FALCON systematically interrogates FFA biology and identifies new mediators of lipotoxicity

Abstract

Cellular vulnerability to free fatty acids (FFA) is implicated in the modern epidemic of obesity and its sequelae, including type 2 diabetes (T2D). However, studies to date have assumed that a few select FFAs are representative of broad structural categories, and currently there are no high-throughput, scalable approaches to characterizing the cellular effects of prolonged exposure to the diverse set of FFAs circulating in plasma. Furthermore, assessing how these FFA-mediated processes interact with genetic risk for disease remains elusive. Here we report the design and implementation of FALCON (a Fatty Acid Library for Comprehensive ONtologies) as an unbiased, multimodal interrogation of 61 structurally diverse FFAs across multiple cell types of interest. We identified a previously unrecognized subset of toxic monounsaturated fatty acids (MUFAs) that, at the cellular level, mimicked the effects of canonically harmful saturated fatty acids (SFAs) by altering ER stress, autophagy, insulin secretion, and inflammation. This subset of FFAs also induced a distinct lipidomic profile associated with decreased membrane fluidity. The integrated signature of a broader set of toxic FFAs, including toxic MUFAs, increased the sensitivity of detecting genes in a type 2 diabetes (T2D) genome-wide association study (GWAS) that could mediate both genetic and environmental risk. Among these loci, we further show that CMIP is a previously unrecognized regulator of cellular energy homeostasis. CMIP deficiency sensitizes multiple pancreatic beta cell models to FFA abundance and broader metabolic insult. This is due to metabolic inflexibility caused by dysregulation of Akt signaling. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism.