We study the biochemical pathways that control mammalian metabolism and physiology

Mammalian metabolism is the fundamental process in which chemical bond energy in nutrients is converted into cellular energy and heat. Metabolism affects nearly every aspect of organismal physiology and homeostasis, ranging from the maintenance of energy levels during fasting to the regulation of body temperature. Dysfunction of metabolic homeostasis contributes to some of the most pressing medical problems of our generation, including obesity, type 2 diabetes, cardiovascular disease, neurodegeneration, and certain cancers.

Metabolites represent critical regulators of mammalian metabolism. These endogenous small molecules can function as energy units, biochemical intermediates, or as bioactive mediators of signaling. We focus on bioactive metabolites because of their critical roles in orchestrating tissue and organismal metabolic homeostasis. Research in our laboratory spans three main areas: 1) discovery of new bioactive metabolites, 2) identification of enzymes, carriers, transporters, and receptors that control their signaling, and 3) development of animal models for characterizing metabolite signaling in metabolic physiology and metabolic dysfunction. To achieve these goals, we use a multidisciplinary approach that combines mouse genetics, organic chemistry, mass spectrometry, and biochemistry.

Because small molecule signaling pathways often represent unique opportunities for pharmacological intervention, our long-term goal is to translate our discoveries into therapeutics that make a difference for human health.


 
metabolites_twoToned.jpg
 
 
 

bioactive metabolite discovery

Despite the fundamental roles of small molecules in controlling energy homeostasis, large portions of biochemical space remain entirely unexplored. Our strategy is to combine untargeted metabolomics platforms with genetics and classical enzymology to concurrently annotate new signaling metabolites and the enzymes that regulate their biosynthesis or degradation. These enzyme-metabolite networks are then a starting point for perturbing cellular and organismal physiology.

 
 
 
Protein3.jpg
 
 

GENETIC CONTROL OF CHEMICAL SIGNALING

Bioactive metabolites do not act alone: their signaling is tightly regulated by a collection of genetically encoded components, including extracellular and cytosolic carriers, membrane exporters and importers, and cell surface or intracellular receptors. Using chemical, proteomic, biochemical, and genetic approaches, we seek to identify the protein factors that control the magnitude and duration of signaling. These targets provide genetic opportunities to perturb bioactive metabolite pathways in vitro and in vivo.

 
 
 
mouse_illustration.jpg
 
 

organismal physiology

Metabolite signaling plays critical roles in organismal physiology. Their dysregulation can lead to metabolic disorders including obesity, type 2 diabetes, cardiovascular disease, or non-alcoholic fatty liver disease. To interrogate the function of metabolite signaling in vivo, we create genetically modified mice with perturbed biochemical pathways. We then comprehensively characterize their metabolic phenotypes under basal and energy-stressed conditions.

 
 

 
 
TC_2.jpg
 
 

Learn more about our projects

 
 

Uncharacterized enzymes from human genome-wide association studies

Human genome-wide association studies (GWAS) have identified metabolic enzymes linked to cardiometabolic traits. However, in many of these cases the precise biochemical pathways regulated by these disease-linked enzymes remain unknown, limiting our mechanistic knowledge of how these biochemical nodes are linked to human disease. Using metabolomics, mouse genetics, and synthetic chemistry, we wish to annotate the biochemical and physiologic functions of uncharacterized enzymes identified from GWAS studies, with the hope that pharmacological targeting of these biochemical pathways may lead to new therapeutic opportunities in the treatment of metabolic disease.

The signaling and physiology of amino acid-conjugated metabolites

Amino acids are abundant metabolites that serve as building blocks for proteins. Remarkably, amino acids can also be conjugated to other metabolites, including fatty acids, lactate, and acetate. The function of such N-conjugated amino acid metabolites is not precisely known but we suspect they may have interesting signaling functions in physiology. We have recently found a family of enzymes that serve as biochemical regulators for these amino acid conjugated metabolites, and wish to use this information as a handle for investigating the signaling bioactivities of these metabolites in cells and in vivo.

Metabolic diversification of neurotransmitter structure and function

Neurotransmitters, including serotonin, dopamines, and GABA are small molecules that regulate a wide range of physiology, including central nervous system control of energy homeostasis. While the biosynthesis of these neurotransmitters is well characterized, their metabolic fates remain more mysterious. For instance, nearly all neurotransmitters have been reported to be derivatized by N-acylation. These "N-acyl" neurotransmitters have been detected in endogenous tissues yet their biochemical and physiologic functions remain unknown. To understand the in vivo actions of neurotransmitter derivatives, we hope use a biochemical approach to purify new enzymes that degrade these amidated metabolites. Ultimately, we wish to understand the biochemistry and physiology of mice lacking such enzymes.

Proteins required for chemical uncoupling

A class of small molecules called "chemical uncouplers" can promote proton leak in mitochondria and cause increases in respiration. Examples of chemical uncouplers include synthetic compounds (e.g., FCCP) as well as those that are endogenous consituents of mammalian tissues (e.g., N-acyl amino acids). However, precisely how these compounds promote a proton leak activity is unknown. Using biochemical as well as genome-wide screening approaches, we hope to find proteins that mediate the action of chemical uncouplers. Such proteins may represent novel receptors that participate in bioenergetics and mitochondrial function more generally.