Anorexigenic protein, nesfatin-1, processed from its precursor protein, nesfatin/nucleobindin-2 (NUCB2), by prohormone convertases, is found in the paraventricular nucleus of the hypothalamus.1 Peripherally administered nesfatin-1 or its mid-segment section also inhibits feeding behavior.2 On the other hand, nesfatin/NUCB2 is ubiquitously expressed in peripheral tissues, including the white adipose tissue.3, 4 Production of nesfatin/NUCB2 in the white adipose tissue is regulated by the sympathetic nervous system.4 Bioactive substances released from adipose tissue are involved in the central regulation of metabolism.5 Nesfatin/NUCB2 and nesfatin-1, released from the adipose tissue, appear to be involved in the transmission of the anorexigenic signal from the periphery to the brain. Recently, intracerebroventricular infusion of nesfatin-1 was demonstrated to activate sympathetic nerve activities;6 intracerebroventricular administration of nesfatin-1also increases mean blood pressure (MBP).6 However, the issue of whether nesfatin/NUCB2, produced in the peripheral tissues, is physiologically involved in regulating blood pressure remains to be clarified. We have demonstrated a physiological role of nesfatin/NUCB2 in regulating blood pressure.

Male ICR (Institute of Cancer Research) mice were obtained from Charles Rivers Japan, Tokyo, Japan. Recombinant murine nesfatin-1 (25 nmol per dose; Bachem AG, Bubendorf, Switzerland) was subcutaneously injected into male ICR mice. Mice were pretreated with intraperitoneal administration of 10 mg kg−1 phentolamine (Sigma-Aldrich, St Louis, MO, USA)7 or 1 μg kg−1 propranolol (Sigma-Aldrich)8 30 min prior to the administration of 25 nmol nesfatin-1. A non-invasive blood pressure monitor (Model MK-2000ST, Muromachi Kikai, Tokyo, Japan) was used for the measurement of blood pressure and heart rate (HR).9, 10 All the data are expressed as mean±s.d. Statistical analysis of the mean values was performed by analysis of variance, followed by a Tukey test for comparisons of individual means. P<0.05 was considered statistically significant.

Peripheral administration of 25 nmol of nesfatin-1 significantly increased MBP in male ICR mice by 100 min after injection, but HR remained unaffected (Figure 1a). Pretreatment by subcutaneous injection of 10 mg kg−1 body weight phentolamine 15 min before nesfatin-1 had no effect on this increase in MBP by nesfatin-1, and HR remained unaffected (Figure 1b). In contrast, the increase in MBP was completely abolished by pretreatment with subcutaneous injection of 1 μg kg−1 body weight propranolol (Figure 1c), indicating that the β-adrenergic receptor is involved in the elevation of MBP caused by peripherally administered nesfatin-1.

Figure 1
figure 1

Changes of mean blood pressure (MBP; left panel) and heart rate (HR; right panel) after peripheral administration of 25 nmol nesfatin-1 in mice without (a) or with intraperitoneal administration of 10 mg kg−1 phentolamine (b) or 1 μg kg−1 propranolol (c) 15 min prior to the experiment. N=3 in each treatment group.

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Central infusion of nesfatin-1 activates the sympathetic nervous system in the brain, resulting in an increase in MBP via the α-adrenoreceptor, although intracerebroventricular infusion of nesfatin-1 does not affect HR.6 Peripheral nesfatin-1 is supposed to cross the blood–brain barrier and reach the brain by nonsaturable mechanism.11, 12 Peripherally administered nesfatin-1 significantly suppressed food intake in mice fed ad libitum,2 as did nesfatin-1 infused into the third ventricle.1 Therefore, peripherally administered nesfatin-1 could directly activate the sympathetic nervous system, a phenomenon that is in agreement with observations on feeding behavior.2 Pretreatment with phentolamine blocked MBP elevation by central nesfatin-1,6 but had no effect on MBP elevation induced by peripherally administered nesfatin-1; pretreatment with propranolol abolished MBP elevation, indicating an involvement of the β-adrenergic system in MBP elevation by peripherally administered nesfatin-1. As it is supposed that the mechanism of blood pressure elevation by β-adrenergic activation is based upon a combination of cardiac (increase of cardiac output) and intra-renal β-adrenergic activation, a hypothalamic mechanism may not have a main role in the regulation of systemic blood pressure. Although renal tubular sodium and water reabsorption is regulated by the β-adrenergic system, the effect of β-adrenergic receptor on the kidney may usually require many hours to develop. In addition, nesfatin-1 was recently found to specifically impair sodium nitroprusside-induced relaxation of vascular smooth muscle by inhibiting cyclic GMP production in rats.13 The present finding that peripheral administration of nesfatin-1 increased MBP without increasing HR in mice indicates a direct action of nesfatin-1 on vascular smooth muscle in vivo. In the future study, those possibilities should be clarified.

It is concluded that nesfatin/NUCB2 and/or nesfatin-1, released from the brain and peripheral tissues, is involved in the regulation of blood pressure in vivo, and it acts by modifying vascular contractility, in addition to the central mechanism. Nesfatin-1 or its precursor protein, nesfatin/NUCB2, may have a role on hypertension in the patients with type 2 diabetes or metabolic syndrome. Nesfatin-1 may probably be a new key molecule involved in hypertension, and can be used as an anti-obesity and anti-T2DM medications.