A Multifaceted Neuropeptide in Appetite Regulation and Fat Metabolism

Neurotensin is a 13-amino acid neuropeptide present both in the Central Nervous System, where it is secreted by Neurotensin Neurons, and in the epithelial cells of the gastrointestinal tract. Its presence was first discovered in Bovine Hypothalamus by Leeman and Carraway3, in 1973. Several studies have investigated the functions of Neurotensin, and it has been showed that its effects are different whether it is secreted centrally or peripherally.

Neurotensin is involved in temperature regulation, Pituitary Hormone secretion1, tension regulation, and vascular permeability2. Three different Neurotensin receptors (NTR) have been discovered: NTR1, NTR2, and NTR3; these receptors recognise the C-terminal 8-13 fragment of the neuropeptide and mediate the actions of neurotensin3.

The term appetite is generally used to characterise the desire for food. Feeding behaviour represents a major survival response, and it has been shown that it is mostly regulated in the Central Nervous System2: several types of hormones are secreted and can induce either an appetite-stimulating response (orexigenic hormones) or an appetite-reducing response (anorexigenic hormones). Along with this survival response, it is important to regulate energy homeostasis, to control body weight.

We are therefore going to discuss the physiological role of Neurotensin in appetite regulation and fat metabolism.

To do so, we will first present neurotensin’s role in appetite. Successively, we will discuss its actions on fat metabolism.

Neurotensin plays a role in appetite regulation. In fact, since its discovery, several studies have been carried out, and neurotensin’s anorexigenic role has been highlighted2. Many studies investigated Neurotensin’s pharmacological effects, and it was proved that the administration of exogenous Neurotensin reduced food intake. This important pharmacological role could reflect one of neurotensin’s physiological function. Exogenous administration of neurotensin causes an increase in neurotensin’s normal levels in the body. Therefore, a higher amount of this neuropeptide could enhance its physiological roles. However, the amount of Neurotensin injected in the subjects tested must be controlled, to make sure not to inject an excessively high quantity that could, potentially, disrupt Neurotensin’s physiological roles.

Remaury A. et al4 (5) research focused on the inactivation of Neurotensin Receptor 1 (NTR1) to identify the neuropeptide’s role in appetite regulation. The study was carried out on mice expressing NTR1 (NTR1+/+ mice) and Knockout mice for NTR1 (NTR1-/- mice). It has been observed that NTR1-/- mice spontaneously consumed a higher quantity of food compared to the NTR1+/+ mice (10% increase in food consumption), which resulted in a significant increase in body weight. Therefore, this indicates that the absence of NTR induces an increase in food consumption. Furthermore, following the administration of 10ng of Neurotensin (in the right intracerebral lateral ventricle), a significant decrease in food consumption was observed in NTR1+/+ mice, and no changes were observed in NTR1-/- mice : Neurotensin, binding to NTR, diminished food-intake. The combination of these two observations witnesses the anorexigenic role of Neurotensin, mediated by NTR1: food consumption increases in mice lacking NTR1; when exogenous Neurotensin is injected, food consumption increases in mice expressing NTR1 (therefore, neurotensin binds to the receptor) and remains unchanged in mice lacking NTR1.

Neurotensin’s role in appetite regulation is also elucidated by its importance in leptin’s action: this has been investigated by a study conducted by Sahu A. et al5. (6). Leptin, an anorexigenic hormone, is secreted by adipose cells, and regulates fat mass in the body: the more fat is present, the more leptin is secreted, and appetite is reduced. Food-deprived rats were first injected either a control rabbit serum or Neurotensin-Antiserum (NT-AS). They were then administered 4ug of leptin, and food consumption was measured.A significant increase in food consumption was observed in rats administered with leptin and NT-AS compared to the control. Therefore, NT-AS reversed leptin’s anorectic action: this suggests that Neurotensin might be involved in leptin’s appetite-regulating functions.

To further investigate this observation, a second experiment was performed. The rats were administered Leptin as well as either 40ug/Kg of the neurotensin-receptor (NTR) antagonist SR48692 or a vehicle-control. An increase in food consumption has been observed in the rats given the NTR-antagonist compared to the rats administered the vehicle. Furthermore, rats who were only given SR48692 (without Leptin) did not show any change in food consumption compared to the vehicle, showing that the NTR-antagonist alone did not have any influence in food consumption. The NTR-antagonist has, therefore, reversed the action of Leptin on food consumption. This study highlights that Leptin and Neurotensin act together to reduce appetite. Neurotensin seems necessary for Leptin to induce its anorexigenic effect.

Finally, Neurotensin’s physiological role in appetite has also been investigated in a research-paper conducted by Ratner. C et al1 (2). This study focuses in particular on Neurotensin’s function in Roux-en-Y Gastric Bypass Surgery (RYGB). Gastric Bypass Surgery is a surgical operation, mostly conducted in obese individuals, that consists in reducing the volume of the stomach, and is particularly characterized by a decrease in appetite. Relative-Neurotensin expression was measured in the gastrointestinal tract (using qPCR) in rats who underwent RYGB (RYGB-rats) and in sham-operated rats (sham-rats) (the rats were given approximatively 15g of chow per day). RYBG-rats weighted less that sham-rats and Neurotensin gene-expression was significantly higher in RYGB-rats. Furthermore, both cohorts of rats were administered Neurotensin-Antagonist SR142848A: an increase in food consumption and body weight was observed in RYBG-rats compared to sham-rats. These observations, therefore, support the role of Neurotensin as an appetite-regulator neuropeptide in Gastric Bypass Surgery.

