Arginine–vasopressin directly promotes a thermogenic and pro-inflammatory adipokine expression profile in brown adipocytes
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)
- et al.
The role of arginine vasopressin and its receptors in the normal and failing rat heart
J Mol Cell Cardiol
(2003) - et al.
V1a-vasopressin specific receptors on human platelets: potentiation by ADP and epinephrine and evidence for homologous down-regulation
Thromb Res
(1987) - et al.
Both V(1A) and V(1B) vasopressin receptors deficiency result in impaired glucose tolerance
Eur J Pharmacol
(2009) - et al.
Thirst and plasma levels of vasopressin, angiotensin II and atrial natriuretic peptide in patients with non-insulin-dependent diabetes mellitus
Diab Res Clin Pract
(1991) - et al.
Modulation of insulin and glucagon secretion from the perfused rat pancreas by the neurohypophysial hormones and by desamino-D-arginine vasopressin (DDAVP)
Peptides
(1984) Short-term hormonal control of hepatic carbohydrate and lipid catabolism
FEBS Lett
(1977)- et al.
Beta(3)-adrenergic stimulation differentially inhibits insulin signaling and decreases insulin-induced glucose uptake in brown adipocytes
J Biol Chem
(1999) - et al.
Altered lipid metabolism in vasopressin V1B receptor-deficient mice
Eur J Pharmacol
(2009) - et al.
Intracerebroventricular interleukin-6 treatment decreases body fat in rats
Biochem Biophys Res Commun
(2002) - et al.
Involvement of low adiponectin levels in impaired glucose tolerance
Metabolism
(2008)