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: Yuanzhong Xu, Jeffrey T Chang, Martin G Myers Jr, Yong Xu, Qingchun Tong
• Journal: Diabetes (Diabetes) Vol. 65 Issue 4 Pg. 1040-9 (04 2016) ISSN: 1939-327X [Electronic] United States
• PMID: 26822087 (Publication Type: Journal Article)
• Copyright: © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• Blood Glucose
• Leptin
• Neurotransmitter Agents
• STAT3 Transcription Factor
• Slc17a6 protein, mouse
• Vesicular Glutamate Transport Protein 2
• Vesicular Inhibitory Amino Acid Transport Proteins
• Viaat protein, mouse

Topics

• Animals
• Blood Glucose (drug effects, metabolism)
• Diabetes Mellitus, Experimental (blood, genetics, metabolism)
• Diabetes Mellitus, Type 1 (blood, metabolism)
• Infusions, Intraventricular
• Leptin (administration & dosage, pharmacology)
• Male
• Mice
• Mice, Transgenic
• Neurons (drug effects, metabolism)
• Neurotransmitter Agents (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects, physiology)
• Vesicular Glutamate Transport Protein 2 (genetics, metabolism)
• Vesicular Inhibitory Amino Acid Transport Proteins (genetics, metabolism)