Conserved and Differential Effects of Dietary Energy Intake on the Hippocampal Transcriptomes of Females and Males

Bronwen Martin,Kevin G Becker,Josephine M Egan,Erin Golden,Titilola Iyun,Mark P Mattson,Olga D Carlson,Alex Keselman,Vinayakumar Prabhu,Michele Pearson,Randall Brenneman,William Wood,Stuart Maudsley,Rafael De Cabo

doi:10.1371/journal.pone.0002398

Abstract

The level of dietary energy intake influences metabolism, reproductive function, the development of age-related diseases, and even cognitive behavior. Because males and females typically play different roles in the acquisition and allocation of energy resources, we reasoned that dietary energy intake might differentially affect the brains of males and females at the molecular level. To test this hypothesis, we performed a gene array analysis of the hippocampus in male and female rats that had been maintained for 6 months on either ad libitum (control), 20% caloric restriction (CR), 40% CR, intermittent fasting (IF) or high fat/high glucose (HFG) diets. These diets resulted in expected changes in body weight, and circulating levels of glucose, insulin and leptin. However, the CR diets significantly increased the size of the hippocampus of females, but not males. Multiple genes were regulated coherently in response to energy restriction diets in females, but not in males. Functional physiological pathway analyses showed that the 20% CR diet down-regulated genes involved in glycolysis and mitochondrial ATP production in males, whereas these metabolic pathways were up-regulated in females. The 40% CR diet up-regulated genes involved in glycolysis, protein deacetylation, PGC-1α and mTor pathways in both sexes. IF down-regulated many genes in males including those involved in protein degradation and apoptosis, but up-regulated many genes in females including those involved in cellular energy metabolism, cell cycle regulation and protein deacetylation. Genes involved in energy metabolism, oxidative stress responses and cell death were affected by the HFG diet in both males and females. The gender-specific molecular genetic responses of hippocampal cells to variations in dietary energy intake identified in this study may mediate differential behavioral responses of males and females to differences in energy availability.

Highlights

The energy content and frequency of meals are fundamental aspects of nutrition that can have significant effects on the health of laboratory animals
The rats in the first four diet groups were fed a diet with a typical composition in which the majority of calories were from complex carbohydrates, whereas the high fat/high glucose diet (HFG) diet contained higher amounts of fat and glucose (Fig. 1B)
We have demonstrated that there are gender-dependent alterations in hippocampal gene regulation in response to perturbations in dietary energy intake

Summary

Introduction

The energy content and frequency of meals are fundamental aspects of nutrition that can have significant effects on the health of laboratory animals. On the other hand, consuming excessive food and calories leads to obesity and morbidity and increases the risk of developing type 2 diabetes and cardiovascular disease [6]. Complex neuroendocrine systems control feeding and energy expenditure in mammals; these regulatory systems include cognitive and motivational systems in the brain and hormones produced by endocrine cells and adipose cells [7,8,9]. Many of the physiological effects of reduced energy intake (e.g. reduced fat and muscle mass, reduced body temperature, decreased morbidity and mortality) and dietary energy excess (e.g. obesity, insulin resistance, cardiovascular disease) are similar in male and female animals. There is evidence that male and female mammals respond differently to alterations in energy intake, both on a neuroendocrine level and on a cognitive level

Methods

Results

Conclusion