Elsevier

Regulatory Peptides

Volume 164, Issues 2–3, 24 September 2010, Pages 126-132
Regulatory Peptides

Arginine–vasopressin directly promotes a thermogenic and pro-inflammatory adipokine expression profile in brown adipocytes

https://doi.org/10.1016/j.regpep.2010.05.016Get rights and content

Abstract

Arginine–vasopressin (AVP) — via activation of the hypothalamic-pituitary-adrenal (HPA) axis — may play a role in the regulation of energy homeostasis and related cardiovascular complications. Brown adipose tissue (BAT) — via dissipation of energy in the form of heat — contributes to whole body energy balance. BAT expresses vasopressin receptors. We investigated direct effects of AVP on brown adipose endocrine and metabolic functions. UCP-1 protein expression in differentiated brown adipocytes was induced after acute exposure of adipocytes to AVP. This effect was time-dependent with a maximum increase after 8 h. AVP also induced a time- and dose-dependent increase in p38 MAP kinase phosphorylation. Pharmacological inhibition of p38 MAP kinase with SB 202190 abolished the induction of UCP-1 protein expression. Furthermore, while acute AVP treatment enhanced mRNA expression of MCP-1 and IL-6, adiponectin mRNA expression was reduced. Yet, on the level of intracellular glucose uptake, there was no AVP-induced change of adipose insulin-induced glucose uptake. Finally, there was no difference in lipid accumulation between control and AVP-treated cells.

Taken together, our data demonstrate direct effects of AVP on thermogenic, inflammatory, and glucoregulatory gene expression in brown adipocytes, thus expanding the hitherto known spectrum of this neuropeptides's biological effects and suggesting a direct adipotropic role as a stress-promoting factor.

Introduction

Arginine–vasopressin (AVP), synthesized in the hypothalamus, is a posterior pituitary hormone. Along with its carrier protein, neurophysin II, AVP is packaged into neurosecretory vesicles and transported axonally in the neurohypophysis where it is either stored or secreted into the bloodstream. AVP is involved in various functions, including regulation of water excretion by direct antidiuretic action on the kidney, vasoconstriction of the peripheral vessels, involvement in cardiomyocyte remodeling, and energy homeostasis. It is also involved in cognition, tolerance, maternal behavior, and in the modulation of adrenocorticotropic hormone (ACTH) release from the pituitary in response to stress [1]. Interestingly, ACTH directly induces insulin resistance, promotes a pro-inflammatory adipokine profile and stimulates UCP-1 in adipocytes [2]. However, direct effects of AVP on adipocyte metabolism and function are unknown. AVP's physiological effects are mediated through the binding to specific membrane receptors of the target cells. The AVP receptors have been classified into at least three types: V1a, V1b (V3), and V2. V1a receptors are expressed in vascular smooth muscle cells [3], [4], cardiomyocytes [5], hepatocytes [6], and platelets [7]. Recently, V1a receptors were identified in white (WAT) and brown (BAT) adipose tissue [8]. V1b receptors are expressed in pituitary cells as well as in WAT [8]. V1a AVP receptor knockout mice exhibit higher levels of ketone bodies and glycerol, increased catabolism of triacylglycerides and free fatty acids [8] and display decreased sympathetic nerve and renin angiotensin activity [9], whereas V1b AVP receptor knockout mice show a higher insulin sensitivity [10]. In mice lacking both V1 receptors an impaired glucose tolerance in response to a high-fat diet could be observed [11]. V2 receptor is found primarily in the kidney and is linked to adenylate cyclase and the production of cAMP, in association with antidiuresis [12]. AVP appears to play a role in the regulation of euglycemia since plasma AVP levels are increased in humans suffering from type 1 and type 2 diabetes [13], [14]. Moreover, insulin- or sulfonylurea-therapy reduced not only plasma glucose level, but also AVP concentration [15], [16], [17]. Infusions with AVP are associated with increased circulating glucose levels in rats and humans [18], [19]. These effects seem to be mediated via stimulation of glucagon release from pancreatic islet cells [20] and direct promotion of glycogenolysis and gluconeogenesis in heptatocytes [21]. Furthermore, previous work showed that AVP is involved in lipid metabolism. Circulating ketone bodies [18] were reduced and free fatty acid release was enhanced in starved rats while treating with AVP [22]. This lends support to an anitilipolytic effect of AVP on adipocytes.

