We study signaling pathways that control energy homeostasis

Mammalian energy metabolism is a fundamental process by which the chemical bond energy in nutrients is converted to cellular energy (ATP) and heat. Energy metabolism is a tightly regulated process that has major effects on nearly all aspects of mammalian physiology, ranging from conditions of acute energy stress (e.g., starvation or exercise), to conditions of acute energy excess (e.g., over-nutrition). Importantly, many age-associated chronic diseases, including obesity, diabetes, dyslipidemia, and cardiovascular disease, are characterized by dysregulated energy metabolism. Therefore, a complete understanding of the molecular pathways of energy homeostasis represents an important basic scientific goal with broad biomedical implications.

Our laboratory focuses on discovering new hormone pathways that control organismal energy storage and energy use. Our approach both classical biochemical and genetic approaches as well as new mass spectrometry-based technologies to characterize and interrogate small molecules and polypeptides in the blood. Recent studies from our laboratory have uncovered new molecules that regulate thermogenesis and energy expenditure, including a family of lipid hormones, the N-acyl amino acids, as well as several other polypeptide hormones physiologically regulated by energy stressors such as exercise (Metrnl) and cold exposure (Slit2c). Ultimately, we seek to translate our discoveries into therapeutic opportunities that matter for metabolic and other chronic diseases.

Our current research interests are described in greater detail below.

Metabolites as signaling molecules

We have recently discovered a family of bioactive lipid hormones called N-acyl amino acids. Their biosynthesis is mediated by a circulating enzyme secreted from brown fat and liver called PM20D1. N-acyl amino acids are taken up by cells and stimulate mitochondrial respiration. We have also identified other classes of circulating amino acid conjugated-metabolites. We are now addressing critical unanswered questions regarding the regulation and function of these small molecule pathways in mouse and human energy homeostasis. [Long et al., PNAS 2018; Lin et al., J. Med Chem. 2018; Long et al., Cell 2016; commentary in Lee, New Engl. J. Med. 2016]

Polypeptides secreted from metabolic tissues

There is a growing appreciation that in addition to their classical functions, metabolic tissues such as adipose, liver, and muscle also function as secretory organs. The polypeptide factors derived from these tissues are thought to mediate peripheral coordination of energy metabolism. Our goal is to understand the key molecular mediators of inter-organ communication between metabolic tissues, especially following organismal energy stressors such as fasting, cold exposure, or exercise. [Svensson et al., Cell Met. 2016; Rao et al., Cell 2014]

Technology development

Complementing the focused studies outlined above, our laboratory also develops and applies chemical and mass spectrometry-based technologies for interrogating the chemical composition of the blood. This is motivated by the fact that large portions of the circulating metabolome and proteome still poorly characterized with respect to composition, biosynthetic source, and physiologic functions. As a part of this effort, we are developing new approaches for unbiased and systematic mapping of circulating polypeptides and for deorphanizing poorly characterized extracellular metabolic pathways. [Kim et al., Cell Chem. Biol. 2019; Blankman et al., PNAS 2013; Long et al., Nat. Chem. Biol. 2011]