We study the biochemical pathways that control mammalian energy metabolism

Mammalian energy metabolism is a fundamental process by which the chemical bond energy in nutrients is converted to cellular energy. Energy metabolism is a tightly regulated process that has major effects on nearly all aspects of mammalian physiology, ranging from conditions of high energy expenditure (e.g., cold exposure or exercise) to conditions of altered energy intake (e.g., fasting or over-nutrition). Dysregulated energy metabolism can lead to, among other conditions, obesity and metabolic disease, which represent some of the most pressing medical and economic problems of our generation. As such, understanding the molecular pathways of energy metabolism represents an important basic scientific goal with broad biomedical implications.

Energy metabolism is a physiologic process that is fundamentally a chemical problem in nature, namely, the transformation of one type of chemical energy to others. We are therefore interested in understanding the chemical and biochemical processes that regulate energy storage and energy use. Our multidisciplinary approach combines classical bucket biochemistry with modern analytical, chemical, and genetic tools. We believe this powerful combination offers a unique lens to re-investigate basic questions regarding bioenergetic processes.

Because biochemical processes often represent unique opportunities for pharmacological intervention, our long-term goal is to translate our discoveries into therapeutics that make a difference for human metabolic health.

For more information, please read about our current research areas below.


 
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N-acyl amino acids in energy expenditure

We have recently discovered that amino acids and fatty acids, two fundamental energy units, can be enzymatically conjugated to generate a family of lipid metabolites called N-acyl amino acids. N-acyl amino acids are endogenously present in the circulation and function to stimulate mitochondrial respiration. We have furthermore de-orphanized the extracellular enzyme PM20D1 as a bidirectional N-acyl amino acids synthase/hydrolase. We are interested in understanding more about the regulation of this previously enigmatic branch of bioactive lipids and their functions in energy homeostasis.

 
 
 
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Metabolic pathway mapping

Metabolic pathways constitute critical biochemical transformations that regulate energy units, biosynthetic intermediates, and signaling molecules. However, many metabolic pathways still remain chemically and functionally undefined. We use a combination of untargeted mass spectrometry along with classical biochemistry and enzymology approaches to both map and interrogate uncharted biochemical space. We hypothesize that this space is rich in heretofore unknown metabolic pathways that regulate energy metabolism.

 
 
 
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Human disease-linked enzymes

Large-scale genetic sequencing has now identified many metabolic enzymes linked to cardiometabolic traits, such as body mass index, glucose metabolism, and fatty liver disease. A major challenge is to connect these genes to molecular functions. Using mouse models, we are studying a family of poorly annotated oxidoreductases that, from human genetic data, are implicated in triglyceride homeostasis. Our goal is to uncover the mechanistic link between these orphan enzymes and human metabolic disease.