Free Linoleic Acid and Oleic Acid Reduce Fat Digestion and Absorption In Vivo as Potent Pancreatic Lipase Inhibitors Derived from Sesame Meal.

Pancreatic lipase catalyzes the cleavage of triacylglycerols at the oil-water interface, and is known as the dominant determiner of dietary fat digestion. Reducing dietary fat digestion and absorption by modulating the activity of pancreatic lipase has become a favorable strategy to tackle obesity. Orlistat is, at present, the only pancreatic lipase inhibitor approved for the treatment of obesity; however, an array of gastrointestinal adverse effects associated with orlistat limits its tolerability. As a safe alternative to orlistat, a number of natural product-derived compounds with varying degrees of pancreatic lipase inhibitory activity have been reported. We herein reported that bioactivity-guided fractionation of sesame meal led to the identification of free linoleic acid and oleic acid as potent inhibitors of porcine pancreatic lipase in vitro with an IC50 of 23.1 µg/mL (82.4 µM) and 11.7 µg/mL (41.4 µM), respectively. In rats, a single oral dose of the mixture of these fatty acids significantly suppressed the elevation of blood triacylglycerol level following fat intake. These results substantiate the role of free linoleic acid and oleic acid as a novel class of natural product-derived functional molecules that act as pancreatic lipase inhibitors, and their potential for healthy, routine-based weight management.

Enzymatic digest of whey protein and wheylin-1, a dipeptide released in the digest, increase insulin sensitivity in an Akt phosphorylation-dependent manner.

We investigated the effects of the enzymatic digest of ß-lactoglobulin, a major bovine milk whey protein, on glucose metabolism in KK-Ay mice, an animal model of type II diabetes. In the glucose tolerance test and insulin tolerance test (ITT), the thermolysin digest of ß-lactoglobulin decreased blood glucose levels, suggesting that it increases insulin sensitivity in diabetic KK-Ay mice. The digest also increased phosphorylation of Akt, an intracellular factor activated in response to the insulin receptor activation, in the liver and skeletal muscle. Next, we searched for a bioactive peptide present in the digest that increased the insulin sensitivity. Wheylin-1 is an anxiolytic-like dipeptide (Met-His) isolated from the thermolysin digest of ß-lactoglobulin. Wheylin-1 decreased blood glucose levels in the ITT test and increased hepatic Akt phosphorylation. Wheylin-1 also increased insulin-induced Akt phosphorylation in hepatic HepG2 cells and muscular C2C12 myotube cells. These results suggest that wheylin-1 increases insulin sensitivity in an Akt-dependent manner in vivo and in vitro. Taken together, we found that the thermolysin digest of bovine milk whey ß-lactoglobulin and wheylin-1 increase insulin sensitivity in an Akt system-dependent manner. Wheylin-1 is the first factor found that increases insulin sensitivity in association with Akt-phosphorylation.

A novel Alaska pollack-derived peptide, which increases glucose uptake in skeletal muscle cells, lowers the blood glucose level in diabetic mice.

We found that the tryptic digest of Alaska pollack protein exhibits a glucose-lowering effect in KK-Ay mice, a type II diabetic model. We then searched for glucose-lowering peptides in the digest. Ala-Asn-Gly-Glu-Val-Ala-Gln-Trp-Arg (ANGEVAQWR) was identified from a peak of the HPLC fraction selected based on the glucose-lowering activity in an insulin resistance test using ddY mice. ANGEVAQWR (3 mg kg(-1)) decreased the blood glucose level after intraperitoneal administration. Among its fragment peptides, the C-terminal tripeptide, Gln-Trp-Arg (QWR, 1 mg kg(-1)), lowered the blood glucose level, suggesting that the C-terminal is critical for glucose-lowering activity. QWR also enhanced glucose uptake into C2C12, a mouse skeletal muscle cell line. QWR did not induce the phosphorylation of serine/threonine protein kinase B (Akt) and adenosine monophosphate-activated protein kinase (AMPK). We also demonstrated that QWR lowered the blood glucose level in NSY and KK-Ay, type II diabetic models.