Chronic Central Administration of Apelin-13 Over 10 Days Increases Food Intake, Body Weight, Locomotor Activity and Body Temperature in C57BL/6 Mice
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Journal of Neuroendocrinology 20, 79–84 ORIGINAL ARTICLE ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd Chronic Central Administration of Apelin-13 Over 10 Days Increases Food Intake, Body Weight, Locomotor Activity and Body Temperature in C57BL/6 Mice A. Valle,* à N. Hoggard, A. C. Adams,à P. Roca* and J. R. Speakmanà *Grup de Metabolisme Energe`tic i Nutricio´, Departament de Biologia Fonamental i Cie`ncies de la Salut, Institut Universitari d’Investigacio´ en Cie`ncies de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, Spain. Division of Obesity and Metabolic Health, Rowett Research Institute, Aberdeen Centre for Energy Regulation and Obesity (ACERO), Aberdeen, UK. àACERO, School of Biological Sciences, University of Aberdeen, Aberdeen, UK. Journal of The peptide apelin has been located in a wide range of tissues, including the gastrointestinal tract, stomach and adipose tissue. Apelin and its receptor has also been detected in the arcuate Neuroendocrinology and paraventricular nuclei of the hypothalamus, which are involved in the control of feeding behaviour and energy expenditure. This distribution suggests apelin may play a role in energy homeostasis, but previous attempts to discern the effects of apelin by acute injection into the brain have yielded conflicting results. We examined the effect of a chronic 10-day intracerebro- ventricular (i.c.v.) infusion of apelin-13 into the third ventricle on food intake, body temperature and locomotor activity in C57BL ⁄ 6 mice. Apelin-13 (1 lg ⁄ day) increased food intake significantly on days 3–7 of infusion; thereafter, food intake of treated and control individuals converged. This convergence was potentially because of progressive conversion of apelin-13 to [Pyr1]apelin- 13 which has a four-fold lower receptor binding affinity at the orphan G protein-coupled recep- tor, APJ. Locomotor activity was also higher in the apelin-treated mice, especially during the nocturnal peak, when most feeding occurs, and the first hours of the light phase. Body temper- ature was also elevated during this increased period of activity, but was otherwise unaffected. Apelin-13-infused animals gained more weight than the saline-infused controls, suggesting the elevated locomotor activity did not offset the increased food intake. Elevated locomotion and the consequent increases in body temperature were probably secondary effects to the increased food intake. These results suggest that apelin-13 may play a central role in the control of feed- ing behaviour and is one of only two peripheral ligands known to stimulate rather than inhibit Correspondence to: intake. As apelin production is elevated during obesity, this may provide an important feed-for- Professor John R. Speakman, ward mechanism exacerbating the problem. Antagonists of the apelin receptor may therefore be Aberdeen Centre for Energy useful pharmaceuticals in the treatment of obesity. Regulation and Obesity (ACERO), School of Biological Sciences, Key words: apelin, intracerebroventricular infusion, food intake, weight gain, activity, body tem- University of Aberdeen, Aberdeen perature, telemetry. AB24 2TZ, UK (e-mail: [email protected]). doi: 10.1111/j.1365-2826.2007.01617.x Apelin is a peptide identified as the endogenous ligand of the lin-17, measured as the extracellular acidification rate in cultured orphan G protein-coupled receptor, APJ (1). This peptide is derived cells expressing the APJ receptor (1). Although little is know about from a 77-amino-acid precursor, which is processed to several the physiological role of apelin, the highly conserved sequence of molecular forms in different tissues, including apelin-36, apelin-17 apelin and APJ suggest an important physiological role (4). To date, and apelin-13 (2, 3). Apelin-13 is the main form circulating in several studies have shown that apelin is involved in the regulation plasma, and it has greater biological activity than apelin-36 or ape- of cardiovascular function (5–8) and fluid homeostasis (9, 10) 80 A. Valle et al. because systemic administration of apelin lowers blood pressure Measurement of motor activity and body temperature and increases water intake (6). Spontaneous motor activity and body temperature were recorded continu- Apelin and its receptor are widely expressed, particularly in the ously using an implanted passive transmitter (E-Mitter, Mini-Mitter, Bend, OR, central nervous system, heart, lung, testis, ovary, kidney, mammary USA). For implantation of the transmitter in the abdominal cavity, animals gland, gastric mucosa and adipose tissue (3). In the gastric mucosa, (n ¼ 12) were anaesthetised with isoflurane and an approximately 1-cm inci- apelin is involved in gastric cell proliferation, exocrine and endo- sion through the skin and abdominal muscle layer was made. After implanta- crine functions (11, 12). Recently, it was