title: Euglycemia Restoration by Central Leptin in Type 1 Diabetes Requires STAT3 Signaling but Not Fast-Acting Neurotransmitter Release.
abstract: Central leptin action is sufficient to restore euglycemia in insulinopenic type 1 diabetes (T1D); however, the underlying mechanism remains poorly understood. To examine the role of intracellular signal transducer and activator of transcription 3 (STAT3) pathways, we used LepRs/s mice with disrupted leptin-phosphorylated STAT3 signaling to test the effect of central leptin on euglycemia restoration. These mice developed streptozocin-induced T1D, which was surprisingly not associated with hyperglucagonemia, a typical manifestation in T1D. Further, leptin action on euglycemia restoration was abrogated in these mice, which was associated with refractory hypercorticosteronemia. To examine the role of fast-acting neurotransmitters glutamate and γ-aminobutyric acid (GABA), two major neurotransmitters in the brain, from leptin receptor (LepR) neurons, we used mice with disrupted release of glutamate, GABA, or both from LepR neurons. Surprisingly, all mice responded normally to leptin-mediated euglycemia restoration, which was associated with expected correction from hyperglucagonemia and hyperphagia. In contrast, mice with loss of glutamate and GABA appeared to develop an additive obesity effect over those with loss of single neurotransmitter release. Thus, our study reveals that STAT3 signaling, but not fast-acting neurotransmitter release, is required for leptin action on euglycemia restoration and that hyperglucagonemia is not required for T1D.
authors.affiliation: Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX.
authors.forename: Yuanzhong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX Department of Integrative Biology and Pharmacology of McGovern Medical School and School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Departments of Internal Medicine and Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.affiliation: Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX qingchun.tong@uth.tmc.edu.
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Tong
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000378:metabolism*; D057967:Infusions, Intraventricular; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D020738:Leptin; D018377:Neurotransmitter Agents; D050796:STAT3 Transcription Factor; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse
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