An obligatory role for neurotensin in high-fat-diet-induced obesity

Abstract

Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

The relationship between hepatocytes and small bowel after early and short food restriction: What the results show in morphometry

“…Contrarily, some studies document connections between the small bowel and liver. In one study it was posited that obesity can be connected with neurotensin, which is predominantly localized in entero-endocrine cells of the small bowel (13). Another study shows that patients with intestinal failure commonly develop abnormal liver function tests (14).…”

Determination of neurotensin projections to the ventral tegmental area in mice

“…In contrast, the caudal “tail” of the VTA that forms a continuum with the rostromedial tegmental nucleus (RMTg) is enriched with GABA-ergic neurons, which inhibit VTA DA neurons and serve as negative regulators of DA-mediated behaviors (Carr and Sesack, 2000; Margolis et al, 2012; Tan et al, 2012; van Zessen et al, 2012). Given that alterations in both VTA DA and Nts signaling have been implicated in the pathogenesis of drug addiction, depression, anxiety, schizophrenia, autism, pain processing and obesity, there is likely functional overlap of these systems (Boules et al, 2014; Caceda et al, 2012; Carey et al, 2017; Ellenbroek et al, 2016; Ferraro et al, 2016; Fitzpatrick et al, 2012; Howes et al, 2017; Kim and Mizuno, 2010; Li et al, 2016; Nestler and Carlezon Jr, 2006; Rothwell, 2016; Theoharides et al, 2016; Volkow et al, 2013). It is therefore critical to define the precise neural mechanisms by which Nts engages the VTA, to understand how it regulates such diverse physiology and how Nts signaling becomes maladaptive in disease.…”

Targeting the gut to treat obesity and its metabolic consequences: view from the Chair

“…14 Recent evidence supports the idea that these cells have a central role in the expression of diet-induced obesity and that gut peptides have a critical role in the control of hunger, satiety, glucose metabolism, metabolic and nutrient sensing. 5,14,[17][18][19] The subpopulation of enteroendocrine cells that contain and release serotonin (5-HT) are also involved in the stimulation of propulsive and segmental motility, epithelial secretion and vasodilation, as well as nausea and vomiting, and recent evidence supports a proinflammatory action of enteroendocrine 5-HT. 20 Enteroendocrine cells release their contents basolaterally into the lamina propria where they can enter the mucosal microcirculation and lymphatic systems, and they can interact with the dense innervation that lies beneath the epithelium.…”

“…14 Recent evidence supports the idea that these cells have a central role in the expression of diet-induced obesity and that gut peptides have a critical role in the control of hunger, satiety, glucose metabolism, metabolic and nutrient sensing. 5,14,[17][18][19] The subpopulation of enteroendocrine cells that contain and release serotonin (5-HT) are also involved in the stimulation of propulsive and segmental motility, epithelial secretion and vasodilation, as well as nausea …”