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Adipogenic and Orexigenic Effects Of European Journal of Endocrinology (2004) 150 893–904 ISSN 0804-4643 EXPERIMENTAL STUDY Adipogenic and orexigenic effects of the ghrelin-receptor ligand tabimorelin are diminished in leptin-signalling- deficient ZDF rats A M Holm, P B Johansen, I Ahnfelt-Rønne and J Rømer Novo Nordisk A/S, Pharmacology Research, Novo Nordisk Park, DK-2760 Ma˚løv, Denmark (Correspondence should be addressed to P B Johansen, Pharmacology Research, Novo Nordisk Park, Building F6.2.30, DK-2760 Ma˚løv, Denmark; Email: [email protected]) Abstract Objective: The aim was to investigate the possible interactions of the two peripheral hormones, leptin and ghrelin, that regulate the energy balance in opposite directions. Methods: Leptin-receptor mutated Zucker diabetic fatty (ZDF) and lean control rats were treated with the ghrelin-receptor ligand, tabimorelin (50 mg/kg p.o.) for 18 days, and the effects on body weight, food intake and body composition were investigated. The level of expression of anabolic and catabolic neuropeptides and their receptors in the hypothalamic area were analysed by in situ hybridization. Results: Tabimorelin treatment induced hyperphagia and adiposity (increased total fat mass and gain in body weight) in lean control rats, while these parameters were not increased in ZDF rats. Treat- ment with tabimorelin of lean control rats increased hypothalamic mRNA expression of the anabolic neuropeptide Y (NPY) mRNA and decreased hypothalamic expression of the catabolic peptide pro- opiomelanocortin (POMC) mRNA. In ZDF rats, the expression of POMC mRNA was not affected by treatment with tabimorelin, whereas NPY mRNA expression was increased in the hypothalamic arcuate nucleus. Conclusion: This shows that tabimorelin-induced adiposity and hyperphagia in lean control rats are correlated with increased hypothalamic NPY mRNA and decreased POMC mRNA expression. The elimination of tabimorelin-induced adiposity and hyperphagia in ZDF rats may be due to lack of POMC mRNA downregulation. In conclusion, we suggest that ghrelin-receptor ligands exert their adipogenic and orexigenic effects via hypothalamic mechanisms that are dependent on intact leptin-receptor signalling. European Journal of Endocrinology 150 893–904 Introduction ghrelin-receptor ligands induces expression of the immediate-early gene c-Fos in many of these arcuate Ghrelin, a recently identified gastric hormone, is the neurons (12, 15, 16). The central effects of ghrelin endogenous ligand for the growth hormone secreta- may in part be mediated via NPY neurons in the arcu- gogue receptor (GHS-R) (1), now also known as the ate nucleus, as NPY mRNA and AGRP mRNA ghrelin receptor. It is well established that both ghrelin expression in these neurons is increased after adminis- and synthetic ghrelin-receptor ligands increase food tration of ghrelin icv (5, 17, 18), and pre-treatment intake and change the energy balance, including a with antibodies and antagonists of NPY and AGRP reduction in fat utilization that results in increased abolishes ghrelin-induced feeding (5). body weight and adiposity in animals (2–7). Upon fast- In contrast to ghrelin, administration of leptin inhi- ing in rats, ghrelin mRNA is upregulated in the ghrelin- bits appetite and adiposity, and augments energy producing oxyntic glands of the stomach, and the expenditure (19, 20). Ghrelin-induced food intake is plasma ghrelin level is elevated (8). suppressed when ghrelin and leptin are co-injected The ghrelin-receptor mRNA is expressed in the pitu- icv (5). Likewise, leptin-induced inhibition of food itary gland and in several areas of the brain (9, 10). intake can be reversed by ghrelin (17). The level of In the hypothalamus, the ghrelin-receptor mRNA is leptin in the circulation correlates with the degree of expressed in neuropeptide Y (NPY)/agouti-related adiposity, and, at least in rodents, leptin has been protein (AGRP)-, leptin-receptor- and growth hor- shown to function as a peripheral signal in a negative mone-releasing hormone (GHRH)-containing neurons feedback loop to hypothalamic nuclei involved in the (9, 11–14). Systemic administration of ghrelin or regulation of energy balance (21, 22). The plasma q 2004 Society of the European Journal of Endocrinology Online version via http://www.eje.org Downloaded from Bioscientifica.com at 09/25/2021 07:56:28AM via free access 894 A M Holm and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 150 leptin level reflects the state of the energy balance; that weight, n ¼ 11–12 in each group. From 13 weeks of is, fasting decreases plasma leptin while overfeeding age and the following 18 days, the rats were treated increases it (23). These opposing effects of leptin and daily p.o. with tabimorelin (50 mg/kg) or vehicle ghrelin on appetite and adiposity are thought to involve (saline), and body weight (n ¼ 11–12 in each group) arcuate neurons. Leptin inhibits NPY/AGRP- and and food intake (per cage) were measured (n ¼ 5–6 activates pro-opiomelanocortin (POMC)-containing in each group). neurons in the arcuate nucleus (20), and The