title: Caloric restriction selectively reduces the GABAergic phenotype of mouse hypothalamic proopiomelanocortin neurons.
abstract: Hypothalamic proopiomelanocortin (POMC) neurons release peptide products that potently inhibit food intake and reduce body weight. These neurons also release the amino acid transmitter GABA, which can inhibit downstream neurons. Although the release of peptide transmitters from POMC neurons is regulated by energy state, whether similar regulation of GABA release might occur had not been examined. The present results show that the GABAergic phenotype of POMC neurons is decreased selectively by caloric deficit and not altered by high-fat diet or stress. The fact the GABAergic phenotype of POMC neurons is sensitive to energy state suggests a dynamic physiological role for this transmitter and highlights the importance of determining the functional consequence of GABA released from POMC neurons in terms of the regulation of normal energy balance.
  
  
  
  In addition to peptide transmitters, hypothalamic neurons, including proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons, also release amino acid transmitters that can alter energy balance regulation. While recent studies show that the GABAergic nature of AgRP neurons is increased by caloric restriction, whether the GABAergic phenotype of POMC neurons is also regulated in an energy-state-dependent manner has not been previously examined. The present studies used fluorescence in situ hybridization to detect Gad1 and Gad2 mRNA in POMC neurons, as these encode the glutamate decarboxylase enzymes GAD67 and GAD65, respectively. The results show that both short-term fasting and chronic caloric restriction significantly reduce the percentage of POMC neurons expressing Gad1 mRNA in both male and female mice, with less of an effect on Gad2 expression. Neither acute nor chronic intermittent restraint stress altered Gad1 expression in POMC neurons. Maintenance on a high-fat diet also did not affect the portion POMC neurons expressing Gad1, suggesting that the GABAergic phenotype of POMC neurons is particularly sensitive to energy deficit. Because changes in Gad1 expression have been previously shown to correlate with altered terminal GABA release, fasting is likely to cause a decrease in GABA release from POMC neurons. Altogether, the present results show that the GABAergic nature of POMC neurons can be dynamically regulated by energy state in a manner opposite to that in AgRP neurons and suggest the importance of considering the functional role of GABA release in addition to the peptide transmitters from POMC neurons.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Brooke C
authors.initials: BC
authors.lastname: Jarvie
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, 80253, USA.
authors.forename: Connie M
authors.initials: CM
authors.lastname: King
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, 80253, USA.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Hughes
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, 80253, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Dicken
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, 80253, USA.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Dennison
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, 80253, USA.
authors.forename: Shane T
authors.initials: ST
authors.lastname: Hentges
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D059305:Diet, High-Fat; D005260:Female; D059330:GABAergic Neurons / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000235:genetics; D007031:Hypothalamus / Q000166:cytology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology; D010641:Phenotype; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D011333:Pro-Opiomelanocortin; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2
keywords: amino acid transmitter; arcuate nucleus; energy balance