Leptin, a metabolic regulator of energy expenditure, exerts its peripheral effects primarily by altering lipid metabolism. The exocrine pancreas has a key role in the digestion of dietary lipids, but the role of leptin in regulating pancreatic lipases remains unknown. Using the exocrine pancreas in vitro AR42J cell model, we studied the direct effects of leptin on pancreatic lipase (PL) secretion and on the mRNA levels of PL and PL-related proteins 1 and 2 (PLRP1, PLRP2). Leptin directly, rapidly (within 30 min) and significantly inhibited both the secretion and intracellular activity of PL. Leptin downregulated mRNA levels of PL and PLRP1, and upregulated transcripts of PLRP2. This study provides the first evidence that leptin directly regulates exocrine lipases at the levels of synthesis, activity and secretion. This rapid regulation may be associated with a short-term control of energy balance.