Gastrokine-1, an anti-amyloidogenic protein secreted by the stomach, regulates diet-induced obesity.

Obesity and its sequelae have a major impact on human health. The stomach contributes to obesity in ways that extend beyond its role in digestion, including through effects on the microbiome. Gastrokine-1 (GKN1) is an anti-amyloidogenic protein abundantly and specifically secreted into the stomach lumen. We examined whether GKN1 plays a role in the development of obesity and regulation of the gut microbiome. Gkn1 mice were resistant to diet-induced obesity and hepatic steatosis (high fat diet (HFD) fat mass (g) = 10.4 ± 3.0 (WT) versus 2.9 ± 2.3 (Gkn1) p < 0.005; HFD liver mass (g) = 1.3 ± 0.11 (WT) versus 1.1 ± 0.07 (Gkn1) p < 0.05). Gkn1 mice also exhibited increased expression of the lipid-regulating hormone ANGPTL4 in the small bowel. The microbiome of Gkn1 mice exhibited reduced populations of microbes implicated in obesity, namely Firmicutes of the class Erysipelotrichia. Altered metabolism consistent with use of fat as an energy source was evident in Gkn1 mice during the sleep period. GKN1 may contribute to the effects of the stomach on the microbiome and obesity. Inhibition of GKN1 may be a means to prevent obesity.