Maria Dolores Moya Garzon

All Publications

• A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites. Cell Moya-Garzon, M. D., Wang, M., Li, V. L., Lyu, X., Wei, W., Tung, A. S., Raun, S. H., Zhao, M., Coassolo, L., Islam, H., Oliveira, B., Dai, Y., Spaas, J., Delgado-Gonzalez, A., Donoso, K., Alvarez-Buylla, A., Franco-Montalban, F., Letian, A., Ward, C. P., Liu, L., Svensson, K. J., Goldberg, E. L., Gardner, C. D., Little, J. P., Banik, S. M., Xu, Y., Long, J. Z. 2024

  Abstract

  β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.

  View details for DOI 10.1016/j.cell.2024.10.032

  View details for PubMedID 39536746

• PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity. Nature Wei, W., Lyu, X., Markhard, A. L., Fu, S., Mardjuki, R. E., Cavanagh, P. E., Zeng, X., Rajniak, J., Lu, N., Xiao, S., Zhao, M., Moya-Garzon, M. D., Truong, S. D., Chou, J. C., Wat, L. W., Chidambaranathan-Reghupaty, S., Coassolo, L., Xu, D., Shen, F., Huang, W., Ramirez, C. B., Jang, C., Li, L., Svensson, K. J., Fischbach, M. A., Long, J. Z. 2024

  Abstract

  Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance.

  View details for DOI 10.1038/s41586-024-07801-6

  View details for PubMedID 39112712

  View details for PubMedCentralID 3501277

• Binding and sequestration of poison frog alkaloids by a plasma globulin. eLife Alvarez-Buylla, A., Fischer, M. T., Moya Garzon, M. D., Rangel, A. E., Tapia, E. E., Tanzo, J. T., Soh, H. T., Coloma, L. A., Long, J. Z., O'Connell, L. A. 2023; 12

  Abstract

  Alkaloids are important bioactive molecules throughout the natural world, and in many animals they serve as a source of chemical defense against predation. Dendrobatid poison frogs bioaccumulate alkaloids from their diet to make themselves toxic or unpalatable to predators. Despite the proposed roles of plasma proteins as mediators of alkaloid trafficking and bioavailability, the responsible proteins have not been identified. We use chemical approaches to show that a ~50 kDa plasma protein is the principal alkaloid-binding molecule in blood of poison frogs. Proteomic and biochemical studies establish this plasma protein to be a liver-derived alkaloid-binding globulin (ABG) that is a member of the serine-protease inhibitor (serpin) family. In addition to alkaloid-binding activity, ABG sequesters and regulates the bioavailability of 'free' plasma alkaloids in vitro. Unexpectedly, ABG is not related to saxiphilin, albumin, or other known vitamin carriers, but instead exhibits sequence and structural homology to mammalian hormone carriers and amphibian biliverdin-binding proteins. ABG represents a new small molecule binding functionality in serpin proteins, a novel mechanism of plasma alkaloid transport in poison frogs, and more broadly points toward serpins acting as tunable scaffolds for small molecule binding and transport across different organisms.

  View details for DOI 10.7554/eLife.85096

  View details for PubMedID 38206862

• Organism-wide, cell-type-specific secretome mapping of exercise training in mice. Cell metabolism Wei, W., Riley, N. M., Lyu, X., Shen, X., Guo, J., Raun, S. H., Zhao, M., Moya-Garzon, M. D., Basu, H., Sheng-Hwa Tung, A., Li, V. L., Huang, W., Wiggenhorn, A. L., Svensson, K. J., Snyder, M. P., Bertozzi, C. R., Long, J. Z. 2023

  Abstract

  There is a significant interest in identifying blood-borne factors that mediate tissue crosstalk and function as molecular effectors of physical activity. Although past studies have focused on an individual molecule or cell type, the organism-wide secretome response to physical activity has not been evaluated. Here, we use a cell-type-specific proteomic approach to generate a 21-cell-type, 10-tissue map of exercise training-regulated secretomes in mice. Our dataset identifies >200 exercise training-regulated cell-type-secreted protein pairs, the majority of which have not been previously reported. Pdgfra-cre-labeled secretomes were the most responsive to exercise training. Finally, we show anti-obesity, anti-diabetic, and exercise performance-enhancing activities for proteoforms of intracellular carboxylesterases whose secretion from the liver is induced by exercise training.

