Hyperphagia (overeating) is often associated with energy over-storage and obesity, which may lead to a myriad of serious health problems, including heart disease, hypertension, and type 2 diabetes. Thus, understanding the complex pathological mechanisms underlying hyperphagia and obesity has an important clinical significance. Leptin, or ob protein, is a key element in the long-term regulation of food intake and body weight homeostasis. It circulates in the blood at levels correlated with body fat mass. Leptin binds to specific receptors in the hypothalamus to mediate events that regulate feeding behavior. In light of new evidence, the initial view that leptin is an adipocyte-derived signal, which acts centrally to decrease body weight, has been modified. It has been shown that leptin may also have specific functions in the gastrointestinal tract, suggesting that feeding and energy homeostasis is regulated by both central and peripheral signals. Evidence supports the view that leptin integrates short-term, meal-related signals from the gut into long-term regulation of energy balance. In addition, the gastric leptin level is altered by the nutritional state and the administration of cholecystokinin. This commentary aims to review the evidence of the role of leptin as a peripherally acting signal in the gut in the regulation of nutrient intake, adiposity, and body weight. Based on currently available data, some potential future studies are suggested.