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

• Published in: The FASEB journal Vol. 28; no. 8; p. 3494
• Main Authors: Sekar, Revathi, Chow, Billy K C
• Format: Journal Article
• Language: English
• Published: United States 01.08.2014
• Subjects: Adiposity - genetics; Adiposity - physiology; Animals; Carrier Proteins - physiology; CD36 Antigens - physiology; Diet, High-Fat - adverse effects; Dietary Fats - pharmacokinetics; Energy Metabolism; Enterocytes - metabolism; Feedback, Physiological; Female; Glucose Tolerance Test; Insulin Resistance; Intestinal Absorption - genetics; Jejunum - metabolism; Leptin - blood; Locomotion; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity - blood; Obesity - etiology; Obesity - genetics; Obesity - physiopathology; Receptors, G-Protein-Coupled - deficiency; Receptors, G-Protein-Coupled - physiology; Receptors, Gastrointestinal Hormone - deficiency; Receptors, Gastrointestinal Hormone - physiology; Secretin - physiology; Triglycerides - blood; Weight Gain; CD36; enterocytes; positive feedback loop; postprandial triglyceride release; long chain fatty acid
• ISSN: 1530-6860
• DOI: 10.1096/fj.13-247536

Secretin, a classical gastrointestinal hormone released from S cells in response to acid and dietary lipid, regulates pleiotropic physiological functions, such as exocrine pancreatic secretion and gastric motility. Subsequent to recently proposed revisit on secretin's metabolic effects, we have confirmed lipolytic actions of secretin during starvation and discovered a hormone-sensitive lipase-mediated mechanistic pathway behind. In this study, a 12 wk high-fat diet (HFD) feeding to secretin receptor-knockout (SCTR(-/-)) mice and their wild-type (SCTR(+/+)) littermates revealed that, despite similar food intake, SCTR(-/-) mice gained significantly less weight (SCTR(+/+): 49.6±0.9 g; SCTR(-/-): 44.7±1.4 g; P<0.05) and exhibited lower body fat content. These SCTR(-/-) mice have corresponding alleviated HFD-associated hyperleptinemia and improved glucose/insulin tolerance. Further analyses indicate that SCTR(-/-) have impaired intestinal fatty acid absorption while having similar energy expenditure and locomotor activity. Reduced fat absorption in the intestine is further supported by lowered postprandial triglyceride concentrations in circulation in SCTR(-/-) mice. In jejunal cells, transcript and protein levels of a key fat absorption regulator, cluster of differentiation 36 (CD36), was reduced in knockout mice, while transcript of Cd36 and fatty-acid uptake in isolated enterocytes was stimulated by secretin. Based on our findings, a novel positive feedback pathway involving secretin and CD36 to enhance intestinal lipid absorption is being proposed.