title: Salsalate activates brown adipose tissue in mice.
abstract: 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-induced obesity. We found that salsalate attenuated and reversed high-fat diet-induced 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[(3)H]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.
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands a.d.van_dam@lumc.nl.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: van Dam
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Nahon
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Kooijman
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Susan M
authors.initials: SM
authors.lastname: van den Berg
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands.
authors.forename: Anish A
authors.initials: AA
authors.lastname: Kanhai
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Mattijs M
authors.initials: MM
authors.lastname: Heemskerk
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Vanessa
authors.initials: V
authors.lastname: van Harmelen
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 693, Le Kremlin-Bicêtre, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.affiliation: Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research, Leiden, the Netherlands.
authors.forename: Anita M
authors.initials: AM
authors.lastname: van den Hoek
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Menno P J
authors.initials: MP
authors.lastname: de Winther
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands Institute for Cardiovascular Prevention, Ludwig Maximilian's University Munich, Munich, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Bruno
authors.initials: B
authors.lastname: Guigas
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands.
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands.
authors.forename: Mariëtte R
authors.initials: MR
authors.lastname: Boon
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism; D012459:Salicylates / Q000008:administration & dosage / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D004041:Dietary Fats; D012459:Salicylates; D005947:Glucose; C014182:salicylsalicylic acid