Neurotensin differentially regulates bile acid metabolism and intestinal FXR‐bile acid transporter axis in response to nutrient abundance

Abstract

Studies demonstrate a role for neurotensin (NT) in obesity and related comorbidities.Bile acid (BA) homeostasis alterations are associated with obesity. We determined the effect of NT on BA metabolism in obese and non-obese conditions. Plasma and fecal BA profiles were analyzed by LC-MS/MS in male and female NT +/+ and NT −/− mice fed low-fat (LFD) or high-fat diet (HFD) for 6 weeks (early stage of obesity) or greater than 20 weeks (late stage of obesity). The nuclear farnesoid X receptor (FXR) and BA transporter mRNA expression were assessed in ileum, mouse enteroids, and human cell lines. HFD decreased plasma primary and secondary BAs in NT +/+ mice; HFD-induced decrease of plasma BAs was improved in NT-deficient mice. In NT +/+ mice, HFD inhibited ileal FXR and BA transporter expression; HFD-decreased expression of FXR and BA transporters was prevented in NT −/− mice. Compared with LFD-fed NT +/+ mice, LFD-fed NT −/− mice had relatively lower levels of ileal FXR and BA transporter expression. Moreover, NT stimulates the expression of FXR and BA transporters in Caco-2 cells; however, stimulated expression of BA transporters was attenuated in NT −/− enteroids. Therefore, we demonstrate that HFD disrupts the BA metabolism and ileal FXR and BA transporter axis which are improved in the absence of NT, suggesting that NT contributes to HFD-induced disruption of BA metabolism and plays an inhibitory role in the regulation of ileal FXR and BA transporter signaling under obese conditions. Conversely, NT positively regulates the expression of ileal FXR and BA transporters under non-obese conditions. Therefore, NT plays a dual role in obese and non-obese conditions, suggesting possible therapeutic strategies for obesity control.

New Insights in the Control of Fat Homeostasis: The Role of Neurotensin

“…In vivo and ex vivo experiments demonstrated that NT is capable of reducing adaptive thermogenesis in brown adipocytes and favoring the development of an obesogenic phenotype via its specific receptor NTSR2 [64]. As confirmation, treatment with a specific NTSR2 inhibitor peptide enhanced the expression of the pro-thermogenic gene uncoupling protein 1 (UCP-1) and lowered lipid content in the adipose tissue of treated mice [71]. Finally, long-term NTSR2 inhibition in experimentally obese mice reduced adiposity, and improved glucose and insulin metabolism and adipose tissue metabolic function, as evaluated by greater UCP and peroxisome proliferator-activated receptor gamma (PPAR-γ expression 71).…”

“…Bile acid circulation is altered in obesity [68][69][70]. Recent experiments investigated the role of NT in mediating the association between HFD-induced decreases in plasma bile acid levels and the presence of obesity, using whole body knockout mice for the NT gene [71]. These studies demonstrated that primary and secondary bile acids were downregulated by HFD in wild-type mice, whereas NT deficiency improved the bile acid pool, attenuating this defect [71].…”

“…FXR overexpression and mimic peptides ameliorate glucose tolerance, insulin sensitivity, and lipid profile in experimental models [74,75]. NT was shown to directly stimulate FXR and bile acid transporter signaling under non-obese conditions, whereas it exerts the opposite effects in obesity, contributing to the alteration of the metabolic phenotype associated with weight excess [71]. Conversely, no data are available on the regulation of hepatic bile acid synthesis, which in turn is mediated by liver X receptor (LXR) signaling, via the NT/NTSRs axis.…”

“…Very recently, the expression of NT and NTRS2 genes has been detected in lymphatic endothelial cells within mesenteric adipose tissue [71]. Lymphatic endothelial cells from mice and humans were demonstrated to highly express NT, and this expression was significantly reduced by cold exposure and norepinephrine.…”

High-Amylose Corn Starch Regulated Gut Microbiota and Serum Bile Acids in High-Fat Diet-Induced Obese Mice

“…Particularly, HFD feeding was also found to lower circulating levels of CA, DCA [ 58 ], ω-muricholic acid (MCA), and α-MCA [ 59 ]. In contrast, this HFD-induced decrease in plasma bile acids could be improved in neurotensin-deficient mice [ 60 ]. Similarly, another study reported that compared with a high glycemic load diet, a diet low in glycemic load led to increases in circulating TLCA, TCA, and GCA, which may have beneficial effects on glucose homeostasis [ 61 ].…”