Obesity and insulin resistance are core components of the metabolic syndrome, which is a major risk factor for the development of cardiovascular disease. There is growing evidence for an implication of adipose dysfunction critically promoting the development of the metabolic syndrome and its complications [23], [24]. Recently, the importance of BAT for energy disposal in obese and overweight subjects has been demonstrated in a number of major human studies [25], [26], [27]. Dysfunction of BAT may include insulin resistance, reduced thermogenesis in response to cold and food intake, as well as alterations in the accurate time- and dose-dependent secretion of adipokines. Here, we reveal direct effects of AVP on thermogenic and endocrine brown adipose functions, thus suggesting a role of this neuropeptide as an adipotropic, endocrine stress-mediating factor.

Section snippets

Materials

Phospho-specific p44/p42 MAP kinase, phospho-specific and total p38 MAP kinase, and PKB/Akt antibodies were purchased from Cell Signaling (Beverly, MA, USA). UCP-1 antibody was purchased from Millipore (Billerica, MA, USA). Glucose uptake assays were performed with 2-deoxy-[3H] glucose from NEN Life Technologies (Boston, MA, USA). Primers for gene expression analysis were ordered from Biometra (Goettingen, Germany). Unless stated otherwise, all chemicals were purchased from Sigma-Aldrich (St.

Chronic AVP-treatment of adipose tissue during differentiation does not alter lipid accumulation of brown adipose tissue (BAT)

The first aim of this study was to investigate the effect of AVP on thermogenesis in brown adipose tissue (BAT). Since the expression of uncoupling protein-1 (UCP-1) is dependent on cell differentiation, effects of chronic AVP-treatment on adipogenesis and lipid accumulation had to be excluded. Microscopic analysis and fat-specific oil red O stain during the differentiation process indicates the extent of stored intracellular triglycerides. Chronic stimulation with AVP (1 μM) had no effect,

Discussion

The hypothalamic-pituitary-adrenal axis (HPA) is pivotal for the organism to react to changing environment as well as stress stimuli. Adrenocorticotropic hormone (ACTH), one of HPA main effectors, is relevant in maintaining energy homeostasis [2] and seems to be modulated by AVP in response to stress [1]. Recent data suggest that AVP is also involved in modulation of glucose homeostasis [10] and possesses antilipolytic properties [8], [30]. Our in vitro study focusses on direct effects of AVP

Acknowledgements

This study was supported by grants from the Deutsche Forschungsgemeinschaft (Kl 1131/2-5 to JK), and by grants from the Federal Ministry of Defense of Germany (07K3-S-200506 and 13K3-S-200708). The authors state no conflict of interest.

References (48)

  • H. Suzuki et al.

    Regulatory mechanism of the arginine vasopressin-enhanced green fluorescent protein fusion gene expression in acute and chronic stress

    Peptides

    (2009)
  • D. Zelena et al.

    The stimuli-specific role of vasopressin in the hypothalamo-pituitary-adrenal axis response to stress

    J Endocrinol

    (2009)
  • K.A. Iwen et al.

    Melanocortin crosstalk with adipose functions: ACTH directly induces insulin resistance, promotes a pro-inflammatory adipokine profile and stimulates UCP-1 in adipocytes

    J Endocrinol

    (2008)
  • F.L. Stassen et al.

    Identification and characterization of vascular (V1) vasopressin receptors of an established smooth muscle cell line

    Mol Pharmacol

    (1987)
  • R.A. Nemenoff

    Vasopressin signaling pathways in vascular smooth muscle

    Front Biosci

    (1998)
  • N.L. Ostrowski et al.

    Expression of vasopressin V1a and V2 receptor messenger ribonucleic acid in the liver and kidney of embryonic, developing, and adult rats

    Endocrinology

    (1993)
  • M. Hiroyama et al.

    Hypermetabolism of fat in V1a vasopressin receptor knockout mice

    Mol Endocrinol

    (2007)
  • T. Aoyagi et al.

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

    Am J Physiol Ren Physiol

    (2008)
  • Y. Fujiwara et al.

    Insulin hypersensitivity in mice lacking the V1b vasopressin receptor

    J Physiol

    (2007)
  • H. Nonoguchi et al.

    Immunohistochemical localization of V2 vasopressin receptor along the nephron and functional role of luminal V2 receptor in terminal inner medullary collecting ducts

    J Clin Invest

    (1995)
  • C.H. Walsh et al.

    Plasma arginine vasopressin in diabetic ketoacidosis

    Diabetologia

    (1979)
  • R.L. Zerbe et al.

    Plasma vasopressin in uncontrolled diabetes mellitus

    Diabetes

    (1979)
  • P.H. Baylis et al.

    Vasopressin function in hypercalcaemia

    Clin Endocrinol (Oxf)

    (1981)
  • J.J. Milles et al.

    Plasma vasopressin during insulin withdrawal in insulin-dependent diabetes

    Diabetologia

    (1981)
  • Cited by (0)

    View full text