demonstrated that apelin tion, the peritoneal muscle and skin layers were closed with absorbable is secreted by adipose tissue, increased in obesity and regulated by sutures (5-0 Silk, Ethicon, Gargrave, England, UK). Each animal was returned to its home cage with ad libitum food and water for the duration of the both insulin and tumour necrosis factor-a (13–15). In the rat hypo- study. The transmitter obtains power from a radiofrequency field produced by thalamus, apelin mRNA expression is detected in several areas, an energiser ⁄ receiver placed below the cage of the animals. Locomotor activ- including the paraventricular, arcuate and supraoptic nuclei, which ity and body temperature were measured 1 min using a Windows-based data are involved in the control of feeding behaviour and circadian acquision system (VitalView, Mini-mitter, Bend, OR, USA). rhythms (16, 17). The reported distribution of apelin and the APJ receptor in the hypothalamus, gastric mucosa and adipose tissue has led to the hypothesis that apelin may have a role in the control Chronic i.c.v. apelin-13 infusion of feeding behaviour and energy homeostasis. Several previous After a 10-day recovery period from transmitter implantation, animals were studies have addressed this hypothesis; however, the results anaesthetised with isoflurane and placed in a stereotactic frame. The surgi- obtained are contradictory. Acute intracerebroventricular (i.c.v.) cal area was shaved and cleaned with povidone-iodine and alcohol swab. A administration of apelin-13 decreased food intake in both fed and dorsal incision of approximately 1.5 cm running laterally on the scalp was made, the skull was exposed and cleaned and then drilled at coordinates: starved rats (18). The same effects were observed when apelin was anterioposterior, )0.82 mm; lateral, Æ 0.30 mm from the bregma. The can- administered acutely i.c.v. nocturnally, but apelin-12 stimulated nula was then implanted at a depth of ) 2.5 mm below the dura. The can- intake following acute i.c.v. administration during the day-time also nula was secured in position by dental cement. Afterwards, an Alzet osmotic in rats (19). A further study of rats reported a slight increase in minipump (Alzet model 2002; Durect Corporation, Cupertino, CA, USA) filled food intake 2–4 h after acute i.c.v. administration, although this with saline or apelin-13 (H-4566; Bachem, Merseyside, UK) was implanted was not significant on the accumulated 24-h food intake (9). As far by insertion under the skin between the scapulae, and was connected by as energy expenditure is concerned, one report in the rat has catheter to the i.c.v. cannula through a subcutaneous tunnel. The pumps were loaded to deliver 1 lg ⁄ 7 ll ⁄ day of apelin-13 (n ¼ 6 animals) or shown that apelin increased core body temperature and locomotor 7 ll ⁄ day of saline alone (n ¼ 6 animals). The dose of apelin-13 we used activity (20); however, the extent to which these are linked and was based on previous acute i.c.v. studies (9, 18–20). These previous studies dependent on feeding behaviour changes remains unclear. Previous have used single injections of 1–30 nmol of apelin each day into rats confusion over the effects of apelin on feeding behaviour may weighing 250–300 g. For an average dose of 10 nmol, which previously reflect variation in the doses and time points of apelin administra- generated observable effects on food intake and thermogenesis, this is tion and potential handling artefacts during acute i.c.v. administra- equivalent to 0.05 lg apelin-13 ⁄ g body weight ⁄ day. Because our mice tion. Taking into account the confusion that currently exists in the weighed approximately 20 g, we also dosed at 0.05 lg apelin-13 ⁄ g body weight ⁄ day. The main difference, however, was that this dose was delivered literature, we determined the effects of chronic i.c.v. administration in our animals by slow infusion over 24 h whereas, in the previous studies, of apelin-13 on feeding behaviour, body weight, activity and body it was delivered as a single bolus injection. All animals were allowed to temperature using implanted transmitters, allowing us to noninva- recover and telemetry recordings were resumed to monitor activity and body sively monitor these traits using the mouse as a standard model. temperature continuously for a further 10 days, along with daily measures of food intake and body temperature. All observations were made blind of the treatment. At the end of the experiment, animals were killed and loca- Materials and methods tion of the cannula tip in the third ventricle was confirmed histologically. Animals Telemetry data sampling and analysis Animals were kept in accordance with UK Home Office guidelines. Female C57BL ⁄ 6 mice were purchased from Harlan UK Ltd (Bicester, Oxon, UK) and Data were sampled from the transmitters every 1 min throughout the individually housed under controlled conditions of temperature (22 °C) and experiment. Data were pooled and averaged (temperature) or accumulated under a 12 : 12 h light ⁄ dark cycle (lights on 07.00 h).