The Hotamışlıgil Lab at the Sabri Ülker Center studies innate adaptive pathways involved in metabolic health and disease clusters such as obesity, diabetes, and cardiovascular disease. For the past 25 years, our lab has made important contributions to the burgeoning field of “immunometabolism”, studying the interactions between metabolic and immune responses as critical drivers of numerous chronic diseases. Our current overall approach has been organized in two pillars: organelle structure and homeostasis and lipid signaling, hormones and metabolism. Using biochemical, genetic, and physiological studies, we aim to find novel pathways and preventive, therapeutic solutions to today’s greatest threats to global human health.

Organelle function and structure have profound effects on cellular and metabolic integrity and its dysfunction is causal to metabolic diseases. In this context, our main focus has been on the endoplasmic reticulum, a cellular compartment comprised of a vast network committed to protein and lipid synthesis, maturation, and trafficking, as well as calcium homeostasis. Our laboratory is particularly interested in the mechanisms by which this organelle integrates nutrient-sensing with metabolic responses and endocrine networks. The ER forms dynamic physical and functional interactions with all other subcellular components of the cells and the architecture of these are central to homeostasis. For example, we find an abnormal increase in MAM formation, contributing to impaired metabolic homeostasis. We are interested in how these inter-organelle interactions and structural organization can shape metabolic regulation. We also explore the molecular mechanisms underlying the metabolic biology of the ER, including calcium homeostasis which is impaired in obesity and diabetes. We have identified the ER-resident transcription factor erythroid 2 related factor-1 (Nrf1/Nfe2L1) as a critical sensor and regulator against excessive cholesterol exposure and adipocyte function. We explore the mechanisms by which ER-resident proteins such as Nrf1.

Lipid signaling, hormones, and metabolism. Lipids, whether dietary or endogenously produced, have a profound influence on several vital physiological and metabolic pathways and are involved in the pathogenesis of many critical metabolic diseases such as fatty liver disease, diabetes, and atherosclerosis. We approach the molecular basis of these interactions by focusing on fatty acid-mediated signaling events and transcriptional regulation and the biological role of lipid hormones and escort proteins, such as fatty acid-binding proteins (FABP), as molecules involved in intracellular lipid trafficking in immune and metabolic cells and in the whole organism. Using systemic approaches and quantitative lipidomics, we identified a fatty acid hormone or a lipokine, regulated by adipose tissue lipid chaperones which regulates lipid metabolism in the liver. We are investigating the biology of this lipid hormone in several metabolic diseases in experimental models and humans and exploring the mechanisms underlying its specific endocrine actions. We have also demonstrated that FABPs are central to many components of metabolic syndrome, including obesity, insulin resistance, type 2 diabetes, fatty liver disease, and cardiovascular disease. These proteins are proximal to the generation of stress and inflammatory responses upon exposure to lipids. More recently, we have discovered that FABP4 is secreted from adipocytes in response to lipolytic signals and acts on beta cells and hepatocytes to control insulin secretion and glucose metabolism. In exploring the mechanism of action and physiological and

pathological importance of this unique adipokine, we most recently discovered a novel hormone complex named Fabkin, a structure formed by FABP4 and two extracellular nucleoside kinases, ADK and NDPK. When assembled, this hormone regulates ATP/ADP ratios and signals through purinergic receptors on beta cells to control insulin secretion. The levels of these proteins are markedly elevated in diabetes and cardiovascular disease in both preclinical models and in humans. We also developed prototype antibody-therapeutics to target Fabkin and demonstrated that both type 1 and type 2 diabetes could be treated with this molecule in preclinical models. We are now exploring mechanistic and translational pathways to develop and test these therapeutic entities for their clinical applications.