Mediobasal hypothalamic leucine sensing regulates food intake through activation of a hypothalamus-brainstem circuit.
In response to nutrient stimuli, the mediobasal hypothalamus (MBH) drives multiple neuroendocrine and behavioral mechanisms to regulate energy balance. While central leucine reduces food intake and body weight, the specific neuroanatomical sites of leucine sensing, downstream neural substrates, and neurochemical effectors involved in this regulation remain largely unknown. Here we demonstrate that MBH leucine engages a neural energy regulatory circuit by stimulating POMC (proopiomelanocortin) neurons of the MBH, oxytocin neurons of the paraventricular hypothalamus, and neurons within the brainstem nucleus of the solitary tract to acutely suppress food intake by reducing meal size. We identify central p70 S6 kinase and Erk1/2 pathways as intracellular effectors required for this response. Activation of endogenous leucine intracellular metabolism produced longer-term reductions in meal number. Our data identify a novel, specific hypothalamus-brainstem circuit that links amino acid availability and nutrient sensing to the control of food intake.
Blouet
Clémence
C
Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.
Jo
Young-Hwan
YH
Li
Xiaosong
X
Schwartz
Gary J
GJ
D000818:Animals; D000855:Anorexia / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D001933:Brain Stem / Q000502:physiology*; D002070:Butadienes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004435:Eating / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D007031:Hypothalamus / Q000033:anatomy & histology / Q000378:metabolism*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular / Q000379:methods; D007651:Keto Acids / Q000494:pharmacology; D007930:Leucine / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D053486:Melanocortins / Q000378:metabolism; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010121:Oxytocin / Q000037:antagonists & inhibitors / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013912:Threonine / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D014668:Vasotocin / Q000494:pharmacology
D002070:Butadienes; D004791:Enzyme Inhibitors; D007651:Keto Acids; D053486:Melanocortins; D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos; C113580:U 0126; D049452:Green Fluorescent Proteins; C103272:SHU 9119; D013912:Threonine; D014443:Tyrosine; D010121:Oxytocin; D011333:Pro-Opiomelanocortin; C013082:alpha-ketoisocaproic acid; D009074:Melanocyte-Stimulating Hormones; D052005:Bone Morphogenetic Protein Receptors, Type I; D007930:Leucine; D014668:Vasotocin