Trypsin is the major serine protease responsible for intestinal protein digestion. An inhibitor, camostat (CS), reduced weight gain, hyperglyce-mia, and dyslipidemia in obese rats; however, the mechanisms for these are largely unknown. We reasoned that CS creates an apparent dietary protein restriction, which is known to increase hepatic fibro-blast growth factor 21 (FGF21). Therefore, metabolic responses to CS and a gut-restricted CS metabolite, FOY-251, were measured in mice. Food intake, body weight, blood glucose, branched-chain amino acids (LC/MS), hormone levels (ELISA), liver pathology (histology), and transcriptional changes (qRT-PCR) were measured in ob/ob, lean and diet-induced obese (DIO) C57BL/6 mice. In ob/ob mice, CS in chow (9-69 mg/kg) or FOY-251 (46 mg/kg) reduced food intake and body weight gain to a similar extent as pair-fed mice. CS decreased blood glucose, liver weight, and lipidosis and increased FGF21 gene transcription and plasma levels. In lean mice, CS increased liver FGF21 mRNA and plasma levels. Relative to pair feeding, FOY-251 also increased plasma FGF21 and induced liver FGF21 and integrated stress response (ISR) transcription.
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