title: Melanocortin-3 receptors expressed in Nkx2.1(+ve) neurons are sufficient for controlling appetitive responses to hypocaloric conditioning.
abstract: Melanocortin-3 receptors (MC3R) have a contextual role in appetite control that is amplified with hypocaloric conditioning. C57BL/6J (B6) mice subjected to hypocaloric feeding schedules (HFS) exhibit compulsive behavioral responses involving food anticipatory activity (FAA) and caloric loading following food access. These homeostatic responses to calorie-poor environs are attenuated in B6 mice in which Mc3r transcription is suppressed by a lox-stop-lox sequence in the 5'UTR (Mc3rTB/TB). Here, we report that optimization of caloric loading in B6 mice subject to HFS, characterized by increased meal size and duration, is not observed in Mc3rTB/TBmice. Analysis of hypothalamic and neuroendocrine responses to HFS throughout the light-dark cycle suggests uncoupling of hypothalamic responses involving appetite-stimulating fasting-responsive hypothalamic neurons expressing agouti-related peptide (AgRP) and neuropeptide Y (Npy). Rescuing Mc3rs expression in Nkx2.1(+ve) neurons is sufficient to restore normal hypothalamic responses to negative energy balance. In addition, Mc3rs expressed in Nkx2.1(+ve) neurons are also sufficient to restore FAA and caloric loading of B6 mice subjected to HFS. In summary, MC3Rs expressed in Nkx2.1(+ve) neurons are sufficient to coordinate hypothalamic response and expression of compulsive behavioral responses involving meal anticipation and consumption of large meals during situations of prolonged negative energy balance.
authors.affiliation: Department of Pharmacology &Physiology, Saint Louis University, Saint Louis, MO 63104, USA.
authors.forename: Clémence
authors.initials: C
authors.lastname: Girardet
authors.affiliation: Department of Pharmacology &Physiology, Saint Louis University, Saint Louis, MO 63104, USA.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mavrikaki
authors.affiliation: Department of Pharmacology &Physiology, Saint Louis University, Saint Louis, MO 63104, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Stevens
authors.affiliation: Departments of Metabolism and Aging and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health &Science University, Portland, OR 97239, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Marks
authors.affiliation: Department of Pharmacology &Physiology, Saint Louis University, Saint Louis, MO 63104, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Butler
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics*; D000818:Animals; D001066:Appetite / Q000235:genetics; D002149:Energy Intake / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D006706:Homeostasis; D007031:Hypothalamus / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism; D009478:Neuropeptide Y / Q000235:genetics*; D017440:Photoperiod; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics*; D000074482:Thyroid Nuclear Factor 1 / Q000235:genetics
chemical_list: D054369:Agouti-Related Protein; D009478:Neuropeptide Y; C000614414:Nkx2-1 protein, mouse; D044104:Receptor, Melanocortin, Type 3; D000074482:Thyroid Nuclear Factor 1