Editors' ChoiceMetabolism

Boosting energy expenditure

Sci. Signal.  26 Jul 2016:
Vol. 9, Issue 438, pp. ec170
DOI: 10.1126/scisignal.aah6238

Understanding the physiology that underlies cellular and organismal energy metabolism is important for developing strategies to treat various types of metabolic disease, such as obesity and the consequent complications. Cellular energy metabolism can be enhanced by stimuli that uncouple mitochondria oxygen consumption from ATP generation, which is a mechanism used by brown and beige adipocytes to increase thermogenesis in response to cold. Uncoupling protein 1 (UCP1), a member of the SLC25 family of transport proteins, is a well characterized mediator of mitochondrial uncoupling in brown and beige adipocytes. Long et al. sought additional physiological mechanisms that promote this process. In a screen for genes that produced secreted products, were induced by cold, and were expressed in brown adipose tissue, a single candidate was identified: the gene encoding peptidase M20 domain containing 1 (PM20D1). Shotgun proteomics identified PM20D1 in mouse blood, and UCP1+ fat cells, liver, and kidney appeared to be the main sources of PM20D1. Mice injected with an adenoviral vector expressing PM20D1 and placed on a high fat diet exhibited less weight gain and increased oxygen consumption without any notable difference in the animal’s level of locomotor activity or an increase in UCP1 abundance when compared with control animals receiving virus expressing green fluorescent protein (GFP). Mass spectrometry profiling revealed that the plasma of mice receiving the PM20D1-expressing virus had an increase in amino acids coupled to medium and long acyl chains, in particular C14-C18 or C18:1 coupled to phenylalanine, valine, leucine, or isoleucine. In vitro biochemical assays with purified recombinant mouse or human PM20D1 demonstrated that the protein catalyzed both the formation of C18:1-Phe from the substrates oleate and phenylalanine as well as the hydrolysis of C18:1-Phe. In vitro, the enzyme had preferred amino acids and fatty acids but exhibited a broad set of possible substrates such that the observed differences in N-acyl amino acids detected in the animals may reflect differences in the abundances of the possible substrates. In cultured brown adipocytes (UCP1+) or cells that were either genetically deficient in UCP1 or did not normally produce this protein (such as C2C12 myoblast cells), C18:1-Phe stimulated mitochondrial oxygen consumption by uncoupling the mitochondria. Application of a photo-crosslinkable form of an N-acyl amino acid to C2C12 cells identified 149 proteins bound to the N-acyl amino acid, of which 31 were mitochondrial with six of the mitochondrial proteins being members of the SLC25 family. Two of these, SLC25A4 and SCL25A5, are ADP/ATP symporters with proton-translocating activity and are thus candidates for the targets of N-acyl amino acid-mediated mitochondrial uncoupling. Although administration of N-acyl amino acids to mice increased energy expenditure and reduced body mass, the mice also exhibited reduced food intake, which could be an indication of toxicity. Instead, the enzyme PM20D1 may be a better therapeutic, because its activity would only produce the N-acyl amino acids and mitochondrial uncoupling at sites where free fatty acids and amino acids were abundant, such as the liver and fat tissue. In contrast, administration of N-acyl amino acids may cause mitochondrial uncoupling nonspecifically throughout the body.

J. Z. Long, K. J. Svensson, L. A. Bateman, H. Lin, T. Kamenecka, I. A. Lokurkar, J. Lou, R. R. Rao, M. R. Chang, M. P. Jedrychowski, J. A. Paulo, S. P. Gygi, P. R. Griffin, D. K. Nomura, B. M. Spiegelman, The secreted enzyme PM20D1 regulates lapidated amino acid uncouplers of mitochondria. Cell 166, 424–435 (2016). [PubMed]

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