A Multifaceted Neuropeptide in Appetite Regulation and Fat Metabolism

Neurotensin is a 13-amino acid neuropeptide. You can find it both in the Central Nervous System, where it's released by Neurotensin Neurons, and in the epithelial cells of the gastrointestinal tract. Back in 1973, Leeman and Carraway discovered its presence in the Bovine Hypothalamus. Studies have shown that Neurotensin's effects differ depending on whether it's secreted centrally or peripherally.

Neurotensin is involved in a bunch of different bodily functions like temperature regulation, Pituitary Hormone secretion, tension regulation, and vascular permeability. There are three known Neurotensin receptors: NTR1, NTR2, and NTR3. These receptors recognize the C-terminal 8-13 fragment of the neuropeptide and mediate its actions.

When we talk about appetite, we generally mean the desire for food. Feeding behavior is a major survival response, mainly regulated in the Central Nervous System. Various hormones are secreted and can either stimulate appetite (orexigenic hormones) or reduce it (anorexigenic hormones). It's crucial to regulate energy homeostasis to control body weight.

Neurotensin’s Role in Appetite Regulation

Neurotensin has a role in appetite regulation. Since its discovery, many studies have highlighted neurotensin’s anorexigenic role. Pharmacological studies showed that administering exogenous Neurotensin reduced food intake. This suggests that increasing Neurotensin levels in the body might enhance its physiological roles. But, the amount of Neurotensin injected must be controlled to avoid disrupting its natural functions.

Remaury A. et al. focused on inactivating Neurotensin Receptor 1 (NTR1) to identify neurotensin’s role in appetite regulation. They studied mice with NTR1 (NTR1+/+ mice) and Knockout mice without NTR1 (NTR1-/- mice). NTR1-/- mice ate more food than NTR1+/+ mice, resulting in significant weight gain. This indicates that the absence of NTR1 increases food consumption. Additionally, administering 10ng of Neurotensin (in the right intracerebral lateral ventricle) decreased food consumption in NTR1+/+ mice, but not in NTR1-/- mice. This shows that Neurotensin binding to NTR diminishes food intake.

Neurotensin’s role in appetite regulation is also linked to leptin’s action, as shown by Sahu A. et al. Leptin, an anorexigenic hormone, is secreted by adipose cells and regulates fat mass in the body. Food-deprived rats were injected with either control rabbit serum or Neurotensin-Antiserum (NT-AS). They were then given 4ug of leptin, and food consumption was measured. Rats administered with leptin and NT-AS consumed more food compared to the control, suggesting that NT-AS reversed leptin’s anorectic action. This implies that Neurotensin might be involved in leptin’s appetite-regulating functions.

To dig deeper, another experiment was done. Rats were given Leptin and either 40ug/Kg of the neurotensin-receptor (NTR) antagonist SR48692 or a vehicle-control. An increase in food consumption was observed in rats given the NTR-antagonist compared to the vehicle. Moreover, rats only given SR48692 (without Leptin) showed no change in food consumption compared to the vehicle. This indicates that the NTR-antagonist alone did not influence food consumption. Therefore, the NTR-antagonist reversed Leptin’s action on food consumption, showing that Leptin and Neurotensin work together to reduce appetite.

Another study by Ratner C. et al. looked at Neurotensin’s function in Roux-en-Y Gastric Bypass Surgery (RYGB). This surgery is a common operation for obese individuals, reducing stomach volume and decreasing appetite. Neurotensin expression was measured in the gastrointestinal tract of RYGB-rats and sham-operated rats (sham-rats). RYGB-rats weighed less and had higher Neurotensin gene expression. Both groups were then given Neurotensin-Antagonist SR142848A, leading to increased food consumption and body weight in RYGB-rats compared to sham-rats. These findings support Neurotensin's role as an appetite-regulator in Gastric Bypass Surgery.

Although many studies confirm neurotensin’s anorexigenic effect, it's essential to consider Neurotensin secretion. Neurotensin is produced by several Neurotensin Neurons in the Central Nervous System. Neurotensin secreted in the Nucleus Accumbens doesn’t affect appetite and feeding behavior, unlike Neurotensin from neurons in the Ventral Tegmental Area or the Lateral Hypothalamic area. Therefore, Neurotensin's role as an appetite-reducing neuropeptide depends on its secretion site. More research is needed to identify the specific Neurotensin-Neurons involved in appetite regulation.

It's also crucial to consider the condition of starvation. Neurotensin’s anorexigenic role is particularly effective in fasting-induced feeding but less evident in homeostatic feeding.

Neurotensin’s Role in Fat Metabolism

Besides its role in appetite, Neurotensin’s function in fat metabolism has been studied. Neurotensin is involved in lipid absorption in the gastrointestinal tract. After a high-fat diet, lipid absorption was significantly lower without neurotensin. Li J. et al. examined neurotensin’s role in lipid absorption in mice exposed to high-fat diets. They studied wild-type mice (NT+/+ mice) and NT-deficient mice (NT-/- mice). NT-/- mice had smaller fat pads and lower body weight when exposed to a high-fat diet. This suggests that NT-deficiency decreases body fat. NT-/- mice also had 25% higher triglyceride fecal content, indicating decreased lipid absorption. Administering SR48692, a neurotensin-receptor 1 (NTR1) antagonist, to NT+/+ mice and giving them olive oil showed decreased fatty-acid absorption. This confirms neurotensin's role in fat absorption.

Insulin is another major regulator of lipid metabolism. It plays roles in fatty-acid synthesis and lipid breakdown. Béraud-Dufour S. et al. studied neurotensin’s effect on insulin secretion. Rat pancreatic islets and insulin-secreting beta-cells were exposed to 0.1uM Neurotensin and glucose at two concentrations (2mM and 20mM). Neurotensin increased insulin secretion in cells exposed to 2mM glucose but significantly decreased insulin-secretion in cells exposed to 20uM glucose. This suggests that Neurotensin regulates insulin-secretion, indirectly affecting lipid metabolism. Neurotensin increases insulin-secretion at low glucose levels, promoting fatty-acid synthesis and fat accumulation. At higher glucose levels, it decreases insulin-secretion, reducing fatty-acid production and fat accumulation.

In conclusion, Neurotensin's role in appetite has been well-studied, showing its anorexigenic effect. Fewer studies have investigated its role in fat metabolism, but it increases fat absorption and regulates insulin secretion. Further research is needed to fully understand Neurotensin’s role in appetite and fat metabolism.

References:

• 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.
• Sahu, A. (2002). Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. Frontiers in Neuroendocrinology, 23(3), 225-253.
• Vincent, J. P., & Mazella, J. (1999). Kitabgi, P: Neurotensin and neurotensin receptors. Trends in Pharmacological Sciences, 20(7), 302-309.
• 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.
• Sahu, A., Kalra, P. S., & Crowley, W. R. (1988). Evidence that neurotensin mediates the central effect of leptin on food intake in rat. Brain Research, 438(1-2), 106-112.
• Opland, D. M., Leinninger, G. M., & Myers Jr, M. G. (2010). Modulation of the mesolimbic dopamine system by leptin. Brain Research, 1350, 65-70.
• 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.
• 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.