The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria.

Brown and beige adipocytes are specialized cells that express uncoupling protein 1 (UCP1) and dissipate chemical energy as heat. These cells likely possess alternative UCP1-independent thermogenic mechanisms. Here, we identify a secreted enzyme, peptidase M20 domain containing 1 (PM20D1), that is enriched in UCP1(+) versus UCP1(-) adipocytes. We demonstrate that PM20D1 is a bidirectional enzyme in vitro, catalyzing both the condensation of fatty acids and amino acids to generate N-acyl amino acids and also the reverse hydrolytic reaction. N-acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. Mice with increased circulating PM20D1 have augmented respiration and increased N-acyl amino acids in blood. Lastly, administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure. These data identify an enzymatic node and a family of metabolites that regulate energy homeostasis. This pathway might be useful for treating obesity and associated disorders.

The Cancer Drug Dasatinib Increases PGC-1α in Adipose Tissue but Has Adverse Effects on Glucose Tolerance in Obese Mice.

Dasatinib (Sprycel) is a tyrosine kinase inhibitor approved for treatment of chronic myeloid leukemia. In this study, we identify dasatinib as a potent inducer of Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α mRNA. Dasatinib increased PGC-1α mRNA expression up to 6-fold in 3T3-F442A adipocytes, primary adipocytes, and epididymal white adipose tissue from lean and diet-induced obese mice. Importantly, gene expression translated into increased PGC-1α protein content analyzed in melanoma cells and isolated mitochondria from adipocytes. However, dasatinib treatment had adverse effect on glucose tolerance in diet-induced obese and Ob/Ob mice. This correlated with increased hepatic PGC-1α expression and the gluconeogenesis genes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. In conclusion, we show that dasatinib is a potent inducer of PGC-1α mRNA and protein in adipose tissue. However, despite beneficial effects of increased PGC-1α content in adipose tissue, dasatinib significantly impaired glucose tolerance in obese but not lean mice. As far as we are aware, this is the first study to show that dasatinib regulates PGC-1α and causes glucose intolerance in obese mice. This should be considered in the treatment of chronic myeloid leukemia.