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[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.

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

“…The compounds recently studied include a modified version of the classic protonophore, DNP (62), which is structurally similar to salicylate (53,67). These mitochondrial uncouplers result in an increase in energy expenditure similar to that obtained when treating with salsalate/salicylate (present work and previous studies [6,10,11,14,15,[52][53][54][55][56][57][58]) and also improve markers of . Therefore, considering that mitochondrial uncouplers improve T2D and NAFLD, and increasing energy expenditure is a potent mechanism to improve T2D and NAFLD (62,63,(68)(69)(70), the present work, together with previous reports in mice and humans, is highly suggestive that salicylate-driven mitochondrial uncoupling is the primary mechanism of action explaining the improvement in T2D and NAFLD associated with salsalate treatment.…”

“…This is the first study to suggest that salicylate-driven mitochondrial uncoupling is the primary mechanism of action to explain the host of beneficial effects associated with salicylate (11,49,50) and salsalate (6-8,14,51,52). Data from the present study and previous investigations suggest that mitochondrial uncoupling resulting from the protonophoric properties of salicylate explains the consistently observed increases in energy expenditure in murine models and human subjects treated with salicylate-based compounds (6,10,11,14,15,(52)(53)(54)(55)(56)(57)(58).Classic studies from the 1950s observed that salicylate stimulates mitochondrial uncoupling (53,59), and previous work established that mitochondrial Δψm is reduced by 1.0 mmol/L salicylate (54). Moreover, proton conductance is increased with 1.0 mmol/L salicylate treatment (present data and ref.…”

“…Salsalate has also been shown to improve symptoms of NAFLD (9) and nonalcoholic steatohepatitis in mice (10). The mechanism by which salsalate improves T2D and NAFLD is currently unclear, although multiple mechanisms have been proposed (10)(11)(12)(13)(14)(15)(16). The mechanism of action most commonly associated with salsalate is the direct repressing effect of salicylate on inhibitor of nuclear factor κ-B kinase subunit β (IKK-β) to reduce inflammation (11)(12)(13).…”

Artemisinin derivatives prevent obesity by inducing browning of WAT and enhancing BAT function

“…UCP1 is unique to thermogenic adipocytes including brown and beige adipocytes, serving as a morphological and functional marker for these cells [3]. A few compounds have been reported to activate thermogenesis [4][5][6]. These compounds were found previously to elicit beneficial effects on metabolism and enhancing thermogenesis was discovered later as one of the mechanisms.…”

“…Taken together, ATM induces browning during the differentiation of white adipocytes. In contrast, among the previously identified thermogenesis-activating compounds, resveratrol [4] and salsalate [5] enhance the function of BAT, while berberine mainly promotes thermogenesis in mature brown and white adipocytes [6]. ATM is a first-line malaria medicine.…”