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. 2016 Apr;65(4):1040-9.
doi: 10.2337/db15-1160. Epub 2016 Jan 28.

Euglycemia Restoration by Central Leptin in Type 1 Diabetes Requires STAT3 Signaling but Not Fast-Acting Neurotransmitter Release

Yuanzhong Xu  1 , Jeffrey T Chang  2 , Martin G Myers Jr  3 , Yong Xu  4 , Qingchun Tong  5
Affiliations

Euglycemia Restoration by Central Leptin in Type 1 Diabetes Requires STAT3 Signaling but Not Fast-Acting Neurotransmitter Release

Yuanzhong Xu et al. Diabetes. 2016 Apr.

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.

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Figures

Figure 1
Figure 1
Effect of central leptin infusion on glucose levels in T1D LIC:Vgatflox/flox and LIC:Vglut2flox/flox mice. A: Representative images of pancreata from non-T1D and T1D mice costained for insulin (red) and glucagon (green). Scale bars = 25 μm. Measurements for plasma glucose levels (B) and daily food intake (C). All data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. other groups (n = 5–8). icv, intracerebroventricular.
Figure 2
Figure 2
Effects of central leptin infusion on glucagon levels in T1D LIC:Vgatflox/flox and LIC:Vglut2flox/flox mice. A: Expression of pSTAT3 in the hypothalamus of the indicated mouse groups. Scale bars = 250 μm. f, fornix. Plasma levels of insulin (B) and glucagon (C) were measured at day 13 of the experiment. All data are presented as the mean ± SEM. **P < 0.01 vs. the other groups (n = 4–7).
Figure 3
Figure 3
Obesity in LIC:Vgatflox/flox:Vglut2 flox/flox mice. A and B: Weekly body weight changes in mice fed with normal chow in males (A) and females (B). **P < 0.01 vs. Vgatflox/flox:Vglut2flox/flox groups. C and D: Body mass changes were measured at 18 weeks old in males (C) and females (D). **P < 0.01, ***P < 0.001 vs. Vgatflox/flox:Vglut2flox/flox groups. All data are reported as the mean ± SEM. Males n = 8–12; females n = 5–8.
Figure 4
Figure 4
Effects of central leptin infusion in LIC:Vgatflox/flox:Vglut2flox/flox mice with T1D. A: Representative images of pancreata from non-T1D and T1D mice costained for insulin (red) and glucagon (green). Scale bars = 25 μm. B: Expression of pSTAT3 in the hypothalamus taken from LIC:Vgatflox/flox:Vglut2 flox/flox mice at day 13 of the experiment. Scale bar = 250 μm. f, fornix. C: Plasma glucose levels (n = 4–6). ***P < 0.001 vs. the other groups, #P < 0.05 vs. control/T1D/leptin group. D: Daily food intake (n = 5–6). *P < 0.05, **P < 0.01, #P < 0.05, ##P < 0.01 vs. control/T1D/saline group. E: Plasma insulin levels were measured at day 13 (n = 5). ***P < 0.001 vs. the other groups. Plasma glucagon (F) and corticosterone (G) levels were measured at day 13 (n = 5–6). *P < 0.05, **P < 0.01 vs. the other groups. All data are represented as the mean ± SEM. icv, intracerebroventricular.
Figure 5
Figure 5
Disruption of the LepR → STAT3 signaling pathway abrogated the antidiabetic effect of central leptin. A: Plasma glucose levels (n = 4–7). ***P < 0.001 vs. the other groups. B: Daily food intake (n = 4–7). **P < 0.01 vs. the other groups. C: Representative images of pancreata from saline- and leptin-treated T1D LepRs/s mice costained for insulin (red) and glucagon (green). Scale bars = 25 μm. D: Plasma insulin levels were measured at day 13 (n = 4–6). ***P < 0.001 vs. all other groups. E: Expression of p-S6 by intraperitoneal (i.p.) leptin treatment in the hypothalamus of the indicated mouse groups. Scale bars = 250 μm. 3V, third ventricle. Levels of plasma glucagon (F) and corticosterone (G) were measured at day 13. *P < 0.05 vs. the other groups. All data are represented as the mean ± SEM. icv, intracerebroventricular.
Figure 6
Figure 6
Changes in the expression of selected genes in the microarray study. A: Plasma glucose levels and representative images of pancreata from T1D/saline mice, control mice, and T1D/leptin mice costained for insulin (red) and glucagon (green). nd, not determined. Scale bars = 25 μm. B: Heat map of RNA microarray showing that changes in the expression of representative neuropeptide genes by STZ-induced T1D were corrected by intracerebroventricular leptin infusion. C: Heat map of RNA microarray showing that changes in the expression of the representative genes in cytokine pathways by STZ-induced T1D were corrected by intracerebroventricular leptin infusion. The value of each gene expression was centered and normalized for clustering and display in the heat map.
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References

    1. Chinookoswong N, Wang JL, Shi ZQ. Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. Diabetes 1999;48:1487–1492 - PubMed
    1. Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW. Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab 2005;2:411–420 - PubMed
    1. Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 1997;389:374–377 - PubMed
    1. Wang MY, Chen L, Clark GO, et al. . Leptin therapy in insulin-deficient type I diabetes. Proc Natl Acad Sci USA 2010;107:4813–4819 - PMC - PubMed
    1. Yu X, Park BH, Wang MY, Wang ZV, Unger RH. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci USA 2008;105:14070–14075 - PMC - PubMed

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