Luminal nutrients are essential for growth and maintenance of digestive tissue including the pancreas and small intestinal mucosa. Long term loss of luminal nutrients such as during animal hibernation has been shown to result in mucosal atrophy and a corresponding stress response characterized by the induction of heat shock protein 70 (Hsp70) expression. This study was conducted to determine if the loss of luminal nutrients during total parenteral nutrition (TPN) would result in atrophy of exocrine pancreas and small intestinal mucosa as well as an induction of Hsp70 expression in rats. In experiment 1, treatment groups included an orally-fed control, a saline-infused surgical control, or TPN treatment for 7 days. In experiment 2, treatment groups included an orally-fed control and TPN alone or co-infused with varying doses of GLP-2, a mucosal proliferation agent, for 7 days. In experiment 1, TPN resulted in a 40% reduction in pancreatic mass that was associated with a dramatic reduction in digestive enzyme expression, enhanced apoptosis, and a 200% increase in Hsp70 expression. Conversely, Hsc70, Hsp27, and Hsp60 expression was not changed in pancreas. In experiment 2, TPN resulted in a 30% reduction in jejunal mucosa mass and a similar induction of Hsp70 expression. Inclusion of GLP-2 during TPN attenuated jejunal mucosal atrophy and inhibited Hsp70 expression suggesting that Hsp70 induction is sensitive to cell growth. These data indicate that pancreatic and intestinal mucosal atrophy caused by a loss of luminal nutrient stimulation is accompanied by a compensatory response involving Hsp70.