Increased Plasma Proneurotensin Levels Identify NAFLD in Adults With and Without Type 2 Diabetes

Ilaria Barchetta; Flavia Agata Cimini; Frida Leonetti; Danila Capoccia; Claudio Di Cristofano; Gianfranco Silecchia; Marju Orho-Melander; Olle Melander; Maria Gisella Cavallo

Disclosures

J Clin Endocrinol Metab. 2018;103(6):2253-2260. 

In This Article

Abstract and Introduction

Abstract

Context: Neurotensin (NT), an intestinal peptide released by fat ingestion, promotes lipid absorption; higher circulating NT levels are associated with type 2 diabetes (T2D), obesity, and cardiovascular disease. Whether NT is related to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has not been fully investigated.

Objective: To study the relationship between plasma proneurotensin 1 to 117 (pro-NT), a stable fragment of the NT precursor hormone, and the presence/severity of NAFLD/NASH and to unravel correlates of increased pro-NT levels.

Design/Setting/Participants: For this cross-sectional study, 60 obese individuals undergoing bariatric surgery for clinical purposes were recruited. The association between pro-NT and NAFLD was further investigated in 260 consecutive subjects referred to our outpatient clinics for metabolic evaluations, including liver ultrasonography. The study population underwent complete metabolic characterization; in the obese cohort, liver biopsies were performed during surgery.

Main Outcome Measures: Plasma pro-NT levels in relation to NAFLD/NASH.

Results: Obese subjects with biopsy-proven NAFLD (53%) had significantly higher plasma pro-NT than those without NAFLD (183.6 ± 81.4 vs 86.7 ± 56.8 pmol/L, P < 0.001). Greater pro-NT correlated with NAFLD presence (P < 0.001) and severity (P < 0.001), age, female sex, insulin resistance, and T2D. Higher pro-NT predicted NAFLD with an area under receiver operating characteristic curve of 0.836 [95% confidence interval (CI), 0.73 to 0.94; P < 0.001]. Belonging to the highest pro-NT quartile correlated with increased NAFLD risk (odds ratio, 2.62; 95% CI, 1.08 to 6.40) after adjustment for confounders. The association between higher pro-NT and NAFLD was confirmed in the second cohort independently from confounders.

Conclusions: Increased plasma pro-NT levels identify the presence/severity of NAFLD; in dysmetabolic individuals, NT may specifically promote hepatic fat accumulation through mechanisms likely related to increased insulin resistance.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is a pathological condition characterized by the macrovesicular accumulation of triglycerides within hepatocytes (hepatic steatosis); in a number of cases, necroinflammatory activity and fibrosis coexist [nonalcoholic steatohepatitis (NASH)]; furthermore, cirrhosis and liver failure may occur in 20% to 25% of affected individuals (1, 2). Nowadays, NAFLD represents the most common cause of chronic liver disease in developed countries (3), being detectable in 20% to 30% of the general population (4, 5) in almost 75% of patients with type 2 diabetes (T2D) (6, 7) and in up to 90% of obese individuals with T2D (8, 9). In dysmetabolic conditions, NAFLD worsens inflammatory and metabolic outcomes (10–12) and is associated with a greater prevalence and severity of microvascular and macrovascular complications in patients with T2D (13–15). Indeed, NAFLD is universally recognized as an independent risk factor for cardiovascular mortality (16). Nowadays, despite the impressively high number of pharmacological interventions proposed, the identification of an effective therapy of NAFLD beyond standard lifestyle measures is still an open issue and represents a major challenge (17).

Neurotensin (NT), a 13–amino acid peptide mainly secreted by neuroendocrine cells in the small intestine (18), displays an important role in regulating food ingestion and fat absorption (19). By doing so, NT influences energy balance and body weight (20). NT mainly acts as a neurotransmitter in the central nervous system and as a hormone in the periphery, exerting its physiological action by binding the specific NT receptors, NTSR1, NTSR12, and NTSR13 (21, 22). Experimental evidence has shown that the NT/NTSR1 system is involved in adaptive energy balance (23–25). Loss of the leptin action mediated by NT neurons coexpressing the long form of the leptin receptor determines overweight and impairs the ability to appropriately respond to energy deprivation in experimental mice (24), pointing out a crucial role of NT in mediating, among others, leptin (23–25) and ghrelin (25) pathways. Indeed, the leptin-mediated systems regulating appetite are controlled by NT-expressing neurons (23). In the periphery, NT influences body weight by controlling macronutrient absorption. Physiology studies have described an acute increase of intestinal NT release immediately after food ingestion, directly associated with meal fat content (26). In addition, several data have been produced on the role of NT in facilitating lipid digestion and fat absorption in the small intestine (27–29). The refined, complex control of energy balance exerted by NT at different levels provides a possible pathophysiological explanation about a correlation between its circulating levels and increased prevalence and incidence of obesity-related diseases (30, 31). In particular, within the large cohort of the Malmö Diet and Cancer Study (30), the fasting concentration of pro-NT, the circulating peptide secreted at equimolar levels to NT, was associated with the incidence of T2D, cardiovascular disease, breast cancer, and total and cardiovascular mortality (30). The association between pro-NT and incident major cardiovascular events has been confirmed in the Framingham Heart Study Offspring cohort, independently of the presence of traditional cardiovascular risk factors (31). Very recently, an extensive investigation on a putative causal role of NT in determining aberrant fat accumulation and metabolic diseases has been carried out (29), showing reduced intestinal fat absorption, along with protection from obesity and NAFLD, in NT-deficient mice fed with a high-fat diet. Furthermore, the same study demonstrated that in humans, higher plasma pro-NT levels were associated with features of insulin resistance and doubled the risk of developing obesity later in life in nonobese individuals.

Despite the strong rationale behind and encouraging evidence from animal models, little is known on circulating pro-NT levels and NAFLD/NASH in humans. Therefore, aims of this study were to investigate the relationship between plasma NT concentration and the presence and severity of NAFLD/NASH in adult obese individuals with or without T2D and to determine clinical correlates of impaired NT levels in this population.

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