Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders

Abstract

The peptide neurotensin (Nts) was discovered within the brain over 40 years ago and is implicated in regulating analgesia, body temperature, blood pressure, locomotor activity and feeding. Recent evidence suggests, however, that these disparate processes may be controlled via specific populations of Nts neurons and receptors. The neuronal mediators of Nts anorectic action are now beginning to be understood, and, as such, modulating specific Nts pathways might be useful in treating feeding and body weight disorders. This review considers mechanisms through which Nts normally regulates feeding and how disruptions in Nts signaling might contribute to the disordered feeding and body weight of schizophrenia, Parkinson’s disease, anorexia nervosa, and obesity. Defining how Nts specifically mediates feeding vs. other aspects of physiology will inform the design of therapeutics that modify body weight without disrupting other important Nts-mediated physiology.

Distinct Subsets of Lateral Hypothalamic Neurotensin Neurons are Activated by Leptin or Dehydration

“…For example, some LHA Nts neurons are activated by LPS-mediated inflammation and inhibit local orexin/hypocretin neurons, and these may contribute to illness-behavior 43 . Nts signaling is also implicated in regulation of analgesia, thermoregulation, stress and addiction 44 , so it will be important to determine if/how the remaining LHA Nts neurons contribute to these diverse aspects of physiology. Characterizing the heterogeneity of LHA Nts neurons may also suggest intersectional or pharmacological strategies to target specific subpopulations of LHA Nts neurons, and hence selective physiological outputs.…”

“…LHA neurons project widely throughout the brain and differentially modify behavior depending on their targets 44 . Our finding that Nts LepRb neurons, and not Nts Dehy neurons, project to the midbrain suggests that there are distinct LHA Nts neural mechanisms for leptin-mediated suppression of feeding vs. regulation of drinking and fluid balance.…”

Determination of neurotensin projections to the ventral tegmental area in mice

“…Given that such different behaviors were regulated by the POA Nts vs. LHA Nts neurons, it seems likely that their released signals are mediated via different subsets of VTA neurons, and possibly via a different Nts receptor isoform. Based on these data, it is tempting to speculate that Nts afferents from other regions might engage specific VTA cells to mediate other behaviors ascribed to Nts, such as analgesia or to attenuate the reinforcing effects of drugs of abuse (Schroeder and Leinninger, 2017). …”

Conformational transitions of a neurotensin receptor 1–Gi1 complex

“…Neurotensin (NTS) is a 13-amino-acid peptide (ELYENKPRRPYIL) 1 working as a neurotransmitter/neuromodulator in the brain and as a hormone in the peripheral organs, mainly in the gastrointestinal tract 2 . NTS regulates a wide range of physiological processes and is associated with the pathogenesis of diverse conditions, including hypotension, hypothermia, obesity, analgesia, drug addiction, cancer cell growth, Parkinson's disease and schizophrenia [3][4][5][6] . Three different neurotensin receptors (NTSRs) have been cloned so far [7][8][9][10] , with most of the biological effects of NTS mediated through neurotensin receptor 1 (NTSR1) 11 .…”