Although several studies confirm the general neurotensin’s anorexigenic effect, it is important to consider the Neurotensin-secreting. Neurotensin is produced by several NeurotensinNeurons, located in the Central Nervous System. Neurotensin that is secreted in the Nucleus Accumbens seems to not affect appetite and feeding behavior, as opposed to Neurotensin secreted by neurons located in the Ventral Tegmental Area, or the Lateral Hypothalamic area6. Therefore, Neurotensin-role as an appetite-reducing neuropeptide seems to be dependent on the site of secretion: further research is needed to identify more precisely the Neurotensin-Neurons that exert a role in appetite.

It is crucial to take into account the condition in which starvation occurs. It was showed that Neurotensin’s anorexigenic role is particularly effective in fasting-induced feeding but less evident in homeostatic feeding (assumption of food to regulate energy)2.

Along with its role in appetite, Neurotensin’s physiological function in fat metabolism has been investigated.

It has been shown that Neurotensin is involved in lipid absorption in the gastrointestinal tract. After exposure to a diet containing an important amount of fats, lipid absorption was significantly lower in the absence of neurotensin. A study conducted by Li J. et al 7 examined neurotensin’s function in lipid absorption, in mice exposed to High-fat diets (60% kcal from fat). Two cohorts of mice were studied: wild-type mice (expressing Neurotensin (NT), called NT+/+ mice) and NT-deficient mice (NT-/- mice). When exposed to a high-fat diet, NT-/- mice’s epididymal, retroperitoneal, and pericardiac fat pads were smaller compared to NT+/+ mice: this resulted in lower body weight for NT-/- mice. NT-deficiency seems to decrease the amount of fat in the body. Successively, Neurotensin’s action on intestinal lipid absorption was investigated. NT-/- mice’s triglycerides fecal content was 25% higher compared to the wild-type mice, indicating a decrease in lipid absorption. To confirm this observation, the mice were administered SR48692, a neurotensin-receptor 1 (NTR1) antagonist, and given olive oil, rich in fatty-acids. A decrease in fatty-acids absorption was observed in NT+/+ mice. When NTR1 is blocked (by the antagonist), Neurotensin is not able to exert its function anymore: lipids are less absorbed, evidencing neurotensin’s role in fat absorption.

Insulin represents another major regulator of lipid metabolism. Among other functions, it exerts different roles in fatty-acids synthesis and lipid breakdown. Béraud-Dufour s. et al 8 ‘s study aimed at analyzing neurotensin’s pharmacological effect on insulin secretion. Isolated rat pancreatic islets and insulin-secreting beta-cells were first exposed to 0.1uM Neurotensin and glucose, at two different concentrations (2mM and 20mM). A similar trend was observed after a 45 minutes incubation in both populations. While Neurotensin increased insulin secretion in cells exposed to 2mM glucose, it significantly decreased insulin-secretion in cells exposed to 20uM glucose. Therefore, because Neurotensin seems to regulate insulin-secretion, it is involved, although indirectly, in lipid metabolism (through insulin’s effects). This observation, however, suggests that Neurotensin’s action on insulin is not fully understood. If glucose is given at low doses, Neurotensin increases insulin-secretion, which, therefore, promotes fatty-acid synthesis, and stimulates the accumulation of fat in adipose tissues. On the other hand, if glucose is administered at higher doses, Neurotensin has the opposite effect: it decreases insulin-secretion, which results in reduced production of fatty-acids, and a decreased accumulation of fat in adipocytes.

In conclusion, we can confirm that the physiological role of neurotensin in appetite has been extensively investigated: several findings, most of them obtained via the study of neurotensin’s pharmacological role, suggests that this neuropeptide exerts an anorexigenic effect. Fewer studies were carried out to investigate its role in fat metabolism,but it was observed that neurotensin increases fat absorption and regulates insulin secretion. However, further studies are needed to deepen our understanding of neurotensin’s role in appetite and fat metabolism.  

References:

1. Leeman, S. E., & Carraway, R. E. (1973). Neurotensin: Discovery, isolation, characterization, synthesis, and possible physiological roles. Annals of the New York Academy of Sciences, 212(1), 7-25.
2. Sahu, A. (2002). Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. Frontiers in Neuroendocrinology, 23(3), 225-253.
3. Vincent, J. P., & Mazella, J. (1999). Kitabgi, P: Neurotensin and neurotensin receptors. Trends in Pharmacological Sciences, 20(7), 302-309.
4. Remaury, A., Vita, N., Gendreau, S., Jung, M., Arnone, M., Poncelet, M., ... & Ferrara, P. (2002). Targeted inactivation of the neurotensin type 1 receptor reveals its role in body temperature control and feeding behavior but not in analgesia. Brain Research, 953(1-2), 63-72.
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7. Li, J., Song, J., Zaytseva, Y. Y., Liu, Y., Rychahou, P., Jiang, K., ... & Evers, B. M. (2013). An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature Communications, 4, 2942.
8. Béraud-Dufour, S., Coppola, T., Massa, F., Mazella, J., & Vincent, J. P. (2009). Neurotensin receptor-2 and -3 are crucial for the anti-apoptotic effect of neurotensin on pancreatic beta-TC3 cells. International Journal of Molecular Medicine, 23(1), 41-47.