Secretin receptor-knockout mice are resistant to diet-induced obesity and exhibit impaired intestinal lipid absorption

Abstract

Secretin (Sct), a gastrointestinal hormone, functions primarily to stimulate exocrine secretion from the pancreas and has recently been shown also to regulate water homeostasis. Sct is released from the gut in response to lipid intake and this has been recently shown to be mediated by Cluster of Differentiation 36 (CD36) dependant signaling pathway. In this study, we investigated the role of Sct in metabolic control and lipid homeostasis in wildtype (Wt) and secretin receptor knockout (SctR-KO) mice under chronic high fat diet (HFD). Body composition of the animals was measured by nuclear magnetic resonance (NMR) and plasma metabolic parameters and food intake were also analyzed. After a HFD treatment for 12 weeks, despite similar levels of food intake as Wt mice, SctR-KO had decreased body weight (Wt, 49.6±0.9g; SctR-KO, 44.7±1.4g; P<0.05) and body fat percentage (12.7±0.8% reduced; P<0.005). In addition, reduced plasma glucose levels and improved glucose and insulin tolerance were also observed in SctR-KO mice. Hyperleptinaemia that is induced by HFD was reduced in SctR-KO (Wt, 28.6±0.2ng/ml; SctR-KO, 25.5±0.6ng/ml; P<0.0005) while levels of GLP-1 were similar. Interestingly, SctR-KO mice had impaired intestinal lipid absorption. Triglyceride (TG) release after oral administration of olive oil was significantly reduced in SctR-KO. Furthermore, at the molecular level, the gene expression level of CD36 (-49±7%; P<0.01), Apolipoprotein B (ApoB) (-42±7%; P<0.05) and mitochondrial transfer protein (MTTP) (-29±11%; P<0.05) were reduced in the intestine of SctR-KO mice. Additionally, to assess the direct effect of Sct on intestinal lipid absorption, jejunal cells of the Wt and SctR-KO mice were isolated and stimulated with Sct which resulted in up-regulation of CD36 (+42±14%; P<0.05) transcript. Thus we provide evidence here that the resistance to diet-induced obesity exhibited by SctR-KO mice is due to impaired intestinal lipid absorption. From the above findings, we propose a novel short positive feedback regulation pathway involving Sct and CD36 that is triggered upon lipid intake and functions to maximize intestinal lipid absorption. This study paves way for improving our understanding of mechanisms involved in nutrient absorption and thus could help in developing novel therapeutic strategies for lipid associated metabolic disorders such as hyper- and dys-lipoproteinemia, atherosclerosis, obesity and associated metabolic syndrome including type 2 diabetes.