We study the signaling pathways that control energy homeostasis

Mammalian energy metabolism is tightly regulated by the action of metabolic hormones and other blood-borne hormone-like molecules. Historically, much work in this area has focused on a handful of circulating molecules secreted by specialized cell types, including pancreatic hormones, gut-derived bioactive peptides, adipose-derived adipokines, and steroids from the adrenal gland. With modern mass spectrometry, it is now recognized that blood plasma contains many more bioactive factors than previously recognized, secreted by cell types that were not previously considered to have endocrine functions. These observations raise critical and unanswered questions: what are the identities of these molecules? Where are they secreted from? What circuits of cell and tissue crosstalk do they participate in? What metabolic and physiologic processes do they control?

To address these questions, we use metabolomics and proteomics technologies as discovery tools. We combine these tools with classical biochemical and genetic approaches in cell and animal models. We engage in extensive collaborations with clinicians at Stanford and elsewhere. Our goal is to uncover fundamental signaling pathways that control organismal energy metabolism. Recent studies from our laboratory have identified a family of cold-regulated circulating lipids that stimulate mitochondrial respiration as well as an exercise-inducible metabolite that suppresses feeding and obesity. We suspect that many more remain to be discovered. In the long term, we hope to translate our discoveries into therapeutic opportunities that matter for metabolic and other age-associated chronic diseases.

Our current research interests are described below.

Metabolic signaling by lipid metabolites

We have recently uncovered a family of blood-borne lipid metabolites called N-acyl amino acids. N-acyl amino acids are biosynthesized by a secreted enzyme, PM20D1, and dramatically elevated in the blood following chronic cold exposure. Functionally, these lipids stimulate mitochondrial respiration and increase whole body energy expenditure. Polymorphisms in PM20D1 and other N-acyl amino acid metabolic enzymes 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; commentary in Lee, New Engl. J. Med. 2016

Physical activity and exercise hormones

Physical activity is well-established to confer metabolic benefits; conversely, physical inactivity is a leading cause of cardiovascular morbidity and mortality. One long-standing yet still provocative hypothesis is that exercise induces beneficial blood-borne signals (e.g., “exercise factors” or “exercise hormones”) that function as molecular transducers of physical activity. We are taking unbiased approaches to identify and functionally interrogate these factors, with the ultimate goal of understanding how physical activity reshapes circulating signals and metabolic homeostasis.

Xiao et al., Nat Metab 2024
Wei et al., Cell Metab 2023
Li et al., Nature 2022; commentary in New York Times, Yahoo! News, Fox News, Daily Mail UK, Fierce Biotech, NewScientist, Nature News & Views

Deorphanization of steroid hormone pathways

Steroid hormones are powerful signaling molecules that exert pleiotropic effects on peripheral metabolic tissues. Recent large-scale sequencing studies have identified previously orphan pathways of steroid hormone metabolism linked to human cardiometabolic disease. The molecular mechanisms that connect these genes to specific steroid molecules and peripheral metabolic processes remains largely unexplored. We are taking metabolomic approaches to de-orphanize these pathways. We anticipate that these studies will provide a scientific and mechanistic foundation that accelerates pharmacological development on these candidate pathways for cardiometabolic disease treatment.

Technology development

Complementing the focused studies outlined above, we are developing 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., Nat. Chem. Biol. 2020
Kim et al., Cell Chem. Biol. 2019