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. 2013 Mar;62(3):801-10.
doi: 10.2337/db11-0785. Epub 2012 Nov 16.

Gliotransmission and brain glucose sensing: critical role of endozepines

Damien Lanfray  1 , Sébastien Arthaud, Johanne Ouellet, Vincent Compère, Jean-Luc Do Rego, Jérôme Leprince, Benjamin Lefranc, Hélène Castel, Cynthia Bouchard, Boris Monge-Roffarello, Denis Richard, Georges Pelletier, Hubert Vaudry, Marie-Christine Tonon, Fabrice Morin
Affiliations

Gliotransmission and brain glucose sensing: critical role of endozepines

Damien Lanfray et al. Diabetes. 2013 Mar.

Abstract

Hypothalamic glucose sensing is involved in the control of feeding behavior and peripheral glucose homeostasis, and glial cells are suggested to play an important role in this process. Diazepam-binding inhibitor (DBI) and its processing product the octadecaneuropeptide (ODN), collectively named endozepines, are secreted by astroglia, and ODN is a potent anorexigenic factor. Therefore, we investigated the involvement of endozepines in brain glucose sensing. First, we showed that intracerebroventricular administration of glucose in rats increases DBI expression in hypothalamic glial-like tanycytes. We then demonstrated that glucose stimulates endozepine secretion from hypothalamic explants. Feeding experiments indicate that the anorexigenic effect of central administration of glucose was blunted by coinjection of an ODN antagonist. Conversely, the hyperphagic response elicited by central glucoprivation was suppressed by an ODN agonist. The anorexigenic effects of centrally injected glucose or ODN agonist were suppressed by blockade of the melanocortin-3/4 receptors, suggesting that glucose sensing involves endozepinergic control of the melanocortin pathway. Finally, we found that brain endozepines modulate blood glucose levels, suggesting their involvement in a feedback loop controlling whole-body glucose homeostasis. Collectively, these data indicate that endozepines are a critical relay in brain glucose sensing and potentially new targets in treatment of metabolic disorders.

