Loss of Action via Neurotensin-Leptin Receptor Neurons Disrupts Leptin and Ghrelin-Mediated Control of Energy Balance.
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.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824.|Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824.
Juliette A
JA
Brown
Department of Physiology, Michigan State University, East Lansing, Michigan 48824.
Raluca
R
Bugescu
Department of Physiology, Michigan State University, East Lansing, Michigan 48824.
Thomas A
TA
Mayer
Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109.
Adriana
A
Gata-Garcia
Department of Physiology, Michigan State University, East Lansing, Michigan 48824.
Gizem
G
Kurt
Department of Physiology, Michigan State University, East Lansing, Michigan 48824.
Hillary L
HL
Woodworth
Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824.|Department of Physiology, Michigan State University, East Lansing, Michigan 48824.
Gina M
GM
Leinninger
D000818:Animals; D004435:Eating / Q000187:drug effects / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics*; D005260:Female; D054439:Ghrelin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000378:metabolism; D057967:Infusions, Intraventricular; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009496:Neurotensin / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*
D054439:Ghrelin; D020738:Leptin; D054411:Receptors, Leptin; D009496:Neurotensin