The gastrointestinal (GI) tract comprises a large endocrine organ that regulates not only nutrient sensing and metabolising but also satiety and energy homeostasis. More than 20 hormones secreted from the stomach, intestine, and pancreas as well as signaling mediators of the gut microbiome are involved in this process. A better understanding of how related pathways affect body weight and food intake will help us to find new strategies and drugs to treat obesity. For example, weight loss secondary to lifestyle intervention is often accompanied by unfavorable changes in multiple GI hormones, which may cause difficulties in maintaining a lower body weight status. Conversely, bariatric surgery favorably changes the hormone profile to support improved satiety and metabolic function. This partially explains stronger sustained body weight reduction resulting in better long-term results of improved metabolic functions. This review focuses on GI hormones and signaling mediators of the microbiome involved in satiety regulation and energy homeostasis and summarizes their changes following weight loss. Furthermore, the potential role of GI hormones as anti-obesity drugs is discussed.