Enteroendocrine hormones, exemplified by GLP-1 control multiple facets of food ingestion, gut motility, nutrient assimilation and energy storage, supporting the development of gut hormone therapies for the treatment of metabolic disorders such as diabetes and obesity. Surprisingly, although the physiological and pharmacological actions of GLP-1 have been extensively studied, the precise mechanisms and cellular sites linking GLP-1 action to the control of metabolism remain controversial. Here we summarize controversies in the field, providing an overview of key concepts linking the secretion of GLP-1 to the control of cardiometabolic actions in distant target tissues.