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

Abstract

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.

Secretin-Activated Brown Fat Mediates Prandial Thermogenesis to Induce Satiation

“…These findings consolidate the existence of a gutsecretin-BAT-brain axis involved in the regulation of satiation. Similar to UCP1-KO mice, secretin and SCTR germline KO mice are not hyperphagic but display normal body weight and food intake (Cheng et al, 2011;Sekar and Chow, 2014a). Disruption of the proposed gut-secretin-BAT-brain axis in the control of satiation is apparently compensated by other anorexigenic pathways preventing long-term disturbances of energy balance, as exemplified by the mild metabolic phenotypes (eat normally and maintain the same body weight as WT mice) of several gut hormone and gut hormone receptor KO mice, such as ghrelin KO mice, CCK and its receptor KO mice, and GLP-1 and its receptor KO mice, highlighting the extensive compensatory mechanisms occurring in vivo (see review in Strader and Woods [2005]).…”

Structure-Activity Relationship Studies of N- and C-Terminally Modified Secretin Analogs for the Human Secretin Receptor

“…Secretin receptors are present in central and peripheral tissues [ 5 ], with an established role in the gastro-intestinal tract in which it regulates intraduodenal pH [ 6 ], acid release, stomach motility [ 7 ] and insulin secretion [ 8 ]. Recently, the roles of secretin in water balance [ 9 ], motor function [ 10 ], lipid homeostasis [ 11 , 12 ], and appetite regulation [ 13 ] have also been demonstrated. This integrated role in physiology makes secretin a potential target for the treatment of metabolic disorders.…”

Secretin, at the hub of water-salt homeostasis

“…The SCT/SCTR signaling axis can also activate PKA and result in hormone sensitive lipase (HSL)induced lipolysis in mouse adipocytes (112). Consistent with this finding, the SCTR -/mice are more resistant to high fat diet-induced obesity compared to control (113). In the heart, SCT is able to increase adenylate cyclase activity in crude membrane preparations from rat atria, and to stimulate contraction rate of the spontaneously beating right atrium in rats (105).…”