  View details for DOI 10.1016/j.cmet.2023.04.011

  View details for PubMedID 37141889

• CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels. The Journal of biological chemistry Tanzo, J. T., Li, V. L., Wiggenhorn, A. L., Moya-Garzon, M. D., Wei, W., Lyu, X., Dong, W., Tahir, U. A., Chen, Z. Z., Cruz, D. E., Deng, S., Shi, X., Zheng, S., Guo, Y., Sims, M., Abu-Remaileh, M., Wilson, J. G., Gerszten, R. E., Long, J. Z., Benson, M. D. 2023: 104764

  Abstract

  N-acyl amino acids are a large family of circulating lipid metabolites that modulate energy expenditure and fat mass in rodents. However, little is known about the regulation and potential cardiometabolic functions of N-acyl amino acids in humans. Here, we analyze the cardiometabolic phenotype associations and genomic associations of four plasma N-acyl amino acids (N-oleoyl-leucine, N-oleoyl-phenylalanine, N-oleoyl-serine, and N-oleoyl-glycine) in 2,351 individuals from the Jackson Heart Study. We find that plasma levels of specific N-acyl amino acids are associated with cardiometabolic disease endpoints independent of free amino acid plasma levels and in patterns according to the amino acid head group. By integrating whole genome sequencing data with N-acyl amino acid levels, we identify that the genetic determinants of N-acyl amino acid levels also cluster according to amino acid head group. Furthermore, we identify the CYP4F2 locus as a genetic determinant of plasma N-oleoyl-leucine and N-oleoyl-phenylalanine levels in human plasma. In experimental studies, we demonstrate that CYP4F2-mediated hydroxylation of N-oleoyl-leucine and N-oleoyl-phenylalanine results in metabolic diversification and production of many previously unknown lipid metabolites with varying characteristics of the fatty acid tail group, including several that structurally resemble fatty acid hydroxy fatty acids (FAHFAs). These studies provide a structural framework for understanding the regulation and disease-associations of N-acyl amino acids in humans and identify that the diversity of this lipid signaling family can be significantly expanded through CYP4F-mediated ω-hydroxylation.

  View details for DOI 10.1016/j.jbc.2023.104764

  View details for PubMedID 37121548

• Structural insights into the mechanism of leptin receptor activation. Nature communications Saxton, R. A., Caveney, N. A., Moya-Garzon, M. D., Householder, K. D., Rodriguez, G. E., Burdsall, K. A., Long, J. Z., Garcia, K. C. 2023; 14 (1): 1797

  Abstract

  Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)-STAT3 signaling axis in a subset of hypothalamic neurons. Leptin signaling is dysregulated in obesity, however, where appetite remains elevated despite high levels of circulating leptin. To gain insight into the mechanism of leptin receptor activation, here we determine the structure of a stabilized leptin-bound LepR signaling complex using single particle cryo-EM. The structure reveals an asymmetric architecture in which a single leptin induces LepR dimerization via two distinct receptor-binding sites. Analysis of the leptin-LepR binding interfaces reveals the molecular basis for human obesity-associated mutations. Structure-based design of leptin variants that destabilize the asymmetric LepR dimer yield both partial and biased agonists that partially suppress STAT3 activation in the presence of wild-type leptin and decouple activation of STAT3 from LepR negative regulators. Together, these results reveal the structural basis for LepR activation and provide insights into the differential plasticity of signaling pathways downstream of LepR.

