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Obesity-associated comorbidities include non-alcoholic fatty liver disease, Type 2 diabetes, and cardiovascular disease. These diseases are associated with accumulation of lipids in non-adipose tissues, which can impact many intracellular cellular signaling pathways and functions that have been broadly defined as “lipotoxic.” This review moves beyond understanding intracellular lipotoxic outcomes and outlines the consequences of lipotoxicity on protein secretion and inter-tissue “cross talk,” and the impact this exerts on systemic metabolism.