Intestinal serine protease inhibition increases FGF21 and improves metabolism in obese mice

Abstract

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 these 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, 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. In DIO mice, FOY-251 (100 mg/kg po) 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. NEW & NOTEWORTHY Trypsin inhibitors, including plant-based consumer products, have long been associated with metabolic improvements. Studies in the 1980s and 1990s suggested this was due to satiety hormones and caloric wasting by loss of protein and fatty acids in feces. This work suggests an entirely new mechanism based on the lower amounts of digested protein available in the gut. This apparent protein reduction may cause beneficial metabolic adaptation by the intestinal-liver axis to perceived nutrient stress.

Discovery and characterization of a small‐molecule enteropeptidase inhibitor, SCO‐792

“…Recently, in vivo enteropeptidase inhibition by SCO‐792 was demonstrated to be highly effective in improving the disease status of diabetes and obesity in mouse models . In addition, inhibition of intestinal trypsin, which is a downstream molecule of enteropeptidase, was shown to decrease body weight and improve metabolism in leptin‐deficient and DIO mice . Taken these together, protein digestion inside the gut likely to have a significant role in regulating body weight and metabolism and inhibiting this step may be a rational strategy to improve obesity and diabetes.…”

COVID-19 and diabetes mellitus: from pathophysiology to clinical management

“…It was reported that camostat mesylate treatment reduced the incidence of new-onset diabetes mellitus in patients with chronic pancreatitis 172 . This drug improved glycaemia and insulin resistance and decreased lipid accumulation in animal models 173 , 174 . The antimalaria drugs chloroquine and hydroxychloroquine have been used to treat SARS-CoV-2 infection despite their potential adverse effects 175 , 176 .…”

Understanding the gastrointestinal tract in obesity: From gut motility patterns to enzyme secretion

“…90 Since then, no human studies have been performed to further elucidate the role of trypsin secretion in obesity. 91 The latter hampers the optimization of efforts that use trypsin inhibition to reduce body weight.…”