  View details for DOI 10.1038/s41467-023-37169-6

  View details for PubMedID 37002197

  View details for PubMedCentralID 4859313

• The role of somatosensory innervation of adipose tissues. Nature Wang, Y., Leung, V. H., Zhang, Y., Nudell, V. S., Loud, M., Servin-Vences, M. R., Yang, D., Wang, K., Moya-Garzon, M. D., Li, V. L., Long, J. Z., Patapoutian, A., Ye, L. 2022

  Abstract

  Adipose tissues communicate with the central nervous system to maintain whole-body energy homeostasis. The mainstream view is that circulating hormones secreted by the fat convey the metabolic state to the brain, which integrates peripheral information and regulates adipocyte function through noradrenergic sympathetic output1. Moreover, somatosensory neurons of the dorsal root ganglia innervate adipose tissue2. However, the lack of genetic tools to selectively target these neurons has limited understanding of their physiological importance. Here we developed viral, genetic and imaging strategies to manipulate sensory nerves in an organ-specific manner in mice. This enabled us to visualize the entire axonal projection of dorsal root ganglia from the soma to subcutaneous adipocytes, establishing the anatomical underpinnings of adipose sensory innervation. Functionally, selective sensory ablation in adipose tissue enhanced the lipogenic and thermogenetic transcriptional programs, resulting in an enlarged fat pad, enrichment of beige adipocytes and elevated body temperature under thermoneutral conditions. The sensory-ablation-induced phenotypes required intact sympathetic function. We postulate that beige-fat-innervating sensory neurons modulate adipocyte function by acting as a brake on the sympathetic system. These results reveal an important role of the innervation by dorsal root ganglia of adipose tissues, and could enable future studies to examine the role of sensory innervation of disparate interoceptive systems.

  View details for DOI 10.1038/s41586-022-05137-7

  View details for PubMedID 36045288

• New salicylic acid derivatives, double inhibitors of glycolate oxidase and lactate dehydrogenase, as effective agents decreasing oxalate production EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Moya-Garzon, M., Rodriguez-Rodriguez, B., Martin-Higueras, C., Franco-Montalban, F., Fernandes, M. X., Gomez-Vidal, J. A., Pey, A. L., Salido, E., Diaz-Gavilan, M. 2022; 237: 114396

  Abstract

  The synthesis and biological evaluation of double glycolate oxidase/lactate dehydrogenase inhibitors containing a salicylic acid moiety is described. The target compounds are obtained in an easily scalable two-step synthetic procedure. These compounds showed low micromolar IC50 values against the two key enzymes in the metabolism of glyoxylate. Mechanistically they behave as noncompetitive inhibitors against both enzymes and this fact is supported by docking studies. The biological evaluation also includes in vitro and in vivo assays in hyperoxaluric mice. The compounds are active against the three types of primary hyperoxalurias. Also, possible causes of adverse effects, such as cyclooxygenase inhibition or renal toxicity, have been studied and discarded. Altogether, this makes this chemotype with drug-like structure a good candidate for the treatment of primary hyperoxalurias.

  View details for DOI 10.1016/j.ejmech.2022.114396

  View details for Web of Science ID 000804173500004

  View details for PubMedID 35500475

• Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias JOURNAL OF PERSONALIZED MEDICINE Dolores Moya-Garzon, M., Antonio Gomez-Vidal, J., Alejo-Armijo, A., Altarejos, J., Roberto Rodriguez-Madoz, J., Xavier Fernandes, M., Salido, E., Salido, S., Diaz-Gavilan, M. 2021; 11 (2)

