Indexed on: 28 May '19Published on: 29 Mar '19Published in: American journal of physiology. Gastrointestinal and liver physiology
Trypsin is the major serine protease responsible for intestinal protein digestion. An inhibitor, camostat (CS), reduced weight gain, hyperglycemia and dyslipidemia in obese rats; however, the mechanisms for this are largely unknown. We reasoned that CS creates an apparent dietary protein restriction, which is known to increase hepatic fibroblast 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 mice, lean or 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. Relative to pair-fed, 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. In DIO mice, FOY-251 (100 mg/kg p.o.) did not alter peak glucose levels, but reduced the AUC of the glucose excursion in response to an oral glucose challenge. FOY-251 increased plasma FGF21 levels. In addition to previously reported satiety-dependent (cholecystokinin-mediated) actions, intestinal trypsin inhibition engages non-satiety related pathways in both leptin deficient and DIO mice. This novel mechanism improves metabolism by a liver integrated stress response and increased FGF21 expression levels in mice.