Colonic leptin: source of a novel proinflammatory cytokine involved in IBD

Leptin, a peptide encoded by the obese (ob) gene, is primarily secreted by adipocytes and is a critical hormone that controls body weight due to its central effects. Recently, additional roles for leptin in the gastrointestinal tract have been suggested because gastric lining cells also produce and release leptin in response to meal-related stimuli. While gastric epithelia might thus directly contribute to circulating leptin following a meal, here we show that inflamed colonic epithelial cells express and release leptin apically into the intestinal lumen. In addition, we demonstrate leptin expression and secretion in vitro in epithelial cells. In response to luminal leptin, model intestinal epithelia critically activate the NF-kappaB, a key signaling system to pro-inflammatory stimuli. The inflammatory effect of luminal leptin was characterized in vivo in mice administered intrarectal leptin. Leptin induced epithelial wall damage and neutrophil infiltration that represent characteristic histological findings in acute intestinal inflammation. These observations provide evidence for an intraluminal biological signaling of leptin and a new pathophysiological role for intraluminal leptin during states of intestinal inflammation such as inflammatory bowel disease.