Jichi Med. Univ.Jichi Med. Univ. Graduate School of Med.





<Address>
Division of Integrative Physiology, Department of Physiology,
Jichi Medical University, School of Medicine

3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan

TEL +81-285-58-7320
FAX +81-285-44-9962
Research

【Theme of research】
■Hormonal regulation of insulin release, blood glucose and feeding: from physiology to therapeutics.

■Hypothalamus and vagal afferents sense systemic signals to regulate feeding, glucose and energy metabolism.

■Application of nesfatin-1 and oxytocin for treatment of obesity, metabolic and cerebral diseases.

■Circadian rhythm of feeding: neural mechanism and (patho)physiological roles.




Our studies have established ghrelin as a novel islet hormone that inhibits insulin release and elevates blood glucose.
Ghrelin and its receptor GHS-R are expressed in pancreatic islets [1,2], and ghrelin is released into the pancreatic vein [3]. Ghrelin immunoneutralization and GHS-R antagonists augment glucose-stimulated insulin secretion (GSIS) from isolated pancreas and islets [2]. Ghrelin acts on islet β-cells and attenuates glucose-induced cAMP production, which drives activation of voltage-dependent Kv channels and inhibition of TRPM2 channels, and suppression of the glucose-induced [Ca2+]i increases and insulin release [4-6]. GSIS is greater in ghrelin- and GHS-R-deficient than wild-type mice [3,6]. Moreover, ghrelin deficiency enhances insulin release and prevents the high-fat diet-induced impaired glucose tolerance [3]. Ghrelin also attenuates glucagon-like peptide-1 (GLP-1)-potentiated insulin release by suppression of cAMP production in β-cells [7]. Low doses of GLP-1 agonist and Kv2.1 channel blocker synergistically stimulate insulin release and lower blood glucose in type 2 diabetic mice [8].
Thus, ghrelin inhibits glucose-induced and GLP-1-potentiated insulin release, and manipulation of insulinostatic function of ghrelin in islets could optimize insulin release to meet the systemic demand, providing a novel therapeutic tool to treat type 2 diabetes [9,10]. We aim to develop a novel ghrelin-based treatment for type 2 diabetes.
Surgery is the main therapy in the patients with gastric cancer, but postoperative reduction in food intake and body weight impairs the quality of life. We aim to elucidate the underlying mechanism and to restore appetite and body weight by new methods including GLP-1 antagonism and Kampo medicine [11].

[1] Diabetes 51:124-129, 2002, [2] Diabetes 53:3142-3151, 2004, [3] Diabetes 55:3486-3493, 2006, [4] Diabetes 56:2319-2327, 2007, [5] Diabetes 60:2315-2324, 2011, [6] Sci Rep 5: 14041, 2015, [7] FEBS Lett 586:2555-2562, 2012, [8] Endocrinology 156:114-123, 2015, [9] Methods Enzymol 514:317-331, 2012, [10] Diabetes Obes Metab 1:111-117, 2014, [11] Surgery 159:1342-1350, 2016.

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The hypothalamus receives peripheral metabolic signals that enter the brain through the blood-brain barrier (BBB), and regulates feeding behavior and energy metabolism. The orexigenic neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC), the first order center, are directly activated by low glucose [1], ghrelin [2], orexin [3] and PACAP [4], while inhibited by leptin [5], insulin [6] and GABA [7]. NPY neurons integrate these orexigenic and anorexigenic signals: leptin counteracts the ghrelin-induced stimulation of NPY neurons and feeding [5]. Type 2 diabetic GK rats display hyperphagia and visceral obesity due to leptin resistance and dysfunction of ARC NPY neurons [8]. We now aim to elucidate the neural circuit that relays the ARC to the paraventricular nucleus (PVN), the second order center, and to feeding behavior. Nesfatin-1 [9], BDNF [10] and GLP-1 [11] in the PVN play a key role in suppressing food intake.
The vagal afferent nerves sense the peripheral information and convey these signals to the brain, resulting in regulation of feeding and metabolism. We established a new method of analyzing the vagal afferent nodose ganglion neuron (NGN). Cytosolic Ca2+ concentrations and membrane currents in single NGNs isolated from rodents are measured by fluorescence imaging and patch clamp technique, followed by immunocytochemical identification of their neurotransmitters. We have found that the vagal afferent NGNs directly sense gastrointestinal/pancreatic hormones, GLP-1 [12], nesfatin-1 [13], peptide YY3-36 [14], ghrelin [15], insulin [16], glucagon [17] and pancreatic polypeptide [14], thereby conveying the signals to the brain to regulate feeding. Recently, we have found that peripheral administration of oxytocin reduces feeding and ameliorates obesity via direct interaction with vagal afferents [18,19]. We are studying the role of the vagal afferent-mediated peripheral-central network in physiological regulation of feeding, metabolism and brain functions. Dysfunction of the vagal afferents may be implicated in the metabolic and neural diseases including feeding disorders, obesity, diabetes, blood pressure, depression and Alzheimer disease.

