The neurohypophysial hormone arginine vasopressin (AVP) is essential for a wide range of physiological functions, including water reabsorption, cardiovascular homeostasis, hormone secretion, and social behavior. These and other actions of AVP are mediated by at least three distinct receptor subtypes: V1a, V1b, and V2. Although the antidiuretic action of AVP and V2 receptor in renal distal tubules and collecting ducts is relatively well understood, recent years have seen an increasing understanding of the physiological roles of V1a and V1b receptors. The V1a receptor is originally found in the vascular smooth muscle and the V1b receptor in the anterior pituitary. Deletion of V1a or V1b receptor genes in mice revealed that the contributions of these receptors extend far beyond cardiovascular or hormone-secreting functions. Together with extensively developed pharmacological tools, genetically altered rodent models have advanced the understanding of a variety of AVP systems. Our report reviews the findings in this important field by covering a wide range of research, from the molecular physiology of V1a and V1b receptors to studies on whole animals, including gene knockout/knockdown studies.

Arginine-vasopressin (AVP) is known to be involved in maintaining glucose homeostasis, and AVP-resistance is observed in poorly controlled non-insulin-dependent diabetes mellitus subjects, resulting in a lowered plasma volume. Recently we reported that V1a vasopressin receptor-deficient (V1aR ؊/؊ ) mice exhibited a decreased circulating blood volume and hypermetabolism of fat accompanied with impaired insulin-signaling. Here we further investigated the roles of the AVP/V1a receptor in regulating glucose homeostasis and plasma volume using V1aR؊/؊ mice. The plasma glucose levels at the baseline or during a glucose tolerance test were higher in V1aR ؊/؊ than wild-type (WT) mice. Moreover, a hyperinsulinemic-euglycemic clamp revealed that the glucose infusion rate was significantly lower in V1aR ؊/؊ mice than in WT mice and that hepatic glucose production was higher in V1aR ؊/؊ mice than WT mice. In contrast to the increased hepatic glucose production, the liver glycogen content was decreased in the mutant mice. These results indicated that the mutant mice had impaired glucose tolerance. Furthermore, feeding V1aR ؊/؊ mice a high-fat diet accompanied by increased calorie intake resulted in significantly overt obesity in comparison with WT mice. In addition, we found that the circulating plasma volume and aldosterone level were decreased in V1aR ؊/؊ mice, although the plasma AVP level was increased. These results suggested that the effect of AVP on water recruitment was disturbed in V1aR ؊/؊ mice. Thus, we demonstrated that one of the AVP-resistance conditions resulting from deficiency of the V1a receptor leads to decreased plasma volume as well as impaired glucose homeostasis, which can progress to obesity under conditions of increased calorie intake. (Endocrinology 148: 2075-2084, 2007)A RGININE-VASOPRESSIN (AVP) is a neuropeptide hormone that is involved in diverse functions, including the regulation of osmotic homeostasis, vasoconstriction, and ACTH release. These physiological effects are mediated by three types of AVP receptors, designated as V1a, V1b, and V2 (1-3). The V1a receptor is widely expressed, whereas the V1b and V2 receptors are predominantly expressed in the anterior pituitary and the kidney, respectively (1-4). The functional role of the V1a receptor is considered to mediate vascular contraction (5), cellular proliferation (6), platelet aggregation (7), and glycogenolysis (1, 8). The V1b receptor stimulates ACTH and insulin release (9, 10). Both V1a and V1b receptors bind to the Gq protein and act through phosphatidylinositol hydrolysis to mobilize intercellular Ca 2ϩ (11,12). The V2 receptor is coupled with the Gs protein and stimulates adenylate cyclase to increase cellular cAMP, which results in the induction of an antidiuretic effect in the kidney (13).There have been several reports indicating the involvement of AVP in regulating the plasma glucose homeostasis. The plasma AVP level was increased in patients with insulindependent diabetes mellitus (IDDM) or non-IDDM (NIDDM) (14, 15), and treati...

