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Here, we identify TRPC6 as a Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel enriched in early adipocyte progenitors that orchestrate white adipose tissue (WAT) homeostasis by integrating cAMP signaling and mitochondrial bioenergetics. In\n                    <jats:italic>Trpc6<\/jats:italic>\n                    knockout mice, WAT emerges as the earliest and most vulnerable site of dysfunction, exhibiting pathological hypertrophic lipid accumulation despite impaired adipogenesis and intact hypothalamic signaling. Mechanistically, TRPC6 deficiency disrupts cAMP-hormone-sensitive lipase signaling and impairs mitochondrial oxidative metabolism, processes sustained by a reciprocal TRPC6\u2013cAMP feedback loop. TRPC6 is transiently expressed during early adipogenic commitment and is indispensable for proper progenitor differentiation and lipid turnover. These findings define TRPC6 as a molecular gatekeeper that links Ca\n                    <jats:sup>2+<\/jats:sup>\n                    and cAMP signaling to mitochondrial metabolism, ensuring adipocyte plasticity and energy balance. Moreover, our study reveals a previously unrecognized mechanism that underlies WAT vulnerability to metabolic dysfunction and highlights the therapeutic potential of the TRPC6\u2013cAMP\u2013mitochondrial axis in obesity and insulin resistance.\n                  <\/jats:p>","DOI":"10.1038\/s12276-026-01775-3","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T09:46:42Z","timestamp":1783072002000},"page":"2268-2279","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TRPC6 loss triggers mitochondrial dysfunction that drives white adipose tissue vulnerability to obesity and insulin resistance"],"prefix":"10.1038","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4645-3558","authenticated-orcid":false,"given":"Phan Anh","family":"Nguyen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyu-Hee","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duyen Thi Thuy","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Sic","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0322-9807","authenticated-orcid":false,"given":"Kyu-Sang","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3201-7950","authenticated-orcid":false,"given":"Seung-Kuy","family":"Cha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"1775_CR1","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1016\/j.mayocp.2023.05.026","volume":"98","author":"B Busebee","year":"2023","unstructured":"Busebee, B., Ghusn, W., Cifuentes, L. & Acosta, A. 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