Enteroendocrine cells are scattered throughout the epithelial lining of the gut wall and synthesise and secrete over 15 different hormones. Many of these, including GLP-1 and PYY, have important metabolic roles. We have shown that enteroendocrine cells sense and respond to changes in their environment including nutrients [1], immune regulators [2] and drugs such as metformin [3], that their density and function change in humans with obesity [4] and gastroparesis [5], and that bi-directional signalling occurs between the gut microbiome and these cells [6] to modulate host glucose metabolism [7]. Co-application of GLP-1 and PYY has synergistic effects on reducing food intake and we therefore study how L cells can be activated, using human gut tissue, as a logical approach to treating metabolic disease. We have defined the pathway through which nutrients such as carbohydrates trigger GLP-1 release in human gut [1], and this has similarities and differences to that in rodents. We now demonstrate in humans that MC4R and α-MSH, associated with central control of body weight and metabolism, exist within the human gut as an intrinsic system which activates GLP-1 and PYY release and modulates L cell nutrient sensing [8]. Recent reports indicate this differs to rodents. Such complex interactions between enteroendocrine cells are of potential relevance to type 2 diabetes and obesity and their treatment, and species differences are observed that provide some caution when interpreting outcomes from rodents.