The pancreas secretes several different lipases. The most abundant is pancreatic triglyceride lipase (PTL). The pancreas also synthesizes two homologues of PTL, the pancreatic lipase-related proteins 1 and 2 (PLRP1 and PLRP2). Cytotoxic T-lymphocytes also express PLRP2 under certain conditions. We sought to determine the role of PLRP2 in fat absorption and in T-cell cytotoxicity by creating a PLRP2-deficient mouse. Adult PLRP2-deficient mice had normal fat absorption. In contrast, suckling PLRP2-deficient mice had fat malabsorption evidenced by increased fecal weight, increased fecal fats, and the presence of undigested and partially digested dietary triglycerides in the feces. As a result, the PLRP2-deficient pups had a decreased rate of weight gain. To assess T cell cytotoxicity, we immunized PLRP2-deficient mice with a mastocytoma cell line, P815, and determined the ability of splenocytes from the immunized mice to kill P815 cells in a 51 Cr release assay. PLRP2-deficient cells had deficient killing activity in this assay, and PLRP2-deficient splenocytes released fewer fatty acid from the target cells than did control cells. Our results provide the first evidence of a physiological function for PLRP2. PLRP2 participates in T cell cytotoxicity, and PLRP2 performs a crucial role in the digestion of dietary fats in suckling animals.

In vitro, pancreatic triglyceride lipase requires colipase to restore activity in the presence of inhibitors, like bile acids. Presumably, colipase performs the same function in vivo, but little data supports that notion. Other studies suggest that colipase or its proform, procolipase, may have additional functions in appetite regulation or in fat digestion during the newborn period when pancreatic triglyceride lipase is not expressed. To identify the physiological role of procolipase, we created a mouse model of procolipase deficiency. The Clps ؊/؊ mice appeared normal at birth, but unexpectedly 60% died within the first 2 weeks of life. The survivors had fat malabsorption as newborns and as adults, but only when fed a high fat diet. On a low fat diet, the Clps ؊/؊ mice did not have steatorrhea. The Clps ؊/؊ pups had impaired weight gain and weighed 30% less than Clps ؉/؉ or Clps ؉/؊ littermates. After weaning, the Clps ؊/؊ mice had normal rate of weight gain, but they maintained a reduced body weight compared with normal littermates even on a low fat diet. Despite the reduced body weight, the Clps ؊/؊ mice had a normal body temperature. To maintain their weight gain in the presence of steatorrhea, the Clps ؊/؊ mice had hyperphagia on a high fat diet. Clps ؊/؊ mice had normal intake on a low fat diet. We conclude that, in addition to its critical role in fat digestion, procolipase has essential functions in postnatal development and in regulating body weight set point.

Suckling mice express colipase before the expression of pancreatic triglyceride lipase. Yet, efficient fat digestion in newborns requires colipase, suggesting that colipase may act as a cofactor for another lipase such as pancreatic lipase-related protein 2 (PLRP2). We determined whether PLRP2 or another lipase depends on colipase for maximal activity in newborn mice by analyzing extracts from the pancreas of 4-d-old colipase-deficient and PLRP2-deficient mice. Pancreatic extracts from colipase-deficient pups had lipase activity that was stimulated onefold by the addition of exogenous colipase (P<0.001). The activity was completely inhibited by an antibody against pancreatic triglyceride lipase that also recognizes PLRP2. In contrast, pancreatic extracts from PLRP2-deficient pups had significantly lower baseline activity and no colipase-dependent activity. The baseline activity was not inhibited by the anti-pancreatic triglyceride lipase antibody or an antibody against carboxyl ester lipase. We next separated the extracts into two fractions, one containing PLRP2 and the other devoid of PLRP2. All of the colipase-dependent activity segregated with the PLRP2-containing fraction, consistent with the conclusion that PLRP2 is the major colipase-dependent lipase in the pancreas of newborns.

A pentapeptide released from procolipase, enterostatin, selectively attenuates dietary fat intake when administered peripherally or centrally. Enterostatin may act through the afferent vagus nerve and in the hypothalamus and amygdala, primarily in the central nucleus of the amygdala. To investigate the physiological role of endogenous enterostatin, we created an enterostatin-deficient, colipase-sufficient (Ent(-/-)) mouse. Ent(-/-) mice are viable, normally active, and fertile. They exhibit normal growth on low-fat and high-fat diets. Furthermore, Ent(-/-) mice develop diet-induced obesity, as do Ent(+/+) mice, and have normal responses to a two-macronutrient choice diet and to a switch from a high-fat to a low-fat diet. Levels of total serum (P = 0.004) and non-HDL (P

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