{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:25:51Z","timestamp":1788870351721,"version":"build-2803163510"},"reference-count":36,"publisher":"American Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2015,11,1]],"date-time":"2015-11-01T00:00:00Z","timestamp":1446336000000},"content-version":"vor","delay-in-days":332,"URL":"http:\/\/www.diabetesjournals.org\/site\/license"}],"funder":[{"name":"Board of Directors of LUMC"},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["2009T038"],"award-info":[{"award-number":["2009T038"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Rembrandt Institute of Cardiovascular Science"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,5,1]]},"abstract":"<jats:p>Salsalate improves glucose intolerance and dyslipidemia in type 2 diabetes patients, but the mechanism is still unknown. The aim of the current study was to unravel the molecular mechanisms involved in these beneficial metabolic effects of salsalate by treating mice with salsalate during and after development of high-fat diet\u2013induced obesity. We found that salsalate attenuated and reversed high-fat diet\u2013induced weight gain, in particular fat mass accumulation, improved glucose tolerance, and lowered plasma triglyceride levels. Mechanistically, salsalate selectively promoted the uptake of fatty acids from glycerol tri[3H]oleate-labeled lipoprotein-like emulsion particles by brown adipose tissue (BAT), decreased the intracellular lipid content in BAT, and increased rectal temperature, all pointing to more active BAT. The treatment of differentiated T37i brown adipocytes with salsalate increased uncoupled respiration. Moreover, salsalate upregulated Ucp1 expression and enhanced glycerol release, a dual effect that was abolished by the inhibition of cAMP-dependent protein kinase (PKA). In conclusion, salsalate activates BAT, presumably by directly activating brown adipocytes via the PKA pathway, suggesting a novel mechanism that may explain its beneficial metabolic effects in type 2 diabetes patients.<\/jats:p>","DOI":"10.2337\/db14-1125","type":"journal-article","created":{"date-parts":[[2014,12,5]],"date-time":"2014-12-05T00:21:59Z","timestamp":1417738919000},"page":"1544-1554","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":38,"title":["Salsalate Activates Brown Adipose Tissue in Mice"],"prefix":"10.2337","volume":"64","author":[{"given":"Andrea D.","family":"van Dam","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly J.","family":"Nahon","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander","family":"Kooijman","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anish A.","family":"Kanhai","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattijs M.","family":"Heemskerk","sequence":"additional","affiliation":[{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands"},{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"van Harmelen","sequence":"additional","affiliation":[{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands"},{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Lomb\u00e8s","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Unit\u00e9 693, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita M.","family":"van den Hoek","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menno P.J.","family":"de Winther","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Lutgens","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands"},{"name":"Institute for Cardiovascular Prevention, Ludwig Maximilian\u2019s University Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Guigas","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands"},{"name":"Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick C.N.","family":"Rensen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u00ebtte R.","family":"Boon","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2014,12,4]]},"reference":[{"key":"2022031303261186400_B1","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1126\/science.1215327","article-title":"The ancient drug salicylate directly activates AMP-activated protein kinase","volume":"336","author":"Hawley","year":"2012","journal-title":"Science"},{"key":"2022031303261186400_B2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/j.1752-8062.2008.00026.x","article-title":"Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes","volume":"1","author":"Goldfine","year":"2008","journal-title":"Clin Transl Sci"},{"key":"2022031303261186400_B3","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1345\/aph.1M483","article-title":"Potential role of salicylates in type 2 diabetes","volume":"44","author":"Rumore","year":"2010","journal-title":"Ann Pharmacother"},{"key":"2022031303261186400_B4","doi-asserted-by":"crossref","first-page":"346","DOI":"10.7326\/0003-4819-152-6-201003160-00004","article-title":"The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial","volume":"152","author":"Goldfine","year":"2010","journal-title":"Ann Intern