1,5-Anhydro-D-Fructose Exhibits Satiety Effects via the Activation of Oxytocin Neurons in the Paraventricular Nucleus.

1,5-Anhydro-D-fructose (1,5-AF) is a bioactive monosaccharide that is produced by the glycogenolysis in mammalians and is metabolized to 1,5-anhydro-D-glucitol (1,5-AG). 1,5-AG is used as a marker of glycemic control in diabetes patients. 1,5-AF has a variety of physiological activities, but its effects on energy metabolism, including feeding behavior, are unclarified. The present study examined whether 1,5-AF possesses the effect of satiety. Peroral administration of 1,5-AF, and not of 1,5-AG, suppressed daily food intake. Intracerebroventricular (ICV) administration of 1,5-AF also suppressed feeding. To investigate the neurons targeted by 1,5-AF, we investigated c-Fos expression in the hypothalamus and brain stem. ICV injection of 1,5-AF significantly increased c-Fos positive oxytocin neurons and mRNA expression of oxytocin in the paraventricular nucleus (PVN). Moreover, 1,5-AF increased cytosolic Ca2+ concentration of oxytocin neurons in the PVN. Furthermore, the satiety effect of 1,5-AF was abolished in oxytocin knockout mice. These findings reveal that 1,5-AF activates PVN oxytocin neurons to suppress feeding, indicating its potential as the energy storage monitoring messenger to the hypothalamus for integrative regulation of energy metabolism.

TRPV1-Mediated Sensing of Sodium and Osmotic Pressure in POMC Neurons in the Arcuate Nucleus of the Hypothalamus.

The central melanocortin system conducted by anorexigenic pro-opiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARC) not only regulates feeding behavior but also blood pressure. Excessive salt intake raises the Na+ concentration ([Na+]) in the cerebrospinal fluid (CSF) and worsens hypertension. The blood-brain barrier is immature in the ARC. Therefore, both AgRP and POMC neurons in the ARC have easy access to the electrolytes in the blood and can sense changes in their concentrations. However, the sensitivity of AgRP and POMC neurons to Na+ remains unclear. This study aimed to explore how the changes in the extracellular Na+ concentration ([Na+]) influence these neurons by measuring the cytosolic Ca2+ concentration ([Ca2+]i) in the single neurons isolated from the ARC that were subsequently immunocytochemically identified as AgRP or POMC neurons. Both AgRP and POMC neurons responded to increases in both [Na+] and osmolarity in C57BL/6 mice. In contrast, in transient receptor potential vanilloid 1 (TRPV1) knockout (KO) mice, POMC neurons failed to respond to increases in both [Na+] and osmolarity, while they responded to high glucose and angiotensin II levels with increases in [Ca2+]i. Moreover, in KO mice fed a high-salt diet, the expression of POMC was lower than that in wild-type mice. These results demonstrate that changes in [Na+] and osmolarity are sensed by the ARC POMC neurons via the TRPV1-dependent mechanism.

Lavender Oil Reduces Depressive Mood in Healthy Individuals and Enhances the Activity of Single Oxytocin Neurons of the Hypothalamus Isolated from Mice: A Preliminary Study.

BACKGROUND: The aim of the present study was to assess the effects of lavender oil inhalation on blood pressure, pulse measurements, cortisol levels, depressive mood, and anxiety in healthy male adults. The mechanism was investigated by the action on oxytocin single neurons in the hypothalamus of rodents. METHODS: The participants (n = 7) were aged 20-40 years. After randomisation, they received an inhaled dose of lavender oil or distilled water for 20 min. They received the other treatment after a washout period of one week. We assessed the outcomes using the Self-Rating Depression Scale, State-Trait Anxiety Inventory, and self-rated unidimensional Visual Analogue Scale for depression; anxiety; and hunger, thirst, and appetite, respectively. Blood pressure, pulse rate, and cortisol concentration in the peripheral blood were assessed before and after inhalation. In the rodent study (n = 4), oxytocin single neurons were isolated from the mouse hypothalamus. Intracellular Ca2+ concentration in the oxytocin neurons isolated from the hypothalamus was measured following direct administration of lavender oil. RESULTS: Seven participants completed the study. Lavender inhalation decreased Self-Rating Depression Scale score and systolic and diastolic blood pressure. Ex vivo administration of lavender oil increased intracellular Ca2+ concentration in the hypothalamic oxytocin neurons. CONCLUSIONS: Lavender oil might be a useful therapy for stress relief, and its mechanism of action may include activation of the central oxytocin neurons.

Central insulin action induces activation of paraventricular oxytocin neurons to release oxytocin into circulation.

