Lactate fluxes mediated by the monocarboxylate transporter-1 are key determinants of the metabolic activity of beige adipocytes

Activation of energy-dissipating brown/beige adipocytes represents an attractive therapeutic strategy against metabolic disorders. While lactate is known to induce beiging through the regulation Ucp1 gene expression, role transporters on beige adipocytes' ongoing activity remains poorly understood. To explore function lactate-transporting monocarboxylate (MCTs), we used a combination primary cell culture studies, 13C isotopic tracing, laser microdissection experiments, and in situ immunofluorescence murine adipose fat pads. Dissecting white tissue heterogeneity revealed that MCT1 expressed inducible as emergence uncoupling protein 1 after cold exposure was restricted subpopulation MCT1-expressing suggesting marker adipocytes. We also observed mediates bidirectional simultaneous inward outward fluxes, which were required for efficient utilization glucose by activated canonical ?3-adrenergic signaling pathway. Finally, demonstrated significant import occurs even when not limiting, feeds oxidative metabolism These data highlight key fluxes finely tuning according extracellular conditions reinforce emerging control energy homeostasis. Thermogenic brown tissues increase systemic expenditure represent putative targets cure obesity related diseases including type II diabetes (1Betz M.J. Enerback S. Targeting thermogenesis muscle treat disease.Nat. Rev. Endocrinol. 2018; 14: 77-87Crossref PubMed Scopus (175) Google Scholar, 2Sidossis L. Kajimura Brown humans: thermogenic homeostasis.J. Clin. Invest. 2015; 125: 478-486Crossref (453) Scholar). The capacity due high mitochondrial content expression (UCP1) inside inner membrane, enables heat production acceleration electron transport chain. Although sharing phenotypic, metabolic, functional similarities with adipocytes, multilocular expressing UCP1 interspaced within (3Cousin B. Cinti Morroni M. Raimbault Ricquier D. 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Because beiging-sensitive 8Dichamp analyzed mRNA levels Mct isoforms i.e., Mct1, Mct2, Mct3, Mct4, regions abilities (Fig. 1A). this gradient lowest periphery (region 1), lying extremity 2), highest close lymph node 3) 1B). mice housed well 48 h Mct1 displayed same pattern Ucp1, increased 3 significantly upregulated following exposure, specifically exhibited 1C). profile no difference regarding Mct2 Mct4 irrespective response 1, D–E). Mct3 detected, accordance exclusive retinal choroid plexus analyze higher precision very tissue, clusters dissected capture (LCM; Fig. 1F), three exhibiting °C. experiments tight positive correlation between (R = 0.881; p < 0.0001; G–H) additional markers such Cidea Cox8b 0.925 R 0.884, respectively; G, I, J). Conversely, negatively correlated leptin (Ob) 0.425; 0.01; G K), enriched (33Cinti Frederich R.C. Flier J.S. Lowell B.B. Immunohistochemical localization tissue.Endocrinology. 1997; 138: 797-804Crossref (171) No found other adipogenic genes Ap2 Pparg2 L, M). Thus, fine dissection cellular tightly agreement patterns, performed existence levels, 2A), °C-housed animals. detected primarily large prone 2A). contrast, faint periphery, highly addition, itself because MCT1? MCT1+ adjacent (white yellow arrows, 2A) identified. display small lipid droplets cytoplasm exhibit paucilocular phenotype (as Scholar)), contrast unilocular (yellow 2, B–C). staining acclimated 28 2D). Analysis outer TOM20 indicated abundance mitochondria 2E; arrows), weakly arrows). almost undetectable top panels). Together, results reveal gathered °C, may capacities. next protein, quantified subpopulations percentage UCP1+ UCP1? cells. exclusively F–H). Interestingly, only 29 ± 11% all them turn (90 4% 92 3% 24 respectively, 2G, panel), cold-inducible reinforced fact fraction negligible did (0.5 0.3 4 2%; bottom panel). conclusion, paucilocular/multilocular mitochondrial-enriched do MCT1, majority bona fide could detect any 3, C), As previously reported (29De BAT 3B [yellow arrows], 3D). Indeed, Note surrounding 3B; findings classical susceptible but process. determine whether 1C) pathway, treated differentiated receptor agonist CL316.243 (CL). CL, expected 4A), 4B). effect cAMP-rising agent forskolin 4, A–B), concluded regulated cAMP-dependent signaling, further study involvement tested AZD3965 (AZD), established inhibitor (34Bola Chadwick A.L. Michopoulos Blount K.G. Telfer B.A. Williams K.J. Smith P.D. Critchlow S.E. Stratford I.J. Inhibition transporter-1 (MCT1) enhances radiosensitivity reducing transport.Mol. Cancer Ther. 13: 2805-2816Crossref 35Curtis N.J. Mooney Hopcroft Whalley Zhong Murray Logie Revill Byth K.F. Benjamin Firth Green Pre-clinical pharmacology AZD3965, selective MCT1: DLBCL, NHL Burkitt's lymphoma anti-tumor activity.Oncotarget. 8: 69219-69236Crossref (84) 36Polanski Hodgkinson C.L. Fusi Nonaka Priest Kelly Trapani Bishop P.W. Blackhall Dive Morrow C.J. Activity lung cancer.Clin. 926-937Crossref (207) 37Tasdogan Faubert Ramesh Ubellacker J.M. Shen Solmonson Murphy M.M. Gu W. Martin Kasitinon S.Y. Vandergriff Mathews T.P. Schadendorf al.Metabolic confers differences melanoma metastatic potential.Nature. 577: 115-120Crossref (192) Treatment 50 nM AZD hamper CL-induced (even doses, shown) involved cascade linking 4C). then investigated lactate-induced using sodium-L-lactate (and lactic acid avoid pH changes) concentration 25 mM, give rise maximal shown dose-dependent effects Scholar)). abrogated 4C), confirming previous obtained MCT inhibitors expression. clearly indicate two independent pathways one mediated MCT1/lactate receptor. Altogether transcriptional agonists. first studied monitoring supernatant Time-course biphasic curve phase net second consumption 32 5A). reduced 5, showing export. residual export probably MCT4 38Petersen Nielsen M.D. Andersen E.S. Basse Isidor Markussen L.K. Viuff Lambert I.H. Hansen J.B. Pedersen S.F. flux impact metabolism.Sci. 13101Crossref Scopu