  Abstract

  Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism. PHs classification based on gene mutations parallel a variety of enzymatic defects, and all involve the harmful accumulation of calcium oxalate crystals that produce systemic damage. These geographically widespread rare diseases have a deep impact in the life quality of the patients. Until recently, treatments were limited to palliative measures and kidney/liver transplants in the most severe forms. Efforts made to develop pharmacological treatments succeeded with the biotechnological agent lumasiran, a siRNA product against glycolate oxidase, which has become the first effective therapy to treat PH1. However, small molecule drugs have classically been preferred since they benefit from experience and have better pharmacological properties. The development of small molecule inhibitors designed against key enzymes of glyoxylate metabolism is on the focus of research. Enzyme inhibitors are successful and widely used in several diseases and their pharmacokinetic advantages are well known. In PHs, effective enzymatic targets have been determined and characterized for drug design and interesting inhibitory activities have been achieved both in vitro and in vivo. This review describes the most recent advances towards the development of small molecule enzyme inhibitors in the treatment of PHs, introducing the multi-target approach as a more effective and safe therapeutic option.

  View details for DOI 10.3390/jpm11020074

  View details for Web of Science ID 000622701200001

  View details for PubMedID 33513899

  View details for PubMedCentralID PMC7912158

• Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1 JOURNAL OF MEDICINAL CHEMISTRY Dolores Moya-Garzon, M., Martin Higueras, C., Penalver, P., Romera, M., Fernandes, M. X., Franco-Montalban, F., Gomez-Vidal, J. A., Salido, E., Diaz-Gavilan, M. 2018; 61 (16): 7144-7167

  Abstract

  Primary hyperoxaluria type 1 (PH1) is a rare life-threatening genetic disease related to glyoxylate metabolism and characterized by accumulation of calcium oxalate crystals. Current therapies involve hepatic and/or renal transplantation, procedures that have significant morbidity and mortality and require long-term immunosuppression. Thus, a pharmacological treatment is urgently needed. We introduce here an unprecedented activity of salicylic acid derivatives as agents capable of decreasing oxalate output in hyperoxaluric hepatocytes at the low micromolar range, which means a potential use in the treatment of PH1. Though correlation of this phenotypic activity with glycolate oxidase (GO) inhibition is still to be verified, most of the salicylic acids described here are GO inhibitors with IC50 values down to 3 μM. Binding mode of salicylic acids inside GO has been studied using in silico methods, and preliminary structure-activity relationships have been established. The drug-like structure and ease of synthesis of our compounds make them promising hits for structural optimization.

  View details for DOI 10.1021/acs.jmedchem.8b00399

  View details for Web of Science ID 000442960800013

  View details for PubMedID 30028141

• Development of a Cannabinoid-Based Photoaffinity Probe to Determine the Delta(8/9)-Tetrahydrocannabinol Protein Interaction Landscape in Neuroblastoma Cells CANNABIS AND CANNABINOID RESEARCH Soethoudt, M., Alachouzos, G., van Rooden, E. J., Moya-Garzon, M., van den Berg, R. N., Heitman, L. H., van der Stelt, M. 2018; 3 (1): 136-151

  Abstract

  Introduction: Δ9-Tetrahydrocannabinol (THC), the principle psychoactive ingredient in Cannabis, is widely used for its therapeutic effects in a large variety of diseases, but it also has numerous neurological side effects. The cannabinoid receptors (CBRs) are responsible to a large extent for these, but not all biological responses are mediated via the CBRs. Objectives: The identification of additional target proteins of THC to enable a better understanding of the (adverse) physiological effects of THC. Methods: In this study, a chemical proteomics approach using a two-step photoaffinity probe is applied to identify potential proteins that may interact with THC. Results: Photoaffinity probe 1, containing a diazirine as a photocrosslinker, and a terminal alkyne as a ligation handle, was synthesized in 14 steps. It demonstrated high affinity for both CBRs. Subsequently, two-step photoaffinity labeling in neuroblastoma cells led to identification of four potential novel protein targets of THC. The identification of these putative protein hits is a first step towards a better understanding of the protein interaction profile of THC, which could ultimately lead to the development of novel therapeutics based on THC.

  View details for DOI 10.1089/can.2018.0003

  View details for Web of Science ID 000616128300015

  View details for PubMedID 29992186

  View details for PubMedCentralID PMC6038054