Med"},{"key":"2022031303261186400_B5","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1210\/jc.2010-1816","article-title":"Stimulation of human whole-body energy expenditure by salsalate is fueled by higher lipid oxidation under fasting conditions and by higher oxidative glucose disposal under insulin-stimulated conditions","volume":"96","author":"Meex","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031303261186400_B6","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/nature11162","article-title":"NPR3 and NPR4 are receptors for the immune signal salicylic acid in plants","volume":"486","author":"Fu","year":"2012","journal-title":"Nature"},{"key":"2022031303261186400_B7","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.atherosclerosis.2007.08.001","article-title":"Atorvastatin increases HDL cholesterol by reducing CETP expression in cholesterol-fed APOE*3-Leiden.CETP mice","volume":"197","author":"de Haan","year":"2008","journal-title":"Atherosclerosis"},{"key":"2022031303261186400_B8","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1194\/jlr.M700108-JLR200","article-title":"Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression","volume":"48","author":"van der Hoogt","year":"2007","journal-title":"J Lipid Res"},{"key":"2022031303261186400_B9","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1161\/01.ATV.0000243925.65265.3c","article-title":"Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice","volume":"26","author":"Westerterp","year":"2006","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2022031303261186400_B10","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1111\/bph.12338","article-title":"The insulin sensitizing effect of topiramate involves KATP channel activation in the central nervous system","volume":"170","author":"Coomans","year":"2013","journal-title":"Br J Pharmacol"},{"key":"2022031303261186400_B11","doi-asserted-by":"crossref","first-page":"5361","DOI":"10.1096\/fj.13-247643","article-title":"Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity","volume":"28","author":"Boon","year":"2014","journal-title":"FASEB J"},{"key":"2022031303261186400_B12","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/S0022-2275(20)39687-5","article-title":"Analysis of techniques to obtain plasma for measurement of levels of free fatty acids","volume":"34","author":"Zambon","year":"1993","journal-title":"J Lipid Res"},{"key":"2022031303261186400_B13","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nm0395-221","article-title":"Selective liver targeting of antivirals by recombinant chylomicrons\u2014a new therapeutic approach to hepatitis B","volume":"1","author":"Rensen","year":"1995","journal-title":"Nat Med"},{"key":"2022031303261186400_B14","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1139\/y59-099","article-title":"A rapid method of total lipid extraction and purification","volume":"37","author":"Bligh","year":"1959","journal-title":"Can J Biochem Physiol"},{"key":"2022031303261186400_B15","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1210\/en.2003-0882","article-title":"Cellular and molecular mechanisms of adipose tissue plasticity in muscle insulin receptor knockout mice","volume":"145","author":"Cariou","year":"2004","journal-title":"Endocrinology"},{"key":"2022031303261186400_B16","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1172\/JCI1915","article-title":"Hibernoma development in transgenic mice identifies brown adipose tissue as a novel target of aldosterone action","volume":"101","author":"Zennaro","year":"1998","journal-title":"J Clin Invest"},{"key":"2022031303261186400_B17","first-page":"2372","article-title":"Activation of the Ras\/mitogen-activated protein kinase signaling pathway alone is not sufficient to induce glucose uptake in 3T3-L1 adipocytes","volume":"14","author":"van den Berghe","year":"1994","journal-title":"Mol Cell Biol"},{"key":"2022031303261186400_B18","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.cmet.2012.02.001","article-title":"Pten positively regulates brown adipose function, energy expenditure, and longevity","volume":"15","author":"Ortega-Molina","year":"2012","journal-title":"Cell Metab"},{"key":"2022031303261186400_B19","doi-asserted-by":"crossref","first-page":"E500","DOI":"10.1152\/ajpendo.00361.2005","article-title":"Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue","volume":"290","author":"Watt","year":"2006","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2022031303261186400_B20","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1172\/JCI26498","article-title":"MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity","volume":"116","author":"Kanda","year":"2006","journal-title":"J Clin Invest"},{"key":"2022031303261186400_B21","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1172\/JCI200319246","article-title":"Obesity is associated with macrophage accumulation in adipose tissue","volume":"112","author":"Weisberg","year":"2003","journal-title":"J Clin