We study the genes and biochemical pathways that control energy homeostasis
Mammalian energy metabolism is tightly regulated by genes and biochemical pathways that influence feeding behaviors, nutrient metabolism, and energy expenditure. We use mass spectrometry-based metabolomics and proteomics as discovery tools to uncover new pathways that control systemic energy homeostasis. We combine these technologies with classical genetic approaches in cells and in mice. Extensive collaborations with physicians at Stanford and internationally help bridge our work from the laboratory to human biology and the clinical setting. Our long-term goal is to translate our discoveries into therapeutic opportunities that matter for obesity, metabolic disorders, and other age-associated chronic diseases.
Our current research interests are described below.
Lactate, exercise, and feeding regulation
Lactate is a fundamental glycolytic metabolite. Our work has focused on an underappreciated aspect of lactate - as a precursor for a lactate-derived metabolite called Lac-Phe - in energy homeostasis. Lac-Phe levels are increased following glycolytic stimuli, including exercise and metformin therapy, and act to suppress feeding behaviors and body weight. We are now uncovering additional genetic and biochemical regulators of Lac-Phe, as well as the downstream central mechanisms by Lac-Phe control energy balance.
Xiao et al., Nat. Metab. 2024
Li et al. Nat. Commun. 2024
Li et al., Nature 2022
Diet, nutrition, and taurine
Despite the important role of diet and nutrition in metabolic health, our understanding of the interaction of diet, genetics, and energy balance remains limited. Our work here focuses on taurine, a conditionally essential amino acid that is especially abundant in certain foods and energy drinks. We have de-orphanized the body mass index-associated orphan enzyme PTER (phosphotriesterase-related) as a physiologic N-acyltaurine hydrolase. 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. Our ongoing studies are focused on uncovering additional genetic and biochemical regulators of taurine metabolism as well as the therapeutic potential and human biology of PTER in body weight regulation.
Lipids, N-acyl amino acids, and mitochondria
We have had a longstanding interest in lipid biochemistry, enzymology, and signaling. Our work here focuses on a family of lipid metabolites called N-acyl amino acids . N-acyl amino acids are conjugates of fatty acids and amino acids and stimulate mitochondrial respiration in vitro and energy expenditure in vivo. Levels of N-acyl amino acids are under tight enzymatic and genetic regulation, including by PM20D1, FAAH, and CY4F enzymes. Polymorphisms in enzymatic pathways of N-acyl amino acid metabolism are linked to human body mass index, thereby connecting this lipid pathway to human obesity. We are now uncovering additional molecules that control N-acyl amino acid function in mouse and human energy homeostasis.
Tanzo et al. J Biol Chem. 2023
Li et al. Diabetes 2020
Kim et al., Cell Chem Biol. 2020
Kim et al., eLife 2020
Long et al., PNAS 2018
Long et al., Cell 2016
Technology development
Complementing the focused studies outlined above, we are developing new mass spectrometry-based technologies for mapping the chemical composition of blood plasma. A long-term goal for these technologies is to enable cell-type specific manipulation of the plasma proteome and metabolome following dynamic energy stressors such as nutrient availability, physical activity, or environmental temperature changes. Currently, we are developing new technologies for systematic profiling of secreted polypeptides, metabolites, and exosomes.
Wiggenhorn et al, Nat. Commun. 2023
Wei et al. Cell Met. 2023
Wei et al., Nat. Chem. Biol. 2020
Kim et al., Cell Chem. Biol. 2019