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. 2009 Dec;58(12):2757-65.
doi: 10.2337/db09-0638. Epub 2009 Sep 14.

Distinct effects of leptin and a melanocortin receptor agonist injected into medial hypothalamic nuclei on glucose uptake in peripheral tissues

Chitoku Toda  1 , Tetsuya Shiuchi, Suni Lee, Maya Yamato-Esaki, Yusuke Fujino, Atsushi Suzuki, Shiki Okamoto, Yasuhiko Minokoshi
Affiliations

Distinct effects of leptin and a melanocortin receptor agonist injected into medial hypothalamic nuclei on glucose uptake in peripheral tissues

Chitoku Toda et al. Diabetes. 2009 Dec.

Abstract

Objective: The medial hypothalamus mediates leptin-induced glucose uptake in peripheral tissues, and brain melanocortin receptors (MCRs) mediate certain central effects of leptin. However, the contributions of the leptin receptor and MCRs in individual medial hypothalamic nuclei to regulation of peripheral glucose uptake have remained unclear. We examined the effects of an injection of leptin and the MCR agonist MT-II into medial hypothalamic nuclei on glucose uptake in peripheral tissues.

Research design and methods: Leptin or MT-II was injected into the ventromedial (VMH), dorsomedial (DMH), arcuate nucleus (ARC), or paraventricular (PVH) hypothalamus or the lateral ventricle (intracerebroventricularly) in freely moving mice. The MCR antagonist SHU9119 was injected intracerebroventricularly. Glucose uptake was measured by the 2-[(3)H]deoxy-d-glucose method.

Results: Leptin injection into the VMH increased glucose uptake in skeletal muscle, brown adipose tissue (BAT), and heart, whereas that into the ARC increased glucose uptake in BAT, and that into the DMH or PVH had no effect. SHU9119 abolished these effects of leptin injected into the VMH. Injection of MT-II either into the VMH or intracerebroventricularly increased glucose uptake in skeletal muscle, BAT, and heart, whereas that into the PVH increased glucose uptake in BAT, and that into the DMH or ARC had no effect.

Conclusions: The VMH mediates leptin- and MT-II-induced glucose uptake in skeletal muscle, BAT, and heart. These effects of leptin are dependent on MCR activation. The leptin receptor in the ARC and MCR in the PVH regulate glucose uptake in BAT. Medial hypothalamic nuclei thus play distinct roles in leptin- and MT-II-induced glucose uptake in peripheral tissues.

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Figures

FIG. 1.
FIG. 1.
Effects of leptin injection into the VMH on glucose uptake and gene expression in peripheral tissues. The rate constant of 2[3H]DG uptake was measured in skeletal muscle (A), BAT and heart (B), spleen (C), and epididymal WAT (D) at 3 and 6 h after injection of leptin or saline (control) into the VMH of mice. □, Saline VMH (6 h); ▧, leptin VMH (3 h); ■, leptin VMH (6 h). E: The mRNA levels of GLUT4, hexokinase II (HKII), and UCP1 in soleus, BAT, and heart were quantified by real-time PCR. Values are normalized by the level of eEF2 mRNA. Gastro-R, red portion of gastrocnemius; Gastro-W, white portion of gastrocnemius. Data are means ± SE for four to seven mice. *P < 0.05 vs. the corresponding value for saline-injected controls. □, Saline VMH (6 h); ■, leptin VMH (6 h).
FIG. 2.
FIG. 2.
Effects of leptin injection into the ARC, DMH, or PVH on glucose uptake in peripheral tissues. The rate constant of 2[3H]DG uptake was measured in skeletal muscle (A), BAT and heart (B), spleen (C), and epididymal WAT (D) at 6 h after injection of leptin into the hypothalamic nuclei of mice. Results obtained after injection of saline into the ARC are shown as a control. Data are means ± SE for six or seven mice. *P < 0.05 vs. the corresponding value for control animals injected with saline into ARC. □, Saline ARC; ■, leptin ARC; ▧ leptin DMH; ⊞, leptin PVH.
FIG. 3.
FIG. 3.
Effects of leptin injection into medial hypothalamic nuclei on tyrosine phosphorylation of STAT3 and c-Fos expression. A: RT-PCR analysis of CRF, POMC, NPY, SF1, and eEF2 (loading control) mRNAs in the PVH, ARC, VMH, and DMH. Data are from two animals in a representative experiment. B–E: Immunoblot analysis of the phosphorylation of STAT3 on Tyr705 in the medial hypothalamic nuclei at 6 h after leptin injection into the VMH (B), DMH (C), PVH (D), or ARC (E). Leptin was injected into the right side of the hypothalamic nuclei, and the same side of the PVH (P), ARC (A), VMH (V), and DMH (D) was collected. Injection of saline into the VMH was used as a control. Figure shows separate saline controls for each nucleus. Representative blots of Tyr705-phosphorylated STAT3 are shown in the upper panels, and quantitative data (means ± SE) from four to six mice are shown in the lower panels. The amount of Tyr 705-phosphorylated STAT3 was normalized by that of total STAT3, and the normalized values were expressed relative to the corresponding value for the PVH of control mice. *P < 0.05 for the indicated comparisons. F: Immunoblot analysis of c-Fos expression in the medial hypothalamic nuclei after leptin injection into the VMH. The right side of the PVH, ARC, VMH, and DMH was collected at 6 h after injection of leptin or saline into the same side of the VMH. A representative blot is shown in the upper panel, and quantitative data (means ± SE) from four to six mice are shown in the lower panel. The amount of c-Fos was normalized by that of β-actin, and the normalized values were expressed relative to the corresponding value for the saline-injected control mice. *P < 0.05.
FIG. 4.
FIG. 4.
Effect of intracerebroventricular injection of SHU9119 on glucose uptake in peripheral tissues induced by injection of leptin into the VMH. The rate constant of 2[3H]DG uptake in skeletal muscle (A), BAT and heart (B), spleen (C), and epididymal WAT (D) was measured 6 h after injection of leptin or saline (control) into the VMH. The effect of SHU9119 was determined by intracerebroventricular injection immediately before injection of leptin. Data are means ± SE for six or seven mice. *P < 0.05 vs. the corresponding value for saline-injected control animals. □, Saline VMH; ▧, SHU9119 i.c.v.; ■, leptin VMH; ⊞, leptin VMH + SHU9119 i.c.v.
FIG. 5.
FIG. 5.
Effects of intracerebroventricular injection of MT-II on glucose uptake in peripheral tissues. The rate constant of 2[3H]DG uptake in skeletal muscle (A), BAT and heart (B), spleen (C), and epididymal WAT (D) was measured at 3 or 6 h after intracerebroventricular injection of MT-II or saline (control). Data are means ± SE for six or seven mice. *P < 0.05 vs. the corresponding value for saline-injected control animals. □, Saline i.c.v. (6 h); ▧, MT-II i.c.v. (3 h); ■, MT-II i.c.v. (6 h).
FIG. 6.
FIG. 6.
Effects of MT-II injection into VMH, PVH, DMH, or ARC on glucose uptake in peripheral tissues. The rate constant of 2[3H]DG uptake in skeletal muscle (A), BAT and heart (B), spleen (C), and epididymal WAT (D) was measured at 6 h after the injection of MT-II into the individual hypothalamic nuclei. Injection of saline into VMH was used as a control. Data are means ± SEM for six or seven mice. *P < 0.05 vs. the corresponding value for saline-injected control animals. □, VMH; ■, MT-II VMH; ▧, MT-II PVH; ⊡, MT-II DMH; ⊞, MT-II ARC.
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