{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:44:54Z","timestamp":1787615094835,"version":"build-2736575974"},"reference-count":107,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation (NRF)","award":["NRF-2018M3A9F3056405"],"award-info":[{"award-number":["NRF-2018M3A9F3056405"]}]},{"name":"National Research Foundation (NRF)","award":["2020R1A2B5B01002789"],"award-info":[{"award-number":["2020R1A2B5B01002789"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ectopic lipid accumulation is a core contributor to insulin resistance and metabolic diseases, including type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Conventional therapies have primarily focused on redistributing lipid burden across tissues or modulating specific pathways. However, this often causes compensatory responses that merely shift the burden rather than resolve the underlying lipid excess. In this review, we introduce the concept of the ballooning effect, wherein single-target interventions inadvertently exacerbate lipid accumulation in non-target tissues. We then explore fundamental strategies for true lipid disposal, which aim either to prevent lipid influx or to promote complete lipid oxidation. Among these, mild mitochondrial uncoupling emerges as a promising solution. By dissipating substrate energy as heat, mitochondrial uncoupling reduces ectopic lipid burden without relying on redistribution. Recent advances have yielded safer chemical uncouplers and novel endogenous protein-based mechanisms that enable controlled uncoupling with minimal toxicity. Together, these provide a new framework for next-generation metabolic therapies that move beyond lipid redistribution and aim for a true lipid disposal, potentially offering a safe and effective strategy.<\/jats:p>","DOI":"10.3390\/ijms26167740","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T11:02:09Z","timestamp":1754910129000},"page":"7740","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mild Mitochondrial Uncoupling for True Ectopic Lipid Disposal"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3464-6382","authenticated-orcid":false,"given":"Hui-Young","family":"Lee","sequence":"first","affiliation":[{"name":"Laboratory of Mitochondria and Metabolic Diseases, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea"},{"name":"Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea"},{"name":"Department of Molecular Medicine, College of Medicine, Gachon University, Incheon 21936, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1056\/NEJMra1011035","article-title":"Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease","volume":"371","author":"Shulman","year":"2014","journal-title":"N. 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