Ketogenic Diet Suppressed T-Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria-Associated Membranes and Inhibiting Mitochondrial Function

Jun Tao,Hai-Feng Zhang,Ya-Jing Wang,Jun-Xiong Qiu,Yu-Li Huang,Jun-Meng Zheng,Zong-Kai Zhao,Jun-Gang Huang,Hao Chen,Ling Li,Rong-Jun Zou,Qing-Qi Meng,Yun-Dai Chen

doi:10.1155/2021/5512322

Abstract

Ketogenic diet (KD) is popular in diabetic patients but its cardiac safety and efficiency on the heart are unknown. The aim of the present study is to determine the effects and the underlined mechanisms of KD on cardiac function in diabetic cardiomyopathy (DCM). We used db/db mice to model DCM, and different diets (regular or KD) were used. Cardiac function and interstitial fibrosis were determined. T-regulatory cell (Treg) number and functions were evaluated. The effects of ketone body (KB) on fatty acid (FA) and glucose metabolism, mitochondria-associated endoplasmic reticulum membranes (MAMs), and mitochondrial respiration were assessed. The mechanisms via which KB regulated MAMs and Tregs were addressed. KD improved metabolic indices in db/db mice. However, KD impaired cardiac diastolic function and exacerbated ventricular fibrosis. Proportions of circulatory CD4+CD25+Foxp3+ cells in whole blood cells and serum levels of IL-4 and IL-10 were reduced in mice fed with KD. KB suppressed the differentiation to Tregs from naive CD4+ T cells. Cultured medium from KB-treated Tregs synergically activated cardiac fibroblasts. Meanwhile, KB inhibited Treg proliferation and productions of IL-4 and IL-10. Treg MAMs, mitochondrial respiration and respiratory complexes, and FA synthesis and oxidation were all suppressed by KB while glycolytic levels were increased. L-carnitine reversed Treg proliferation and function inhibited by KB. Proportions of ST2L+ cells in Tregs were reduced by KB, as well as the production of ST2L ligand, IL-33. Reinforcement expressions of ST2L in Tregs counteracted the reductions in MAMs, mitochondrial respiration, and Treg proliferations and productions of Treg cytokines IL-4 and IL-10. Therefore, despite the improvement of metabolic indices, KD impaired Treg expansion and function and promoted cardiac fibroblast activation and interstitial fibrosis. This could be mainly mediated by the suppression of MAMs and fatty acid metabolism inhibition via blunting IL-33/ST2L signaling.

Highlights

Diabetic individuals suffer from much more cardiovascular complications than nondiabetic patients
We found that Ketogenic diet (KD) impaired cardiac function and addressed the roles of mitochondria-associated endoplasmic reticulum membranes (MAMs), T-regulatory cell (Treg) substrate metabolism, and IL-33/ST2L signaling in this process
Results found that, compared with the vector control, reinforcement of ST2L in Tregs prevented the loss of MAMs (Figure 5(f)) in ketone body (KB)-treated CD4+CD25+Fopx3+ Tregs (Figure 5(g)). All these results indicated that the depressed IL-33/ST2L signaling is crucial for KB-induced MAM reduction and Treg suppression

Summary

Introduction

Diabetic individuals suffer from much more cardiovascular complications than nondiabetic patients. Ventricular damage is frequently evident in diabetic patients, which refers to a term of “diabetic cardiomyopathy” (DCM). The incidence of DCM greatly contributes to heart failure, which is the main complication leading to life and health loss in diabetic patients. Cardiomyocyte hypertrophy and interstitial cardiac fibrosis are the fundamental changes [1]. In the field of cardiac remodeling, KD is reported to be associated with improved cardiac function, cardiomyocyte survival, and attenuated cardiac fibrosis in both T2DM and aging mice [4, 5]. Ketogenic diet was shown to be associated with cardiac remodeling in hypertensive rats [6]. More studies are needed in order to clarify the detailed roles of KD on DCM

Objectives

Methods

Conclusion