Physiological and brain alterations produced by high-fat diet in male and female rats can be modulated by increased levels of estradiol during critical periods of development

Abstract

Background: Overnutrition due to a high-fat diet (HFD) can increase the vulnerability of the metabolic system to maladjustments. Estradiol has an inhibitory role on food intake and this hormone has demonstrated to be a crucial organizer during brain development.

Objective: Our aim was to determine whether increased levels of estradiol in the early postnatal period modulate the alterations in metabolism and brain metabolic circuits produced by overnutrition.

Methods: Twenty-four male and 24 female Wistar rats were submitted to a HFD (34.9% fat) or a control diet (5% fat) from gestational day 6. From postnatal (P) 6 to P13, both control and HFD groups were administered a s.c. injection of vehicle or estradiol benzoate (0.4 mg/kg), resulting in eight experimental groups (n = 6 in each group). Body weight, food intake and subcutaneous, visceral, and brown fat pads were measured. Agouti-related peptide, neuropeptide Y, orexin, and proopiomelanocortin (POMC) were analyzed by quantitative real-time polymerase chain reaction assay and plasma estradiol levels were measured by ELISA.

Results: Males fed a HFD showed an increase in body weight and the amount of visceral and subcutaneous fat, which was coincident with an increase in the number of kilocalories ingested. Neonatal estradiol treatment restored the body weight and subcutaneous fat of HFD males to control levels. Hypothalamic POMC mRNA levels in HFD females were increased with respect to control females. This increase was reverted with estradiol treatment during development.

Discussion: HFD and estradiol treatment have different effects on males and females. Overnutrition affects physiological parameters, such as body weight, visceral, and subcutaneous fat content, in males, while females present alterations in hypothalamic POMC mRNA levels. Hence, the increase in estradiol levels during a period that is critical for the programing of the feeding system can modulate some of the alterations produced by the continuous intake of high-fat content food.

Keywords:

• High-fat diet
• Short-term estradiol treatment
• Programing feeding system
• Orexigenic anorexigenic peptides
• PCR-rat-sex differences

Acknowledgements

We are grateful to Mr L. Carrillo, Mr A. Marcos, and Mr G. Moreno for their technical assistance. BC, PC, HP designed research, conducted research, analyzed data, wrote paper, and had primary responsibility for final content. FD conducted research and analyzed data, JAC wrote paper and had primary responsibility for final content, MAP conducted research. All authors read and approved the final manuscript.

Disclaimer statements

Contributors None.

Funding The present work was supported by grant Ministerio de Economía, Industria y Competitividad (MINECO) PSI2014-57362-P (PC) and BFU2014-51836-C2-2 and CIBEROBN (JAC).

Conflict of interest None.

Ethics approval For this study, animal care and handling practices were approved by the Local Ethics Committees (UNED), date 28-04-2015 and were in accordance with the European Union Directive, (2010/63/UE) and Spanish Government Directive (R.D. 53/2013).

ORCID

Beatriz Carrillo http://orcid.org/0000-0002-7393-3675

Paloma Collado http://orcid.org/0000-0002-2925-6806

Helena Pinos http://orcid.org/0000-0002-5323-6602