different between groups. Further, gWAT was isolated in mice after one week of LF or HF, and mRNA was isolated for nanoString analysis of transcription factors (nanoString Technologies, Inc, Seattle, WA). We found that one week of HF significantly downregulated: Foxo1 (−1.24±0.07 fold), Sirt1 (−1.51±0.24 fold), Stat5a (−1.53±0.16 fold), Foxp2 (−3.02±0.96 fold), and IL‐6 (−2.74±0.55 fold) compared with controls (p<0.05). Overall, the effect of MSEW on fat mass and glucose metabolism is independent of sex and diet in weanlings and young adults. Downregulation of transcription factors such as Sirt1 could promote lipogenesis by reducing lipolysis. Our study suggests that a chronic HF feeding is required for greater fat expansion and cardio‐metabolic dysfunction in adult female mice.Support or Funding InformationThis study was supported by funds from the NIH National Heart, Lung, and Blood Institute to A.S.L (R00 HL111354), start‐up funds from the University of Kentucky to A.S.L, and the pilot project from the University of Kentucky Center of Research in Obesity and Cardiovascular Disease COBRE P20 GM103527‐06 to A.S.L.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Previously, we have shown that female mice exposed to maternal separation and early weaning (MSEW), a model of postnatal neglect, increases fat mass and worsens the cardiometabolic function in response to high fat diet (HF) feeding. We also found that β3 adrenergic receptor mRNA expression, involved in local lipolysis stimulation, was reduced in gonadal white adipose tissue (gWAT). Thus, the aim of this study was to test the hypothesis that female MSEW mice display reduced lipolysis in‐vivo and in‐vitro. MSEW was performed by separating the pups from the mother for periods of 4–8 hr during postnatal days 2–16. Mice were weaned at P17. Control mice remained undisturbed in the home cage all times and weaned at P21. At weaning, mice were placed on a low fat (10% kcal from fat) or high fat (60% kcal from fat) diet for 16 weeks. At week 14, an in‐vivo lipolysis test was performed by injecting with 1mg/kg BW of isoproterenol, IP. Free fatty acids (FFA) were measured in plasma obtained after 15 minutes of the injection. At week 16, an in‐vitro lipolysis test was performed in gWAT. As such, gWAT was removed from female control and MSEW mice, weighed, and washed with ice‐cold PBS. In‐vitro lipolysis was performed in the presence or absence of isoproterenol (10uM, Sigma Aldrich). Free glycerol kit (Sigma Aldrich) was used to measure lipolytic products and results were normalized to tissue weight. In‐vivo, FFAs were reduced in female MSEW mice fed a HF (102±13 uM/ml) when compared with controls (144±24 uM/ml, p=0.066). In‐vitro, we found similar free glycerol levels in control and MSEW mice fed a LF (9.2±0.8 vs. 10.5±1.4 mg/dl/g tissue, respectively). Although HF reduced isoproterenol‐induced free glycerol levels, control and MSEW mice showed not statistically significant differences (4.4±0.6 vs. 3.5±0.6 mg/dl/g tissue, respectively). Taken together, these data indicate that HF reduced lipolysis capacity either in control and MSEW mice. Also, MSEW reduced lipolysis when determined in‐vivo conditions, suggesting that neuroendocrine and autonomic factors may be implicated in the mechanism by which MSEW mice are prone to increase fat mass.Support or Funding InformationThis study was supported by funds from the NIH National Heart, Lung, and Blood Institute to A.S.L (R00 HL111354), start‐up funds from the University of Kentucky to A.S.L, and the pilot project from the University of Kentucky Center of Research in Obesity and Cardiovascular Disease COBRE P20 GM103527‐06 to A.S.L.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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