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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\u2010regulatory cell (Treg) number and functions were evaluated. The effects of ketone body (KB) on fatty acid (FA) and glucose metabolism, mitochondria\u2010associated endoplasmic reticulum membranes (MAMs), and mitochondrial respiration were assessed. The mechanisms <jats:italic>via<\/jats:italic> 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<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>Foxp3<jats:sup>+<\/jats:sup> cells in whole blood cells and serum levels of IL\u20104 and IL\u201010 were reduced in mice fed with KD. KB suppressed the differentiation to Tregs from naive CD4<jats:sup>+<\/jats:sup> T cells. Cultured medium from KB\u2010treated Tregs synergically activated cardiac fibroblasts. Meanwhile, KB inhibited Treg proliferation and productions of IL\u20104 and IL\u201010. Treg MAMs, mitochondrial respiration and respiratory complexes, and FA synthesis and oxidation were all suppressed by KB while glycolytic levels were increased. L\u2010carnitine reversed Treg proliferation and function inhibited by KB. Proportions of ST2L<jats:sup>+<\/jats:sup> cells in Tregs were reduced by KB, as well as the production of ST2L ligand, IL\u201033. Reinforcement expressions of ST2L in Tregs counteracted the reductions in MAMs, mitochondrial respiration, and Treg proliferations and productions of Treg cytokines IL\u20104 and IL\u201010. 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 <jats:italic>via<\/jats:italic> blunting IL\u201033\/ST2L signaling.<\/jats:p>","DOI":"10.1155\/2021\/5512322","type":"journal-article","created":{"date-parts":[[2021,4,20]],"date-time":"2021-04-20T01:20:58Z","timestamp":1618881658000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Ketogenic Diet Suppressed T\u2010Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria\u2010Associated Membranes and Inhibiting Mitochondrial 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