Postnatal treatment with metyrapone attenuates the effects of diet-induced obesity in female rats exposed to early-life stress

Margaret O. Murphy, Joseph B. Herald, Caleb T. Wills, Stanley G. Unfried, Dianne M. Cohn, Analia S. Loria

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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 dietinduced 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 stressenhanced obesity and metabolic disease.

Original languageEnglish
Pages (from-to)E98-E108
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number2
StatePublished - 2017

Bibliographical note

Funding Information:
This study was supported by grants from the National Heart, Lung, and Blood Institute (to A. S. Loria; R00-HL-111354) and the University of Kentucky Center of Research in Obesity and Cardiovascular Disease (COBRE P20 GM103527-06; Pathology Core).

Publisher Copyright:
© 2017 the American Physiological Society.


  • Early-life stress
  • High fat diet
  • Maternal separation
  • Metyrapone
  • Sex differences in developmental programming of metabolic disease

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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