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Interactions of Amylinergic and Melanocortinergic Systems in The Diabetes, Obesity and Metabolism 14: 608–615, 2012. original article © 2012 Blackwell Publishing Ltd Interactions of amylinergic and melanocortinergic systems in the control of food intake and body weight in rodents J. D. Roth, L. D’Souza, P. S. Griffin, J. Athanacio, J. L. Trevaskis, R. Nazarbaghi, C. Jodka, J. Athanacio, J. Hoyt, B. Forood & D. G. Parkes article original Amylin Pharmaceuticals, Inc., San Diego, CA, USA Aims: Amylinergic and melanocortinergic systems have each been implicated in energy balance regulation. We examined the interactive effects of both systems using gene knockout and pharmacological approaches. Methods: Acute food consumption was measured in overnight fasted male wild-type (WT) and melanocortin-4 receptor (MC-4R) deficient rats and in male and female WT and amylin knockout mice (AmyKO). Changes in food intake, body weight and composition in male WT and MC-4R deficient rats and in male diet-induced obese (DIO) rats. Pharmacological treatments included either rat amylin, murine leptin and/or the MC-4R agonist, Ac-R[CEH-dF-RWC]-amide. Results: Amylin (10 μg/kg, IP) decreased food intake in WT but not in MC-4R deficient rats (30 and 60 min post-injection). Ac-R[CEH-dF-RWC]- amide (100 μg/kg, IP) suppressed food intake similarly in male WT and AmyKO, but was ineffective in female AmyKO. Amylin (50 μg/kg/day for 28 days) and leptin (125 μg/kg/day) synergistically reduced food intake and body weight in WT and MC-4R deficient rats to a similar extent. Amylin (100 μg/kg) combined with Ac-R[CEH-dF-RWC]-amide (100 μg/kg, IP) decreased acute food intake over 3 h to a greater extent than either agent alone in fasted mice. In DIO rats, additive anorexigenic, weight- and fat-lowering effects were observed over 12 days with the combination of rat amylin (50 μg/kg/day) and Ac-R[CEH-dF-RWC]-amide (2.3 mg/kg, SC injected daily). Conclusions: Although amylin’s acute anorexigenic effects are somewhat blunted in MC-4R deficiency and those of MC-4R agonism in amylin deficiency, these effects are surmountable with pharmacological administration lending therapeutic potential to combined amylin/melanocortin agonism for obesity. Keywords: amylin, body weight obesity, combination, food intake, melanocortins Date submitted 28 November 2011; date of first decision 22 December 2011; date of final acceptance 19 January 2012 Introduction Peptidic and small molecule MC-4R agonists have received significant interest as potential antiobesity drugs [10,11]. Among the peripheral signals implicated in the control of To our knowledge the interaction of amylinergic and energy balance is amylin, a 37-amino acid peptide hormone melanocortinergic systems has only been investigated to a produced in pancreatic β-cells and co-secreted with insulin in limited extent. Amylin retained its acute anorexigenic effects response to nutrient ingestion. In diet-induced obese (DIO) in agouti mice (in which ectopic expression of the agouti- rats and overweight/obese humans, the weight-lowering effects related protein (AgRP) antagonizes central MC-3Rs and of amylin agonism have been repeatedly showed, and mech- MC-4Rs) and sustained administration of amylin, but not anistic studies in rodents suggest that body weight is reduced caloric restriction, modestly upregulated hypothalamic pro- in a fat-specific, lean mass-preserving manner [1–3]. Amylin opiomelanocortin (POMC) levels in DIO rats [3]. Our present agonism has also been shown to restore leptin responsiveness studies further investigate the interactive effects of these two in preclinical models, as well as in obese humans [4–6]. systems by: (i) exploring the antiobesity effects of amylin in An important downstream regulator of leptin is the hypotha- an MC-4R-deficient state, and conversely, MC-4R agonism in lamic melanocortin (MC) systems. Convergent lines of evi- an amylin-deficient state, (ii) establishing whether MC-4Rs are dence underscore the importance of the MC subtype-4 receptor necessary for the synergistic action of amylin/leptin to reduce (MC-4R) as a key regulator of feeding behaviour. MC-4R body weight, and (iii) evaluating the utility of amylin/MC-4R combination therapy in DIO rats. knockout mice are severely obese [7], MC-4R antagonism stimulates food intake and weight gain [7,8] and mutations in the human MC-4R have been associated with obesity [9]. Materials and Methods Animals, Housing, Diet and Drug Correspondence to: Jonathan D. Roth, PhD, Amylin Pharmaceuticals, Inc., 9360 Towne Centre Drive, San Diego, CA 92121, USA. All studies were approved by the Institutional Animal Care E-mail: [email protected] and Use Committee at Amylin Pharmaceuticals, in accordance DIABETES, OBESITY AND METABOLISM original article with Animal Welfare Act guidelines. Animals were housed Food was returned 30 min later and cumulative intake (cor- ◦ individually in standard caging at 22 C in a 12-h light, 12-h rected for spillage) was measured at 30, 60, 120, 180 and dark cycle. 