We study the molecules and pathways that control energy and metabolic homeostasis

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Using untargeted metabolomics, we have recently discovered that amino acids and fatty acids, two major energy units, can be conjugated in blood to generate a family of bioactive lipid hormones called N-acyl amino acids. This reaction 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 are now addressing critical unanswered questions regarding the regulation and function of this lipokine pathway 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]


Metabolic tissues as secretory organs

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 secretory factors derived from these tissues are thought to mediate peripheral coordination of energy metabolism. However, nearly all efforts to date have largely focused on individual, specific candidate polypeptides. We are devising strategies for systematically capturing and interrogating these factors en masse. 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]

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The human genetics of metabolic disease

Large-scale human sequencing studies have now identified many loci linked to cardiometabolic traits such as body mass index, glucose metabolism, and fatty liver. A major challenge is to connect these genes to molecular pathways. Using mass spectrometry and genetics-based approaches, we are studying an orphan steroid pathway that is implicated in triglyceride homeostasis. Our goal is to uncover the mechanistic link between these pathways and human metabolic disease in order to provide critical guidance for preclinical and clinical development. [Blankman et al., PNAS 2013; Long et al., Nat. Chem. Biol. 2011]