rats were killed at day 18. Blood was collected leptin-induced reduction of hypothalamic NPY mRNA under isoflurane anaesthesia by cardiac puncture. is abolished by co-injection of ghrelin (17). Samples were taken in standard K3EDTA glass tubes In the present study, we have investigated the poss- (Vacutainer, VWR International, Albertslund, Den- ible interactions of the two peripheral hormones, mark), and plasma was isolated. The rats (n ¼ 5in leptin and ghrelin, that regulate the energy balance each group) were decapitated, and the brains were in opposite directions. Leptin-receptor mutated Zucker quickly removed, frozen in 2-methylbutane and kept at diabetic fatty (ZDF) and lean control rats were treated 280 8C until use. Coronal sections of 14 mm through with the ghrelin-receptor ligand, tabimorelin (NNC the hypothalamic area were cut with a Jung CM3000 26-703) (7), and the effects on body weight, food cryostat (Leica, Glostrup, Denmark), collected on Super- intake and body composition were investigated. Finally, Frost/Plus slides (Menzel-Gla¨ser, Braunschweig, the metabolic effects were correlated to changes Germany) and stored at 280 8C until further processing. induced in the hypothalamic pathways, as reflected The care and use of laboratory animals was according to by the level of expression of anabolic and catabolic an animal licence complying with federal regulations for hypothalamic neuropeptides and receptors. use of animals in research (the Danish Committee for Animal Research). The study design is illustrated in Materials and methods Fig. 1. For anatomical orientation, every fifteenth slide was Animals and tissue counterstained with haematoxylin and eosin (HE). Sec- Obese male ZDF (fa/fa), and lean male control rats (fa/þ) tions through the paraventricular nucleus (PVN), and were obtained from Genetic Models, Inc (Indianopolis, the middle and the caudal part of the arcuate nucleus USA). The rats arrived at 12 weeks of age, and were were selected. These sections were located at a distance housed under standardized environmental conditions of approximately 21.80, 23.00 and 23.70 mm from (18–22 8C; a 12-h light/dark cycle, lights on at Bregma, according to the rat brain atlas of Paxinos 0600 h; and two rats in each cage). The rats were and Watson (24). given free access to water and a diet of Purina 5008 Dual energy X-ray absorptiometry (DEXA) chow (PMI, Nutrition International, Richmond, IN, USA). At day 14, the body composition was determined by The rats were randomly assigned to four experimen- DEXA (pDEXA Sabre, Stratec Medizintechnic; Norland tal groups (vehicle and tabimorelin) according to body Medical Systems, Pho¨rzheim, Germany) in rats fasted Figure 1 Study design. Lean control rats and ZDF rats were treated daily with tabimorelin or vehicle for 18 days. Food intake and body weight were measured daily from day 0 to day 11. Body composition was determined by dual energy X-ray absorptiometry (DEXA) at day 14. Rats were killed at day 18, plasma was collected for leptin analysis and brains were collected for in situ hybridization. www.eje.org Downloaded from Bioscientifica.com at 09/25/2021 07:56:28AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 150 No effects of tabimorelin in ZDF rats 895 for 18 h. The rats were anaesthesized with a for transcription with T7 (sense probe) and T3 combination of Hypnorm and Dormicum (both diluted (antisense probe) RNA polymerase respectively. 1:1 in distilled water, mixed 1:1 and administered 2 ml/kg i.p.) (Hypnmorm, Janssen Animal Health, MC3-R The rat MC3-R cDNA fragment (bp 458-888, Belgium; Dormicum, Roche, Switzerland). The instru- GenEMBL no. x70667) was generated by RT-PCR ment settings used were as follows: a scan speed of with the primers 50-TGG AAA ACA TCC TGG TGA 40 mm/s, a resolution of 1.0 £ 1.0 mm, and automatic/ TCC TGG and 50-AAG AAC ATG GTG ATG AGG CAC manual histogram width estimation (n ¼ 11–12 in ACG. The plasmid was linearized with BamHI for each group). transcription with T3 (antisense probe) and NotI for transcription with T7 (sense probe) polymerase. Plasma leptin MC4-R The rat MC4-R cDNA fragment (bp 441-918, Plasma leptin was measured at day 18 with a commer- GenEMBL no. u67863) was generated by RT-PCR cially available mouse leptin enzyme-linked immuno- with the primers 50-GTC AGA AAC CAT CGT CAT sorbent assay kit (Crystal Chemical, Chicago, IL, CAC CC and 50-GCA GAC AAC AAA CAC TCC AAT USA), showing over 95% cross-reactivity to rat leptin. CAG. The plasmid was linearized with BamHI and NotI for transcription with T3 (antisense probe) and T7 (sense probe) RNA polymerase respectively. Plasmid preparation Rat NPY, POMC, AGRP, MC3-R, MC4-R, and ghrelin- Probe preparation receptor cDNA fragments were generated by RT-PCR, and each of these was subcloned into the pCR-Script For the synthesis of radiolabelled probes, linearized SK(þ) cloning vector, which was subsequently trans- plasmids were transcribed in 40 mM Tris, pH 7.5; formed into Epicurian Coli XL1-Blue MRF’Kan cells 6 mM NaCl2; 2 mM spermidine; 10 mM NaCl; 10 mM (Stratagene, La Jolla, CA, USA).
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