Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.
Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan
BMJ Open Diabetes Res Care. 2021 Apr;9(1). doi: 10.1136/bmjdrc-2020-002104.
Sodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake.
We administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Intraperitoneal administration of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin.
Bolus ICV injection of tofogliflozin induced a robust increase in food intake starting at 1.5 hours postinjection, and lasting for 5 days. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. ICV dapagliflozin and empagliflozin significantly enhanced food intake, although the strength of these effects varied among drugs. Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. ICV tofogliflozin increased phosphorylation of AMPK and c-fos expression in the lateral hypothalamus.
SGLT2 inhibitors in the CNS increase food intake. SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area.
钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂被广泛用于糖尿病治疗。虽然临床观察到 SGLT2 抑制剂会增加食物摄入，但 SGLT2 在中枢神经系统（CNS）中的作用甚至存在尚未确定。我们旨在阐明 SGLT2 在中枢神经系统中的潜在功能，以及中枢靶向 SGLT2 抑制剂对食物摄入的影响。
我们将三种 SGLT2 抑制剂，托格列净、达格列净和恩格列净，注入大鼠侧脑室（LV），并评估它们对食物摄入的影响。我们还评估了托格列净在第三脑室（3V）和第四脑室（4V）中的作用。腹腔内给予胰高血糖素样肽-1（GLP-1）受体激动剂利拉鲁肽，已知其可抑制食物摄入，与中枢托格列净联合给药，以阐明 GLP-1 信号是否拮抗中枢 SGLT2 抑制剂对食物摄入的影响。为了阐明介导摄食变化的潜在分子机制，在侧脑室给药后采集并分析与食物摄入调节相关的下丘脑区域。
托格列净的脑室内推注诱导了起始于注射后 1.5 小时的强烈的食物摄入增加，并持续 5 天。相同剂量的托格列净腹腔内给药则没有效果。脑室内给予达格列净和恩格列净也显著增加了食物摄入，尽管这些药物的作用强度不同。当托格列净注入 LV 时，食物摄入增加最为明显。分别注入 3V 或 4V 时，效果较少或没有。全身给予利拉鲁肽可抑制脑室内托格列净对食物摄入的影响。脑室内托格列净增加了外侧下丘脑 AMPK 的磷酸化和 c-fos 的表达。
CNS 中的 SGLT2 抑制剂会增加食物摄入。CNS 中的 SGLT2 活性可能通过外侧下丘脑区域的 AMPK 磷酸化来调节食物摄入。