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Figures

FIG. 1.
FIG. 1.
Glucose stimulates the expression of endozepines in the rat hypothalamus. A: Hypothalamic DBI mRNA levels from normally fed (Fed) and overnight-fasted saline-injected (0.9% NaCl, Fast+Sal) or glucose-injected (Fast+Glc) animals. Quantitation was performed in area A (floor of the third ventricle) and area B (infralateral wall of the third ventricle). Values are normalized to those obtained with fed animals (n = 6). B: Extrahypothalamic DBI mRNA levels from Fed, Fast+Sal (0.9% NaCl), or Fast+Glc animals. Quantitation was performed in hippocampal CA1 area (Area A), in the cells lining the lateral ventricle (Area B), and in the cortex (Area C). Values are normalized to those obtained with fed animals (n = 6). C: POMC mRNA levels in the arcuate nucleus (ARC) from Fed, Fast+Sal, or Fast+Glc animals. Values are normalized to those obtained with fed animals (n = 5). D: Hypothalamic explants were preincubated in 0.2 g/L glucose (Glc) and then incubated in 0.2 or 1 g/L glucose. ODN-like immunoreactivity (ODN-LI) released during the incubation in 0.2 or 1 g/L was normalized to that released during the preincubation period (n = 6–8). Data are expressed as mean ± SEM. Unpaired t test: *P < 0.05; **P < 0.01; ***P < 0.001; NS, not statistically different.
FIG. 2.
FIG. 2.
Arcuate endozepines regulate feeding behavior. A, top row: Hypothalamic section labeled with ODN (a, c, and d) and dopamine- and cAMP-regulated phosphoprotein-32 (DARPP-32) (b and c) antibodies. d: Higher magnification view of panel a. A, bottom row: Hypothalamic section labeled with ODN (e and g) and vimentin (f and g) antibodies. Arrows show tanycyte processes that extend into the parenchyma. ARC, arcuate nucleus; ME, median eminence; 3V, third ventricle. Scale bars = 50 µm. B: Rats fasted for 18 h (from ZT8 to ZT26) received a single unilateral injection of OP (+) or vehicle (–) in the arcuate nucleus. Access to food was restored 45 min later, and cumulative food intake was measured at the indicated time points (n = 7–8). Data are expressed as mean ± SEM. Unpaired t test: ***P < 0.001. C: Verification of cannula placement (*). Photomicrograph of a thionin-stained coronal section from an animal in which cannula has been inserted at the top of the arcuate nucleus. (A high-quality digital representation of this figure is available in the online issue.)
FIG. 3.
FIG. 3.
The anorexigenic effect of glucose is suppressed by an ODN antagonist. A, B, and C: Rats fasted for 18 h (from ZT8 to ZT26) received a single intracerebroventricular injection containing the indicated substances diluted in 0.9% NaCl. Access to food was restored 45 min later, and cumulative food intake was measured at the indicated time points (n = 6–8). D: Rats fasted for 18 h (from ZT8 to ZT26) received an intracerebroventricular injection of cyclo1–8[dLeu5]OP (+) or vehicle (–), immediately followed by an intraperitoneal administration of glucose (+; 1 g/kg body weight) or vehicle (–). Access to food was restored 45 min later, and cumulative food intake was measured at the indicated time points (n = 7–8). Data are expressed as mean ± SEM. One-way ANOVA, followed by a post hoc multiple comparison Student-Newman-Keuls test: *P < 0.05; ***P < 0.001; NS, not statistically different.
FIG. 4.
FIG. 4.
The hyperphagic response to 2-DG is suppressed by an ODN agonist. Normally fed rats received a single intracerebroventricular injection at ZT5 containing the indicated substances diluted in 0.9% NaCl. Access to food was restored 45 min later, and cumulative food intake was measured at the indicated time points (n = 7–8). Data are expressed as mean ± SEM. One-way ANOVA, followed by a post hoc multiple comparison Student-Newman-Keuls test: **P < 0.01; ***P < 0.001; NS, not statistically different.
FIG. 5.
FIG. 5.
MC3/4-Rs relay the anorexigenic effect of endozepines. A and B: Rats fasted for 18 h (from ZT8 to ZT26) received a single intracerebroventricular injection containing the indicated substances diluted in 0.9% NaCl. Access to food was restored 45 min later, and cumulative food intake was measured at the indicated time points. Data are expressed as mean ± SEM (n = 7–8 for data presented in A; n = 5–6 for data presented in B). One-way ANOVA, followed by a post hoc multiple comparison Student-Newman-Keuls test: *P < 0.05; **P < 0.01; ***P < 0.001; NS, not statistically different.
FIG. 6.
FIG. 6.
MC3/4-Rs relay the anorexigenic effect of glucose. A: Rats fasted for 18 h (from ZT8 to ZT26) received a single intracerebroventricular injection containing the indicated substances diluted in 0.9% NaCl. Access to food was restored 45 min later, and cumulative food intake was measured at the indicated time points (n = 6–7). Data are expressed as mean ± SEM. One-way ANOVA, followed by a post hoc multiple comparison Student-Newman-Keuls test: *P < 0.05; **P < 0.01; ***P < 0.001; NS, not statistically different. B: Model summarizing the role of endozepines in the regulation of central glucose sensing.
FIG. 7.
FIG. 7.
Peripheral blood glucose levels are regulated by central endozepines. A: Variation of glycemia in normally fed rats after an intracerebroventricular (i.c.v.) injection at ZT2 of OP (2 µg), cyclo1–8[dLeu5]OP (20 µg), or saline vehicle (Sal). Data are expressed as mean ± SEM (n = 4–6). Two-way ANOVA, followed by a post hoc Bonferroni test: *P < 0.05; ***P < 0.001 vs. intracerebroventricular vehicle-injected animals. Glycemia (mean ± SEM) measured in each group just before intracerebroventricular injections (time 0) was as follows: OP, 1.23 ± 0.03 g/L; cyclo1–8[dLeu5]OP, 1.26 ± 0.03 g/L; vehicle, 1.26 ± 0.06 g/L. B: Glucose tolerance test on fasted rats after intracerebroventricular injection of ODN (2 µg) or Sal. Data are expressed as mean ± SEM (n = 5). Two-way ANOVA, followed by a post hoc Bonferroni test: ***P < 0.001; NS, not statistically different vs. intracerebroventricular vehicle-injected animals.
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References

    1. Blouet C, Schwartz GJ. Hypothalamic nutrient sensing in the control of energy homeostasis. Behav Brain Res 2010;209:1–12 - PubMed
    1. Rossi M, Kim MS, Morgan DG, et al. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of α-melanocyte stimulating hormone in vivo. Endocrinology 1998;139:4428–4431 - PubMed
    1. Stanley BG, Leibowitz SF. Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior. Proc Natl Acad Sci U S A 1985;82:3940–3943 - PMC - PubMed
    1. Bady I, Marty N, Dallaporta M, et al. Evidence from glut2-null mice that glucose is a critical physiological regulator of feeding. Diabetes 2006;55:988–995 - PubMed
    1. Marty N, Dallaporta M, Foretz M, et al. Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors. J Clin Invest 2005;115:3545–3553 - PMC - PubMed

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