[1] Neurosci Lett 264:113-6, 1999, [2] Diabetes 52:948-56, 2003, [3] Eur J Neurosci 19:1524-34, 2004, [4] Neruosci Lett 370:252-6, 2004, [5] Endocrinology 148:2251-63, 2007, [6] Aging 3:1092-7, 2011, [7] Neuroreport 16:897-901, 2005, [8] J Neuroendocrinol 18:748-756, 2006, [9] Cell Metabolism 10:355-65, 2009, [10] J Neuroendocrinology 22:987-95, 2010, [11] BBRC 451:276-81, 2014, [12] Auton Neurosci 102:39-44, 2002, [13] BBRC 390:958-962, 2009, [14] Neuropeptides 47:19-23, 2013, [15] Neuropeptide 52:55-60, 2015, [16] PLOS ONE 8:e67198, [17] BBRC 456:727-32, 2015, [18] Aging 3:1169-77, 2011, [19] Am J Physiol Regul Integr Comp Physiol 308:R360-9, 2015.

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To develop an effective treatment of obesity and metabolic syndrome, it is essential to clarify the regulation of feeding and energy metabolism. We discovered a novel neuro-circuit operated by new and clasic neuropeptides, nesfatin-1 (Nesf) and oxytocin (Oxt), in the hypothalamic paraventricular nucleus (PVN). The PVN Nesf neurons induce oxytocinergic signaling to proopiomelanocortin (POMC) neurons located in the arcuate nucleus (ARC) [1] and in the brain stem nucleus tractus solitarius (NTS) [2]. The PVN Nesf is regulated by leptin and mediates the anorexigenicic effect of leptin [3]. Nesf in PVN is activated by meal [4], the neural projection from the ARC [5], and glucose and insulin [6]. Nesf neurons are also activated by stressors and in turn provoke CRH-ACTH-glucocorticoid and serotonin pathways [7].
PVN Nesf/NUCB2 mRNA expression is raised in light phase (LP), forming diurnal Nesf/NUCB2 rhythm. The diurnal Nesf/NUCB2 rhythm drives diurnal Oxt rhythm and circadian feeding rhythm [8,9].
Nesf and Oxt, when injected peripherally, inhibit feeding [10,11]. Peripheral Oxt treatment corrects obesity and metabolic syndrome [11]. Peripheral Oxt exerts these effects by activating the vagal afferent nerve and resultant signaling to the brain [12]. Nasal and IP administrations of Oxt similarly inhibit feeding [13]. Our final goal is to invent Oxt-based medicines to effectively and safely treat obesity, metabolic and cerebral diseases.

[1] FEBS Letters 588:4404-4412, 2014, [2] Cell Metabolism 10:355-365, 2009, [3] Biochem Biophys Res Commun 456:913-918, 2015, [5] Endocrinology 149:1295-1301, 2008, [5] NeuroReport 25:1453-1458, 2014, [6] Biochem Biophys Res Commun 420:811-815, 2012, [7] Aging 2:775-784, 2010, [8] Biochem Biophys Res Commun 434:434-438, 2013, [9] Endocrinology 2016(in press), [10] Endocrinology 150:662-671, 2009, [11] Aging 3:1169-1177, 2011, [12] Am J Physiol 308:R360-R369, 2015, [13] Neuroendocrinology 101:35-44, 2015.

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The circadian system in mammals is organized by a network of circadian oscillators. The master clock is located in the hypothalamic suprachiasmatic nucleus (SCN), in which approximately 20,000 neurons are synchronized in their activities. Partly under the influence and partly independently of the SCN master clock, circadian oscillators are present in other brain areas and peripheral organs, which are thought to be implicated in the circadian rhythms of physiological functions, including the rhythms of feeding and hormone release.  
We intend to demonstrate that the impairment of circadian rhythms induced by environment factors induces feeding disorder, metabolic syndrome and depression, and to elucidate the underlying mechanisms.
PVN is considered a regulatory center for feeding and circadian activities of hormone release and autonomic nerve. Nucleobindin2 (NUCB2) and its processing product nesfatin-1 (NUCB2/nesfatin-1) are localized in the hypothalamic paraventricular nucleus (PVN) and implicated in regulation of feeding. We reported that NUCB2 mRNA expression in the PVN rises during early light phase (LP) in parallel with suppression of food intake [1]. Furthermore, the rise of PVN NUCB2 mRNA during LP was blunted in obese rats which exhibited LP-preferential hyperphagia. Moreover, PVN-specific NUCB2 knockdown using AAV vector resulted in increases in food intake during LP and body weight gain, without affecting energy expenditure. This PVN specific NUCB2 knockdown Impaired LP rise of oxytocin mRNA expression in PVN and caused LP-selective hyperphagia [2]. These results show that the circadian expression of PVN NUCB2 and oxytocin produces circadian feeding. In addition, the function of nesfatin-1/NUCB2 neuron in PVN is regulated by meal-induced factors such as high glucose, insulin and leptin [3,4]. Nesaftin-1/NUCB2 and oxytocin are implicated in both satiety and circadian feeding rhythm. Using conditional knockout mice, we aim to further explore the function of NUCB2 and oxytocin in feeding behaviour.

[1] Sedbazar U et al. Biochem Biophys Res Commun. 434:434-438, 2013.
[2] Nakata M et al. Endocrinology. in press
[3] Gantulga D et al. Biochem Biophys Res Commun. 420:811-815, 2012.
[4] Gantulga D et al. Biochem Biophys Res Commun. 456:913-918, 2014

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