Neurotensin Is a Lipid-Induced Gastrointestinal Peptide Associated with Visceral Adipose Tissue Inflammation in Obesity

Abstract

Neurotensin (NT) is a 13-amino acid peptide localized in the neuroendocrine cells of the small intestine, which promotes fat absorption and fatty acids translocation in response to lipid ingestion. NT-knock-out mice fed with a high-fat diet are protected from obesity, fatty liver, and the development of insulin-resistance. In humans, higher plasma levels of pro-NT, which is the stable circulating precursor of NT, predict obesity, type 2 diabetes (T2D), and cardiovascular disease. In obesity, the presence of visceral adipose tissue (VAT) inflammation leads to unfavorable metabolic outcomes and is associated with the development of T2D and non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the relationship between plasma pro-NT levels and the presence of VAT inflammation in biopsies from 40 morbidly obese subjects undergoing bariatric surgery. We demonstrated that higher proNT levels are significantly associated with greater macrophages infiltration, HIF-1α, WISP-1, and UNC5B expression in VAT (all p < 0.01) due to the diagnosis of T2D and NAFLD. The overall results show that, in obesity, pro-NT is a biomarker of VAT inflammation and insulin-resistance. Additionally, NT may be involved in the development of dysmetabolic conditions likely mediated by increased gut fat absorption and the presence of a proinflammatory milieu in the adipose tissue.

A novel Mendelian randomization method identifies causal relationships between gene expression and low-density lipoprotein cholesterol levels

“…For the other genes identified, there was no direct evidence in the literature for a direct role in cholesterol metabolism, although some interesting patterns were evident. For example, we observed multiple genes involved in immunoglobulin production ( IGLC5, IGLC6 and IGLV4-69 ) and insulin metabolism ( UNC5B, DEPP1 ), observations at least consistent with the role of cholesterol in inflammation and insulin resistance 36,37 . Of note, for all 15 genes, the effect direction estimated by MR-link was concordant with the direction estimated by other MR-methods ( Table 1, Table 2, Supplemental Figure 3 and Supplemental Table 6 ).…”

Identification of U-shaped curve relation between proneurotensin and risk of coronary artery disease (CAD) in patients with premature CAD

“…Previously, serum pro-NT levels have been reported to be notably increased in several metabolic diseases such as obesity [19], type 2 diabetes mellitus [20,21], and nonalcoholic fatty liver disease (NAFLD) [22]. Our present results first found that serum pro-NT levels were significantly higher in patients with premature CAD (males <55 years and females <65 years), especially for patients with BMI<25 kg/m 2 , and premature CAD was an independent contributor to serum pro-NT levels after adjusting for some confounders.…”

Magnitude of rise in proneurotensin is related to amount of triglyceride appearance in blood after standardized oral intake of both saturated and unsaturated fat

“…It is assumed that the absolute majority of the NT that is measurable in blood comes from the periphery, i.e. from the small intestine, where it is stimulated by dietary fat intake [6].…”