[Arg8]Vasopressin (AVP) has an antilipolytic action on adipocytes, but little is known about the mechanisms involved. Here, we examined the involvement of the V1a receptor in the antilipolytic effect of AVP using V1a receptor-deficient (V1aR-/-) mice. The levels of blood glycerol were increased in V1aR-/- mice. The levels of ketone bodies, such as acetoacetic acid and 3-hydroxybutyric acid, the products of the lipid metabolism, were increased in V1aR-/- mice under a fasting condition. Triacylglyceride and free fatty acid levels in blood were decreased in V1aR-/- mice. Furthermore, measurements with tandem mass spectrometry determined that carnitine and acylcarnitines in serum, the products of beta-oxidation, were increased in V1aR-/- mice. Most acylcarnitines were increased in V1aR-/- mice, especially in the case of 2-carbon (C2), C10:1, C10, C14:1, C16, C18:1, and hydroxy-18:1-carbon (OH-C18:1)-acylcarnitines under feeding rather than under fasting conditions. The analysis of tissue C2-acylcarnitine level showed that beta-oxidation was promoted in muscle under the feeding condition and in liver under the fasting condition. An in vitro assay using brown adipocytes showed that the cells of V1aR-/- mice were more sensitive to isoproterenol for lipolysis. These results suggest that the lipid metabolism is enhanced in V1aR-/- mice. The cAMP level was enhanced in V1aR-/- mice in response to isoproterenol. The phosphorylation of Akt by insulin stimulation was reduced in V1aR-/- mice. These results suggest that insulin signaling is suppressed in V1aR-/- mice. In addition, the total bile acid, taurine, and cholesterol levels in blood were increased, and an enlargement of the cholecyst was observed in V1aR-/- mice. These results indicated that the production of bile acid was enhanced by the increased level of cholesterol and taurine. Therefore, these results indicated that AVP could modulate the lipid metabolism by the antilipolytic action and the synthesis of bile acid via the V1a receptor.

A. Vasopressin regulates the renin-angiotensin-aldosterone system via V1a receptors in macula densa cells.

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We have reported that [Arg 8 ]-vasopressin-stimulated insulin release is blunted in islet cells isolated from V1b receptor-deficient (V1bR−/− ) mice. In this study, we used V1bR −/− mice to examine the physiological role of the V1b receptor in regulating blood glucose levels in vivo, and we found that the fasting plasma glucose, insulin and glucagon levels were lower in V1bR −/− mice than in wild-type (V1bR +/+ ) mice. Next, we evaluated glucose tolerance by performing an intraperitoneal glucose tolerance test (GTT). The plasma glucose and insulin levels during the GTT were lower in V1bR −/− mice than in V1bR +/+ mice. An insulin tolerance test (ITT) revealed that, after insulin administration, plasma glucose levels were lower in V1bR −/− mice than in V1bR +/+ mice. In addition, a hyperinsulinaemic-euglycaemic clamp study showed that the glucose infusion rate was increased in V1bR −/− mice, indicating that insulin sensitivity was enhanced at the in vivo level in V1bR −/− mice. Furthermore, we found that the V1b receptor was expressed in white adipose tissue and that insulin-stimulated phosphorylation of Akt as an important signaling molecule was increased in adipocytes isolated from V1bR −/− mice. Thus, the blockade of the V1b receptor could result, at least in part, in enhanced insulin sensitivity by altering insulin signalling in adipocytes.

Here, we report the highly efficient in vitro differentiation of human bone marrow-derived mesenchymal stem/progenitor cells (MPCs) using a novel nanotechnology-based culture plate, nanoculture plate(®) (NCP). The NCP contains uneven microfabrications with diameters of ∼2-3 μm arranged in a honeycomb pattern on its culture surface, which is devoid of animal-derived protein sources. When human MPCs were subjected to three-dimensional (3D) culture using an NCP, they rapidly formed adhesive spheroids. We showed that adipogenic differentiation in NCP-mediated 3D cultures led to more rapid accumulation of triglycerides than that in two-dimensional cultures. During adipogenesis in 3D cultures, the rapid and intense induction of adipocyte-specific gene expressions, such as peroxisome proliferator-activated receptor γ (PPAR-γ), CCAAT-enhancer-binding protein α (C/EBP-α), adipocyte protein 2 (aP2), and adiponectin was observed. Together, these results indicate that this 3D culture system is suitable for the differentiation of human MPCs into adipogenic lineage, and could be applicable to adipose tissue engineering under xeno-free condition.

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