Invest"},{"key":"2022031303261186400_B22","doi-asserted-by":"crossref","first-page":"E517","DOI":"10.1152\/ajpendo.00045.2005","article-title":"Differential regulation of fatty acid elongation enzymes in brown adipocytes implies a unique role for Elovl3 during increased fatty acid oxidation","volume":"289","author":"Jakobsson","year":"2005","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2022031303261186400_B23","doi-asserted-by":"crossref","first-page":"880","DOI":"10.2337\/db13-0194","article-title":"Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice","volume":"63","author":"Geerling","year":"2014","journal-title":"Diabetes"},{"key":"2022031303261186400_B24","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1152\/physrev.00015.2003","article-title":"Brown adipose tissue: function and physiological significance","volume":"84","author":"Cannon","year":"2004","journal-title":"Physiol Rev"},{"key":"2022031303261186400_B25","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1124\/jpet.111.185686","article-title":"Modeling diabetes disease progression and salsalate intervention in Goto-Kakizaki rats","volume":"339","author":"Cao","year":"2011","journal-title":"J Pharmacol Exp Ther"},{"key":"2022031303261186400_B26","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.bbrc.2014.09.066","article-title":"Salicylate acutely stimulates 5\u2032-AMP-activated protein kinase and insulin-independent glucose transport in rat skeletal muscles","volume":"453","author":"Serizawa","year":"2014","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031303261186400_B27","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1172\/JCI62308","article-title":"Brown adipose tissue regulates glucose homeostasis and insulin sensitivity","volume":"123","author":"Stanford","year":"2013","journal-title":"J Clin Invest"},{"key":"2022031303261186400_B28","first-page":"812","article-title":"Impact of brown adipose tissue on body fatness and glucose metabolism in healthy humans","volume-title":"Int J Obes","author":"Matsushita","year":"2013"},{"key":"2022031303261186400_B29","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.cell.2012.09.010","article-title":"Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria","volume":"151","author":"Fedorenko","year":"2012","journal-title":"Cell"},{"key":"2022031303261186400_B30","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1126\/science.8052854","article-title":"Inhibition of NF-kappa B by sodium salicylate and aspirin","volume":"265","author":"Kopp","year":"1994","journal-title":"Science"},{"key":"2022031303261186400_B31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7326\/0003-4819-159-1-201307020-00003","article-title":"Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial","volume":"159","author":"Goldfine","year":"2013","journal-title":"Ann Intern Med"},{"key":"2022031303261186400_B32","doi-asserted-by":"crossref","first-page":"289","DOI":"10.2337\/dc07-1338","article-title":"Salsalate improves glycemia and inflammatory parameters in obese young adults","volume":"31","author":"Fleischman","year":"2008","journal-title":"Diabetes Care"},{"key":"2022031303261186400_B33","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1172\/JCI67803","article-title":"Recruited brown adipose tissue as an antiobesity agent in humans","volume":"123","author":"Yoneshiro","year":"2013","journal-title":"J Clin Invest"},{"key":"2022031303261186400_B34","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s00125-008-1239-x","article-title":"The effect of salsalate on insulin action and glucose tolerance in obese non-diabetic patients: results of a randomised double-blind placebo-controlled study","volume":"52","author":"Koska","year":"2009","journal-title":"Diabetologia"},{"key":"2022031303261186400_B35","doi-asserted-by":"crossref","first-page":"R285","DOI":"10.1152\/ajpregu.00652.2010","article-title":"Implications of nonshivering thermogenesis for energy balance regulation in humans","volume":"301","author":"van Marken Lichtenbelt","year":"2011","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2022031303261186400_B36","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.mce.2013.04.017","article-title":"Energy dissipation in brown adipose tissue: from mice to men","volume":"379","author":"Vosselman","year":"2013","journal-title":"Mol Cell Endocrinol"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/64\/5\/1544\/579151\/db141125.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/64\/5\/1544\/579151\/db141125.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T12:43:46Z","timestamp":1667393026000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/64\/5\/1544\/40500\/Salsalate-Activates-Brown-Adipose-Tissue-in-Mice"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,4]]},"references-count":36,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2014,12,4]]},"published-print":{"date-parts":[[2015,5,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db14-1125","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12,4]]}}}