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The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria

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The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria Article The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria Graphical Abstract Authors Jonathan Z. Long, Katrin J. Svensson, Leslie A. Bateman, ..., Patrick R. Griffin, Daniel K. Nomura, Bruce M. Spiegelman Correspondence [email protected] (D.K.N.), [email protected] (B.M.S.) In Brief Brown and beige fat cells secrete an enzyme that tacks lipids on to amino acids. These N-acyl amino acids directly activate mitochondria for thermogenesis. Highlights d PM20D1 is a secreted enzyme that regulates N-acyl amino acids in vivo d N-acyl amino acids are endogenous metabolites that uncouple mitochondria d Increased PM20D1 or N-acyl amino acid administration augments energy expenditure Long et al., 2016, Cell 166, 1–12 July 14, 2016 ª 2016 Elsevier Inc. http://dx.doi.org/10.1016/j.cell.2016.05.071 Please cite this article in press as: Long et al., The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.05.071 Article The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria Jonathan Z. Long,1,2 Katrin J. Svensson,1,2 Leslie A. Bateman,3 Hua Lin,4 Theodore Kamenecka,4 Isha A. Lokurkar,1 Jesse Lou,1 Rajesh R. Rao,1,2,5 Mi Ra Chang,4 Mark P. Jedrychowski,1,2 Joao A. Paulo,2 Steven P. Gygi,2 Patrick R. Griffin,4 Daniel K. Nomura,3,* and Bruce M. Spiegelman1,2,* 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA 2Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA 3Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA 4Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA 5Present address: Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA 92121, USA *Correspondence: [email protected] (D.K.N.), [email protected] (B.M.S.) http://dx.doi.org/10.1016/j.cell.2016.05.071 SUMMARY Most studies of adaptive thermogenesis and thermogenic fat have centered on the expression and function of UCP1. This pro- Brown and beige adipocytes are specialized cells tein catalyzes a ‘‘proton leak’’ whereby protons that are pumped that express uncoupling protein 1 (UCP1) and dissi- out of the mitochondrial matrix in the electron transport chain pate chemical energy as heat. These cells likely (ETC) are transported back across the inner mitochondrial mem- possess alternative UCP1-independent thermogenic brane (Nicholls et al., 1978; Rousset et al., 2004). This results mechanisms. Here, we identify a secreted enzyme, in oxidative metabolism with no production of ATP, a process peptidase M20 domain containing 1 (PM20D1), that referred to as uncoupled respiration. While UCP1 is a very À important part of adaptive thermogenesis, in principle, any is enriched in UCP1+ versus UCP1 adipocytes. biochemical process that requires energy and is not linked to We demonstrate that PM20D1 is a bidirectional energy storage or work can function as a thermogenic event. enzyme in vitro, catalyzing both the condensation Indeed, data have emerged indicating that UCP1 is not the of fatty acids and amino acids to generate N-acyl only mediator of this process (Kazak et al., 2015; Ukropec amino acids and also the reverse hydrolytic reaction. et al., 2006). Moreover, other carriers of the mitochondrial N-acyl amino acids directly bind mitochondria and SLC25 family, of which UCP1 is only one member (SLC25A7), function as endogenous uncouplers of UCP1-inde- also have the ability catalyze a proton leak across the inner mito- pendent respiration. Mice with increased circulating chondrial membrane (Brand et al., 2005). PM20D1 have augmented respiration and increased In addition to storing chemical energy, adipose cells are now N-acyl amino acids in blood. Lastly, administration recognized to be important sensors of energy balance and of N-acyl amino acids to mice improves glucose ho- secrete many bioactive proteins, including adipsin, leptin, and adiponectin (Kershaw and Flier, 2004). Proteins secreted by meostasis and increases energy expenditure. These brown and beige fat cells in particular have not been extensively data identify an enzymatic node and a family of or systematically studied (Svensson et al., 2016; Wang et al., metabolites that regulate energy homeostasis. This 2014). We recently developed the UCP1-TRAP mouse to identify pathway might be useful for treating obesity and the gene expression signature of brown and beige cells in vivo, associated disorders. regardless of their anatomical localization (Long et al., 2014). These initial experiments elucidated a smooth muscle-like origin INTRODUCTION for beige adipocytes, while also providing a comprehensive molecular inventory of the thermogenic