We study the biochemical pathways that control mammalian metabolism and physiology
Mammalian metabolic homeostasis is a tightly regulated process that affects nearly all aspects of organismal physiology. A key aspect of metabolic homeostasis is the coordinated response of multiple tissues to changes in energy supply or energy demand. We are interested in understanding the biochemical signaling pathways that orchestrate these responses. We focus on chemical messengers, a fundamental class of endogenous molecules that mediate intercellular and inter-organ communication. Our studies have applications to diseases associated with dysfunctional metabolic homeostasis, including obesity, diabetes, cardiovascular disease, neurodegeneration, and certain cancers.
bioactive metabolite discovery
Despite the fundamental roles of chemical messengers 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.
GENETIC CONTROL OF CHEMICAL SIGNALING
Chemical messengers do not act alone: their signaling is orchestrated 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.
Metabolic tissues dramatically alter their function in response to changes in organismal energy states. To understand how chemical messenger signaling pathways regulate these homeostatic responses, our approach is to create genetically modified mice in which these signaling pathways are perturbed. We then comprehensively characterize their metabolic phenotypes under basal and stressed conditions.
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. In many of these cases, such enzymes remain uncharacterized with respect to their endogenous physiologic substrates, products, and mechanism by which they regulate metabolic health. 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 their enzymatic activity may lead to new therapeutic opportunities in the treatment of metabolic disease.
Endogenous metabolite uncouplers that generate heat during fever
Fever, the heat generating response that accompanies infection, is surprisingly poorly characterized at a molecular level. Specifically, the precise chemical and biochemical genesis of heat during fever is not known. We hypothesize that endogenous metabolite uncouplers are responsible for heat generation under hyperthermic conditions. To identify such bioactive metabolites, we propose to take an untargeted metabolomics approach to identify common small molecules upregulated under hypermetabolic conditions in mice.
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 genome-wide screening approaches, we hope to find proteins that mediate the action of chemical uncouplers. Such proteins may represent novel lipid receptors that participate in bioenergetics and mitochondrial function more generally.