Age- and Sex-Dependent Modulation of Exogenous Ketone Supplement-Evoked Effects on Blood Glucose and Ketone Body Levels in Wistar Albino Glaxo Rijswijk Rats.

Zsolt Kovács,Csilla Ari,Brigitta Brunner,Dominic P D’Agostino

doi:10.3389/fnins.2020.618422

Abstract

In certain disease states, such as epilepsy, the elevation of blood ketone levels with ketogenic diets (KDs) has beneficial effects, while exogenous ketone supplements (EKSs) were shown to increase the level of blood ketone bodies (such as β-hydroxybutyrate, βHB) and decrease blood glucose levels without dietary restrictions. It has been suggested that ketone body and glucose utilization of the body may be modified by age and gender resulting in changes in blood βHB and glucose levels, but it was not investigated through several months yet. Thus, we investigated whether the effect of an EKS on blood βHB and glucose level is modulated by age and sex in Wistar Albino Glaxo Rijswijk (WAG/Rij) rats, a model animal of human absence epilepsy. We used KEMCT (1:1 mix of ketone ester/KE and medium-chain triglyceride/MCT oil) by oral gavage in female and male WAG/Rij rats. Animals were fed with standard diet, which was supplemented by KEMCT (2.5 g/kg) once per month by oral gavage for 17 months. One hour after KEMCT treatment, changes in blood R-beta-hydroxybutyrate (R-βHB) and glucose levels were measured. KEMCT gavage significantly increased blood R-βHB and decreased blood glucose levels, in both male and female rats, compared with the controls. In male rats, the KEMCT-induced increase in blood R-βHB levels was lower at the 7th and 8th months and higher at the 16th and 17th months, compared with the results at the 1st month. KEMCT-generated increase in R-βHB levels was higher in female rats, compared with male rats between the 2nd and 11th months, but older (between the 14th and 17th months) female rats showed lower levels than males. KEMCT gavage induced significantly lower glucose levels at the 4th, 9th, 10th, 12th, and 13th months in both sexes, but between the 14th and 17th months, only males showed significantly lower levels, compared with the results at the 1st month. KEMCT treatment induced lower blood glucose levels in female than in male rats between the 1st and 8th months, but higher glucose levels were measured in female rats at the 17th month than in males. These findings suggest that age and sex can modify the EKS-evoked effects on blood R-βHB and glucose concentrations.

Highlights

Emerging evidence suggests that ketogenic diet (KD)- and exogenous ketone supplement (EKS)-evoked ketosis may have a modulatory role in physiological and pathophysiological processes of the central nervous system (CNS)
Mix of ketone ester (KE) and medium-chain triglyceride (MCT) gavage significantly increased blood R-βHB levels in both female (Figure 1A) and male (Figure 1B) Wistar Albino Glaxo Rijswijk (WAG/Rij) rats every month, compared with the control, except on the 2nd, 4th, and 7th months in male rats
mix of KE and MCT oil (KEMCT)-induced increase in R-βHB levels was significantly higher in female rats than in male rats between the 2nd and 11th months, but lower R-βHB levels were measured in female rats, compared with male rats between the 14th and 17th months (Figure 2B and Table 1, sixth column)

Summary

Introduction

Emerging evidence suggests that ketogenic diet (KD)- and exogenous ketone (ketogenic) supplement (EKS)-evoked ketosis may have a modulatory role in physiological and pathophysiological processes of the central nervous system (CNS). It has been demonstrated that ketone bodies may have therapeutic potential in the treatment of several CNS diseases, such as epilepsy, neurodegenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease), and psychiatric disorders (e.g., anxiety and depression), likely through ketosis-evoked neuroprotective effects (Hashim and VanItallie, 2014; Ari et al, 2016; Kovács et al, 2019a), and other age-associated diseases (e.g., cardiovascular diseases and cancer) (Han et al, 2020). EKS administrationgenerated therapeutic ketosis may be a safe alternative method (D’Agostino et al, 2013; Ari et al, 2016; Stubbs et al, 2017) to circumvent dietary restrictions and adverse effects by KDs (e.g., nephrolithiasis, growth retardation, constipation, and hyperlipidemia) (Branco et al, 2016) and to treat several CNS diseases, such as epilepsy, psychiatric diseases (e.g., anxiety), neurodegenerative disorders (e.g., Alzheimer’s disease), and cancer (Newport et al, 2015; Kovács et al, 2017, 2019a; Berk et al, 2020), and, among others, non-alcoholic fatty liver

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