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Age-dependent changes in amino acid phenotype and the role of glutamate release from hypothalamic proopiomelanocortin neurons.

ABSTRACT: Hypothalamic proopiomelanocortin (POMC) neurons are important regulators of energy balance. Recent studies indicate that in addition to their peptides, POMC neurons can release either the amino acid (AA) transmitter gamma-aminobutyric acid (GABA) or glutamate. A small subset of POMC neurons appears to have a dual AA phenotype based on coexpression of mRNA for the vesicular glutamate transporter (vGlut2) and the GABA synthetic enzyme Gad67. To determine whether the colocalization of GABAergic and glutamatergic markers may be indicative of a switch in AA transmitter phenotype, fluorescent in situ hybridization was used to detect vGlut2 and Gad mRNA in POMC neurons during early postnatal development. The percentage of POMC neurons expressing vGlut2 mRNA in POMC neurons progressively decreased from ?40% at day 1 to less than 10% by 8 weeks of age, whereas Gad67 was only expressed in ?10% of POMC neurons at day 1 and increased until ?45% of POMC neurons coexpressed Gad67 at 8 weeks of age. To determine whether the expression of vGlut2 may play a role in energy balance regulation, genetic deletion of vGlut2 in POMC neurons was accomplished using Cre-lox technology. Male, but not female, mice lacking vGlut2 in POMC neurons were unable to maintain energy balance to the same extent as control mice when fed a high-fat diet. Altogether, the results indicate that POMC neurons are largely glutamatergic early in life and that the release of glutamate from these cells is involved in sex- and diet-specific regulation of energy balance.

SUBMITTER: Dennison CS

PROVIDER: S-EPMC4747788 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Age-dependent changes in amino acid phenotype and the role of glutamate release from hypothalamic proopiomelanocortin neurons.

Dennison Christina S CS King Connie M CM Dicken Matthew S MS Hentges Shane T ST

The Journal of comparative neurology 20150928 6

Hypothalamic proopiomelanocortin (POMC) neurons are important regulators of energy balance. Recent studies indicate that in addition to their peptides, POMC neurons can release either the amino acid (AA) transmitter gamma-aminobutyric acid (GABA) or glutamate. A small subset of POMC neurons appears to have a dual AA phenotype based on coexpression of mRNA for the vesicular glutamate transporter (vGlut2) and the GABA synthetic enzyme Gad67. To determine whether the colocalization of GABAergic and ...[more]

PMID: 26361382

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Project description:ObjectiveProopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus are essential regulators of energy balance. Selective loss of POMC production in these cells results in extreme obesity and metabolic comorbidities. Neurogenesis occurs in the adult hypothalamus, but it remains uncertain whether functional POMC neurons emerge in physiologically significant numbers during adulthood. Here, we tested whether Rax-expressing precursors generate POMC neurons in adult mice and rescue the metabolic phenotype caused by congenital hypothalamic POMC deficiency.MethodsInitially, we identified hypothalamic Rax-expressing cell types using wild-type and Rax-CreERT2:Ai34D mice. Then we generated compound Rax-CreERT2:ArcPomcloxTB/loxTB mice in which endogenous hypothalamic Pomc expression is silenced, but can be restored by tamoxifen administration selectively in neurons derived from Rax+ progenitors. The number of POMC neurons generated by Rax+ progenitors in adult mice and their axonal projections was determined. The metabolic effects of these neurons were assessed by measuring food intake, bodyweight, and body composition, along with glucose and insulin levels.ResultsWe found that Rax is expressed by tanycytes and a previously unrecognized cell type in the hypothalamic parenchyma of adult mice. Rax+ progenitors generated ~10% of the normal adult hypothalamic POMC neuron population within two weeks of tamoxifen treatment. The same rate and steady state of POMC neurogenesis persisted from young adult to aged mice. These new POMC neurons established terminal projections to brain regions that were involved in energy homeostasis. Mice with Rax+ progenitor-derived POMC neurons had reduced body fat mass, improved glucose tolerance, increased insulin sensitivity, and decreased bodyweight in proportion to the number of new POMC neurons.ConclusionsThese data demonstrate that Rax+ progenitors generate POMC neurons in sufficient numbers during adulthood to mitigate the metabolic abnormalities of hypothalamic POMC-deficient mice. The findings suggest that adult hypothalamic neurogenesis is a robust phenomenon in mice that can significantly impact energy homeostasis.

Dataset Information

Age-dependent changes in amino acid phenotype and the role of glutamate release from hypothalamic proopiomelanocortin neurons.

Publications

Age-dependent changes in amino acid phenotype and the role of glutamate release from hypothalamic proopiomelanocortin neurons.

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