240 min. Food intake studies were performed in normal female NIH Swiss mice (Harlan, Indianapolis, IN, USA). Studies using Study 3: Effects of Amylin and/or Leptin on 28-day mice deficient for the amylin gene, hereafter referred to as Food Intake and Body Weight in WT and amylin knockout (AmyKO) mice, were backcrossed at least six Mc4rK314X/K314X Rats generations onto the C57Bl/6J strain (as described in Ref. [6]). The original AmyKO line was established on a mixed 129Ola/B6 For chronic infusion studies we selected doses of amylin background in which the amylin coding sequence in exon 3 of and leptin that reliably synergize to promote weight loss in the amylin gene was replaced by a neomycin resistance cassette. lean and DIO rat models [5,6]. Each drug (or vehicle) was AmyKO and WT littermate controls were genotyped at weaning delivered by a separate surgically implanted subcutaneous (SC) (Taconic, Hudson, NY, USA). All mice were maintained ad osmotic minipump (Durect Corporation, Cupertino, CA, USA) libitum on standard chow (7012; Harlan Teklad, Madison, containing either drug or vehicle (50% DMSO/sterile water WI, USA). for amylin, sterile water for leptin). Food intake (corrected Male MC-4R deficient rats (Mc4rK314X/K314X) and littermate for spillage) and body weight (expressed as percent vehicle WT controls were obtained from Transposagen Biopharma- corrected due to the differing starting body weights of these ceuticals (Lexington, KY, USA). These rats carry an N-ethyl- strains) were recorded on days 0, 1, 3, 7, 14, 21 and 28. At N-nitrosourea-induced mutation that introduces a premature the start of the study body weights (in grams ± s.e.m.) of stop codon in the eighth helix of Mc4r, resulting in a full knock- the treatment groups were: WT-vehicle, 520 ± 9; WT-amylin, out phenotype [12]. WT and Mc4rK314X/K314X were maintained 523 ± 12; WT-leptin, 524 ± 14; WT-amylin + leptin, 521 ± 13; ad libitum on a moderately high-fat diet (32% kcal from fat; Mc4rK314X/K314X-vehicle, 568 ± 33; Mc4rK314X/K314X -amylin, Research Diets D1226B, New Brunswick, NJ, USA). 564 ± 20; Mc4rK314X/K314X-leptin, 566 ± 9; Mc4rK314X/K314X- DIO rat studies used male Sprague–Dawley rats from amylin + leptin, 567 ± 4. Charles River Laboratories (CRL: CD rats; Wilmington, MA, USA). DIO rats were also maintained ad libitum on Study 4: Effects of the Amylin/MC-4R Combination on the moderately high-fat diet (Research Diets D1226B) for Food Intake in Overnight Fasted Mice approximately 8 weeks before and during treatment to induce = a DIO state. This study used group-housed (n 3/cage) female NIH Swiss Murine leptin was recombinantly synthesized at Amylin mice (24–30 g). Cages were randomized into treatment groups = = Pharmaceuticals (San Diego, CA, USA) and was dissolved in (n 4 cages per peptide). All mice within a cage (n 3per sterile water for injection and infusion studies. Rat amylin cage) received the same treatment. Mice received an IP injec- was obtained from Peptisyntha (Torrance, CA, USA) and tion either peptide or vehicle, and food intake per cage was dissolved in 10% dimethyl sulfoxide (DMSO)/sterile water measured 30, 60, 120 and 180 min post-injection. for acute injection studies and 50% DMSO/sterile water for minipump infusion studies. The MC-4R agonist Ac-R[CEH- Study 5: Effects of Combined Amylin and MC-4R dF-RWC]-amide was synthesized at Amylin Pharmaceuticals Agonism on Food Intake, Body Weight and Body as previously described [13] and dissolved in saline before Composition in DIO Rats injection. This compound was selected from the series of MC analogues because it displayed potent binding affinity and This study was designed to test the interactive effects of rat functional activity for MC-4R (Ki = 0.4nM;EC = 0.4nM) amylin and an MC-4R selective agonist on body weight and 50 μ versus MC-3R (Ki = 39.4 nM) [13]. food intake. We selected a dose of amylin (50 g/kg/day) that has reliably shown additive/synergistic effects on weight loss Study 1: Acute Food Intake Study in Mc4rK314X/K314X with a variety of test agents [14–16]. A pilot dose response Rats study was conducted in rats to identify a dose of Ac-R[CEH- dF-RWC]-amide that would suppress food intake over 24 h. K314X/K314X = Male WT and Mc4r (n 6/group) rats were fasted DIO rats were injected with either 0.46, 2.3 or 4.6 mg/kg overnight and injected IP with either vehicle or rat amylin and 24-h food intake was reduced by 20, 35 and 47%, μ (10 g/kg). Food was returned 30 min later and cumulative respectively. Based on these findings, we selected a dose of intake (corrected for spillage) was measured at 30, 60 and 2.3 mg/kg for repeated administration.
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