Oxytocin neurons in the paraventricular nucleus (PVN) of hypothalamus regulate energy metabolism and reproduction. Plasma oxytocin concentration is reduced in obese subjects with insulin resistance. These findings prompted us to hypothesize that insulin serves to promote oxytocin release. This study examined whether insulin activates oxytocin neurons in the PVN, and explored the underlying signaling. We generated the mice deficient of 3-phosphoinositide-dependent protein kinase-1 (PDK1), a major signaling molecule particularly for insulin, specifically in oxytocin neurons (Oxy Pdk1 KO). Insulin increased cytosolic calcium concentration ([Ca2+]i) in oxytocin neurons with larger (≧25 µm) and smaller (<25 µm) diameters isolated from PVN in C57BL/6 mice. In PDK1 Oxy Pdk1 KO mice, in contrast, this effect of insulin to increase [Ca2+]i was markedly diminished in the larger-sized oxytocin neurons, while it was intact in the smaller-sized oxytocin neurons. Furthermore, intracerebroventricular insulin administration induced oxytocin release into plasma in Oxy Cre but not Oxy Pdk1 KO mice. These results demonstrate that insulin PDK1-dependently preferentially activates PVN magnocellular oxytocin neurons to release oxytocin into circulation, possibly serving as a mechanism for the interaction between metabolism and perinatal functions.

GLP-1 receptor agonist liraglutide exerts central action to induce ß-cell proliferation through medulla to vagal pathway in mice.

Endogenous GLP-1 and GLP-1 receptor agonists (GLP-1RAs) regulate glucose metabolism via common and distinct mechanisms. Postprandial release of GLP-1 is modest and it is degraded by DPP-4 within 2 min, and hence it cannot enter the brain in substantial amount. In contrast, DPP-4-resistant GLP-1RAs are administered at 10 times higher concentration than endogenous GLP-1 level, which enables them to reach several brain regions including ARC and AP, the areas implicated in glucose metabolism. Hence, some of the effects of GLP-1RAs observed clinically and experimentally, including pancreatic ß-cell proliferation, are thought to involve the brain. However, the effects of centrally acting GLP-1/GLP-1RAs on glucose metabolism and underlying neural mechanism are unclear. This study aimed to establish the link of central GLP-1/GLP-1RA action to pancreatic ß-cell proliferation. Both subcutaneous (SC) and intracerebroventricular (ICV) injections of liraglutide increased the number of pancreatic ß-cells expressing Ki67 and PCNA, proliferation markers, in C57BL/6J mice. This effect was induced by single ICV administration of liraglutide at relatively low dose that was incapable of suppressing food intake. These SC and ICV liraglutide-induced effects were inhibited by 50% and 70%, respectively, by pretreatment with atropine, a muscarinic receptor blocker. ICV liraglutide induced c-Fos expression in the area postrema (AP), nucleus tractus solitaries (NTS), and dorsal motor nucleus of the vagus (DMX) of the brain stem. These results demonstrate that central action of liraglutide induces pancreatic ß-cell proliferation via the pathway involving the brain stem AP/NTS/DMX area and vagus nerve. This route is highly sensitive to GLP-1/GLP-1RA. Hence, this brain-pancreatic ß-cell pathway may operate in type 2 diabetic patients treated with GLP-RAs and serve to counteract the reduction of ß-cell mass.

Suprachiasmatic vasopressin to paraventricular oxytocin neurocircuit in the hypothalamus relays light reception to inhibit feeding behavior.

Light synchronizes the body's circadian rhythms by modulating the master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. In modern lifestyles that run counter to normal circadian rhythms, the extended and/or irregular light exposure impairs circadian rhythms and, consequently, promotes feeding and metabolic disorders. However, the neuronal pathway through which light is coupled to feeding behavior is less elucidated. The present study employed the light exposure during the dark phase of the day in rats and observed its effect on neuronal activity and feeding behavior. Light exposure acutely suppressed food intake and elevated c-Fos expression in the AVP neurons of SCN and the oxytocin (Oxt) neurons of paraventricular nucleus (PVN) in the hypothalamus. The light-induced suppression of food intake was abolished by blockade of the Oxt receptor in the brain. Retrograde tracer analysis demonstrated the projection of SCN AVP neurons to the PVN. Furthermore, intracerebroventricular injection of AVP suppressed food intake and increased c-Fos in PVN Oxt neurons. Intra-PVN injection of AVP exerted a stronger anorexigenic effect than intracerebroventriclar injection. AVP also induced intracellular Ca2+ signaling and increased firing frequency in Oxt neurons in PVN slices. These results reveal the novel neurocircuit from SCN AVP to PVN Oxt that relays light reception to inhibition of feeding behavior. This light-induced neurocircuit may serve as a pathway for forming the circadian feeding rhythm and linking irregular light exposure to arrhythmic feeding and, consequently, obesity and metabolic diseases.

[Roles and functional interplay of the gut, brain stem, hypothalamus and limbic system in regulation of feeding].

The brain controls feeding via two components; homeostatic and accessory regulation. Homeostatic regulation is executed by the hypothalamic centers. Accessory regulation occurs in response to environmental conditions and stimuli such as memory, stress, emotion, reward and hedonic feeling, which are operated by the limbic system, particularly the hippocampus and amygdala. Nutrients and visceral hormones, representing peripheral metabolic states, regulate activity of these brain areas, which is performed by direct action after entering through blood-brain area and by sending information via the vagus nerve and brain stem. We here review how the hippocampus and amygdala as well as gut, brain stem and hypothalamus function and interact with each other to achieve integrative regulation of feeding.