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The identity of these signaling molecules can be discerned by experimental adipose tissue-specific silencing studies showing that biological events induced by adiposity and occurring selectively in adipose tissue can promote each element of the CKM syndrome. Suppression of the renin-angiotensin system specifically and selectively only in adipose tissue alleviates hypertension and atherosclerosis, whereas overexpression of the mineralocorticoid receptor specifically and only in adipocytes promotes vascular injury. Silencing of autotaxin, platelet-derived growth factor D, resistin and microRNA-410-5P selectively and specifically only in adipose tissue ameliorates the development of cardiac hypertrophy and fibrosis, thus preventing experimental HFpEF. The suppression of cytoprotective adipokines (e.g., adiponectin) simultaneous with the activation of proinflammatory adipokines (e.g., leptin) promotes renal tubular sodium reabsorption and plasma volume expansion. Experimental aldosterone-induced kidney injury is accompanied by augmented expression of lipocalin-2 in visceral adipose tissue, and selective and specific deletion of lipocalin-2 only in adipose tissue\u2014but not in the kidney\u2014counteracts renal inflammation and fibrosis. Silencing of fatty acid binding protein 4 and 12\/15-lipoxygenase selectively and specifically in adipose tissue prevents the development of insulin resistance. These observations support the conceptual framework that the accumulation of dysfunctional fat can promote each of the pathophysiological features of the CKM syndrome by altering the expression and\/or secretion of signaling molecules in an adipose tissue-specific and -selective manner.<\/jats:p>","DOI":"10.1186\/s12933-026-03103-5","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T11:05:03Z","timestamp":1770721503000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Causal demonstration of adiposity-induced adipose-specific signaling derangements in the pathogenesis of the clinical features of the cardiovascular-kidney metabolic syndrome"],"prefix":"10.1186","volume":"25","author":[{"given":"Milton","family":"Packer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,10]]},"reference":[{"key":"3103_CR1","doi-asserted-by":"publisher","first-page":"1606","DOI":"10.1161\/CIR.0000000000001184","volume":"148","author":"CE Ndumele","year":"2023","unstructured":"Ndumele CE, Rangaswami J, Chow SL, Neeland IJ, Tuttle KR, Khan SS, Coresh J, Mathew RO, Baker-Smith CM, Carnethon MR, Despres JP, Ho JE, Joseph JJ, Kernan WN, Khera A, Kosiborod MN, Lekavich CL, Lewis EF, Lo KB, Ozkan B, Palaniappan LP, Patel SS, Pencina MJ, Powell-Wiley TM, Sperling LS, Virani SS, Wright JT, Rajgopal Singh R, Elkind MSV, American Heart Association. 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This is a Hypothesis article.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Dr. Packer reports consulting fees from Abbvie, Actavis, Alnylam, Altimmune, Ardelyx, Amgen, ARMGO, AstraZeneca, Attralus, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Daiichi Sankyo, Eli Lilly and Company, Imara, Medtronic, Moderna, Novartis, Preload, Pharmacosmos, PriveBio, Regeneron, Salamandra.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"86"}}