fat cell in vivo. Adaptive thermogenesis has gained increasing attention as a Here, by combining the UCP1-TRAP molecular inventory with process to fight the epidemic of obesity and type 2 diabetes. other datasets, we have compiled a core thermogenesis gene Mammals have brown and beige fat, two tissues that express un- set that is co-expressed in vivo with Ucp1. We hypothesized coupling protein 1 (UCP1) and that are specialized to dissipate that such a gene set might be used to identify secreted proteins stored chemical energy in the form of heat (Cannon and Neder- that play a significant role in adaptive thermogenesis. This anal- gaard, 2004; Harms and Seale, 2013). Either ablation of brown or ysis led to the identification of a previously unstudied secreted beige cells (Cohen et al., 2014; Lowell et al., 1993) or knockout enzyme, peptidase M20 domain containing 1 (PM20D1). We (KO) of the Ucp1 gene (Feldmann et al., 2009) predisposes demonstrate that PM20D1 is a biosynthetic enzyme for a class mice to obesity and diabetes. Conversely, increasing the number of N-lipidated amino acids in vivo, and these metabolites func- or activity of brown and beige cells is protective against weight tion as endogenous uncouplers of mitochondrial respiration in gain and metabolic disease (Seale et al., 2011). a UCP1-independent manner. Cell 166, 1–12, July 14, 2016 ª 2016 Elsevier Inc. 1 Please cite this article in press as: Long et al., The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.05.071 A B C Room temperatureD Thermoneutrality 50 40 Enrichedhed in 5 weekswee GFP PM20D1 GFP * GFP MW ** BAT vs. WAT cold induinduced PM20D1 * PM20D1 150 35 ** 40 100 * 32 HFD 30 ** 75 HFD start Weight (g) Weight 30 (g) Weight start Brown and beige 1 weeweek 25 50 (UCP1-TRAP) cold indinduced IB: Flag 20 20 0 7 12 19 27 33 40 47 54 0 7 19 26 33 40 47 Days post injection Days post injection E F G H Body composition VO2 Movement 40 GFP ** GFP PM20D1 5500 GFP 2500 GFP PM20D1 PM20D1 PM20D1 5000 2000 30 4500 1500 20 4000 * ** Counts ml/kg/hr 1000 Weight (g) Weight 3500 10 3000 500 0 BAT iWAT 2500 0 Fat Lean Total Time Time Figure 1. Increased Circulating PM20D1 Augments Whole Body Energy Expenditure (A) Schematic diagram of search strategy to identify factors expressed by UCP1+ cells. The following publicly available datasets were used for the comparisons: UCP1-TRAP (NCBI GEO: GSE56248), brown versus white adipose tissues (NCBI GEO: GSE8044), and inguinal fat following 1 or 5 weeks cold exposure (NCBI GEO: GSE13432). (B and C) Anti-flag western blot of plasma 40 days post injection (B) and whole body weight curves (C) from male C57BL/6 mice after tail vein injection of AAV-GFP or AAV-PM20D1 fed high fat diet (HFD) at room temperature. Mice were 7 weeks old at the time of injection, HFD was started 7 days post injection, and mice were maintained at room temperature for the duration of the experiment. (B) Arrow indicates band corresponding to PM20D1-flag. (C) n = 8–10/group, mean ± SEM, *p < 0.05. (D–F) Whole body weight curves (D), MRI analysis of total body composition (E), and representative images of adipose tissues (F) from male C57BL/6 mice after tail vein injections of AAV-GFP or AAV-PM20D1 fed HFD at thermoneutrality. Mice were placed into thermoneutrality (30C) at 6 weeks old, injected with virus at 7 weeks old, and HFD was started 7 days post injection. Mice were maintained at 30C for the duration of the experiment. (E and F) Data are from 47 days post injection. n = 8–10/group, mean ± SEM, *p < 0.05, **p < 0.01. (G and H) VO2 (G) and movement (H) of male C57BL/6 mice over a period of 2 days. Mice were 7 weeks old at the time of injection, high fat diet (HFD) was started 7 days post injection, and mice were maintained at room temperature for the duration of the experiment. Measurements were taken at 4 weeks post injection, a time point prior to any significant divergence of body weight (body weight means ± SEM: GFP 33.3 ± 1.3 g, PM20D1 31.6 ± 1.3 g, p > 0.05). n = 8/group, mean ± SEM, *p < 0.05. See also Figures S1 and S2 and Tables S1 and S2. RESULTS Protein Resource (UniProt) demonstrated that half of these candidates (16 out of 32) were mitochondrial in subcellular local- PM20D1 Is Expressed in UCP1+ Adipocytes and ization (Table S1). Of the remainder, only one, PM20D1, con- Promotes Energy Expenditure In Vivo tained a signal peptide without any transmembrane domains, To identify secreted factors from brown and beige adipocytes, two features characteristic of a classically secreted protein. we first generated a list of ‘‘core thermogenesis’’ genes that We validated the original microarray/RNA-seq datasets in a are co-expressed with Ucp1 in vivo.
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