Loss of neurotensin receptor-1 disrupts the control of the mesolimbic dopamine system by leptin and promotes hedonic feeding and obesity

Opland, Darren M.; Sutton, Amy K.; Woodworth, Hillary L.; Brown, Juliette A.; Bugescu, Raluca; Garcia, Adriana; Christensen, Lyndsay; Rhodes, Christopher J.; Myers, Martin G.; Leinninger, Gina M.

doi:10.1016/j.molmet.2013.07.008

Cited by 108 publications

(116 citation statements)

References 73 publications

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…NT exerts its pleiotropic biological actions via three NT receptors; NTR1, NTR2, and NTR3, that are widely distributed with the brain and peripherally. Central NT administration reduces energy intake via the NTR1 45 and is implicated in controlling food reward interacting with the dopaminergic system and leptin 46 . GI NT is released in response to nutrient-ingestion, in particular to fat, and regulates GI motility, pancreatic and biliary secretion, facilitates fat translocation and acts as an incretin.…”

Section: Neurotensin (Nt)mentioning

confidence: 99%

The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance

Monteiro

Batterham

2017

Gastroenterology

View full text Add to dashboard Cite

The gastrointestinal (GI) tract, the key interface between ingested nutrients and the body, plays a critical role in regulating energy homeostasis. Gut-derived signals convey information regarding incoming nutrients to the brain, initiating changes in eating behavior and energy expenditure, to maintain energy balance. Here we review hormonal, neural and nutrient signals emanating from the GI tract and evidence for their role in controlling feeding behavior. Mechanistic studies that have utilized pharmacological and/or transgenic approaches targeting an individual hormone/mediator have yielded somewhat disappointing bodyweight changes, often leading to the hormone/mediator in question being dismissed as a potential obesity therapy. However, the recent finding of sustained weight-reduction in response to systemic administration of a long-acting analog of the gut-hormone glucagon-like peptide-1 (GLP-1) highlights the therapeutic potential of gut-derived signals acting via non-physiological mechanisms. Thus, we also review therapeutics strategies being utilized or developed to leverage GI signals in order to treat obesity.

show abstract

Section: Neurotensin (Nt)mentioning

confidence: 99%

The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance

Monteiro

Batterham

2017

Gastroenterology

View full text Add to dashboard Cite

show abstract

“…Recombinant mouse leptin was purchased from the National Hormone and Peptide Program (Los Angeles Biomedical Research Institute, Los Angeles, CA), and mice were treated with 5 mg/kg leptin via intraperitoneal (IP) injection; this leptin dose optimally identifies leptin-responsive LepRb neurons throughout the hypothalamus [12,23]. Recombinant rat ghrelin was purchased from the PolyPeptide Group (Torrance, CA).…”

Section: Reagentsmentioning

confidence: 99%

“…For example, there are leptinregulated Nts LepRb neurons and ghrelin-regulated OX neurons that each project to the dopaminerich ventral tegmental area (VTA) [20,21] and promote dopamine release to the nucleus accumbens (NAc) that can modify feeding and locomotor activity. Furthermore, leptin and ghrelin action via the LHA engages the dopamine signaling system to suppress or promote feeding, respectively [12,22,23]. Thus, there may be separate leptin and ghrelin-mediated LHA circuits to coordinate peripheral need and dopamine-mediated behaviors required to restore energy balance.…”

mentioning

confidence: 99%

Loss of Action via Neurotensin-Leptin Receptor Neurons Disrupts Leptin and Ghrelin-Mediated Control of Energy Balance

et al. 2017

Self Cite

View full text Add to dashboard Cite

The hormones ghrelin and leptin act via the lateral hypothalamic area (LHA) to modify energy balance, but the underlying neural mechanisms remain unclear. We investigated how leptin and ghrelin engage LHA neurons to modify energy balance behaviors and whether there is any crosstalk between leptin and ghrelin-responsive circuits. We demonstrate that ghrelin activates LHA neurons expressing hypocretin/orexin (OX) to increase food intake. Leptin mediates anorectic actions via separate neurons expressing the long form of the leptin receptor (LepRb), many of which coexpress the neuropeptide neurotensin (Nts); we refer to these as NtsLepRb neurons. Because NtsLepRb neurons inhibit OX neurons, we hypothesized that disruption of the NtsLepRb neuronal circuit would impair both NtsLepRb and OX neurons from responding to their respective hormonal cues, thus compromising adaptive energy balance. Indeed, mice with developmental deletion of LepRb specifically from NtsLepRb neurons exhibit blunted adaptive responses to leptin and ghrelin that discoordinate the mesolimbic dopamine system and ingestive and locomotor behaviors, leading to weight gain. Collectively, these data reveal a crucial role for LepRb in the proper formation of LHA circuits, and that NtsLepRb neurons are important neuronal hubs within the LHA for hormone-mediated control of ingestive and locomotor behaviors.

show abstract

“…164 AgRP and POMC neurons express LepRb, 165,166 which is also expressed on GABA neurons devoid of AgRP and NPY, but which might control POMC neuronal tone. 167 However, leptin can also act at the level of the DMH to modulate energy expenditure, 168 and exert effects at the LH level to modulate the corticomesolimbic dopamine circuit by stimulating neurotensin neurons, 169 which connect with VTA dopaminergic cells that reach to the ventral striatum. Leptin might also directly act on the VTA dopaminergic cells 170 and brainstem nuclei that include the PBN where it modulates food intake without affecting the incentive salience for food.…”

Section: Homeostatic Sensing and Signallingmentioning

confidence: 99%

Cognitive and autonomic determinants of energy homeostasis in obesity

Richard

2015

Nat Rev Endocrinol

View full text Add to dashboard Cite

Obesity ensues from an imbalance between energy intake and expenditure that results from gene-environment interactions, which favour a positive energy balance. A society that promotes unhealthy food and encourages sedentary lifestyle (that is, an obesogenic environment) has become a major contributory factor in excess fat deposition in individuals predisposed to obesity. Energy homeostasis relies upon control of energy intake as well as expenditure, which is in part determined by the themogenesis of brown adipose tissue and mediated by the sympathetic nervous system. Several areas of the brain that constitute cognitive and autonomic brain systems, which in turn form networks involved in the control of appetite and thermogenesis, also contribute to energy homeostasis. These networks include the dopamine mesolimbic circuit, as well as the opioid, endocannabinoid and melanocortin systems. The activity of these networks is modulated by peripheral factors such as hormones derived from adipose tissue and the gut, which access the brain via the circulation and neuronal signalling pathways to inform the central nervous system about energy balance and nutritional status. In this Review, I focus on the determinants of energy homeostasis that have emerged as prominent factors relevant to obesity.

show abstract

Loss of neurotensin receptor-1 disrupts the control of the mesolimbic dopamine system by leptin and promotes hedonic feeding and obesity

Cited by 108 publications

References 73 publications

The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance

The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance

Loss of Action via Neurotensin-Leptin Receptor Neurons Disrupts Leptin and Ghrelin-Mediated Control of Energy Balance

Cognitive and autonomic determinants of energy homeostasis in obesity

Contact Info

Product

Resources

About