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Review
. 2022 Feb 17;23(4):2209.
doi: 10.3390/ijms23042209.

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

Ilaria Barchetta  1 , Marco Giorgio Baroni  2   3 , Olle Melander  4   5 , Maria Gisella Cavallo  1
Affiliations
Review

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

Ilaria Barchetta et al. Int J Mol Sci. .

Abstract

Neurotensin (NT) is a small peptide with pleiotropic functions, exerting its primary actions by controlling food intake and energy balance. The first evidence of an involvement of NT in metabolism came from studies on the central nervous system and brain circuits, where NT acts as a neurotransmitter, producing different effects in relation to the specific region involved. Moreover, newer interesting chapters on peripheral NT and metabolism have emerged since the first studies on the NT-mediated regulation of gut lipid absorption and fat homeostasis. Intriguingly, NT enhances fat absorption from the gut lumen in the presence of food with a high fat content, and this action may explain the strong association between high circulating levels of pro-NT, the NT stable precursor, and the increased incidence of metabolic disorders, cardiovascular diseases, and cancer observed in large population studies. This review aims to provide a synthetic overview of the main regulatory effects of NT on several biological pathways, particularly those involving energy balance, and will focus on new evidence on the role of NT in controlling fat homeostasis, thus influencing the risk of unfavorable cardio-metabolic outcomes and overall mortality in humans.

Keywords: NAFLD; fatty liver; gastrointestinal hormones; gut peptides; insulin resistance; neurotensin; obesity; type 2 diabetes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The mechanisms of increased lipid absorption from the gut lumen mediated by intestinal neurotensin. Elevated FA concentrations in the intestinal lumen and the link between LCFAs /MCFAs and FFAR1/FFAR4 lead to increased intracellular Ca2+ concentrations in enteroendocrine cells, signaling cascade activation and the secretion of NT. NT directly promotes FA uptake by inhibiting AMPK, and indirectly by favoring bile acids’ absorption though several mechanisms. See Section 3.1, Section 3.2 and Section 3.3 for detailed descriptions and references. Abbreviations: AMPK: 5′ adenosine monophosphate-activated protein kinase; ASBT: apical sodium-dependent bile acid transporter; FA: fatty acid; FFAR1: free fatty acid receptor 1; FFAR4: free fatty acid receptor 4; FXR: farnesoid X receptor; LCFA: long-chain fatty acid; MCFA: medium-chain fatty acid; NT: neurotensin; NTSR1: neurotensin receptor 1; NTSR3: neurotensin receptor 3.
Figure 2
Figure 2
NT in metabolic diseases: potential direct and indirect mechanisms linking high NT to metabolic impairment and cardiovascular disease. Bold arrows indicate direct NT effects, dotted arrows show indirect NT influences on cardio-metabolic risk factors. Abbreviations: CRH: corticotropin-releasing hormone; CVD: cardiovascular disease; HCC: hepato-cellular carcinoma; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; NT: neurotensin; NTSR1: neurotensin receptor 1; TRH: thyrotropin-releasing hormone.
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