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Amylin/Calcitonin Receptor–Mediated Signaling in POMC Neurons Influences Energy Balance and Locomotor Activity in Chow-Fed Male Mice

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Amylin/Calcitonin Receptor–Mediated Signaling in POMC Neurons Influences Energy Balance and Locomotor Activity in Chow-Fed Male Mice 1110 Diabetes Volume 69, June 2020 Amylin/Calcitonin Receptor–Mediated Signaling in POMC Neurons Influences Energy Balance and Locomotor Activity in Chow-Fed Male Mice Bernd Coester, Christina Koester-Hegmann, Thomas A. Lutz, and Christelle Le Foll Diabetes 2020;69:1110–1125 | https://doi.org/10.2337/db19-0849 Amylin, a pancreatic hormone and neuropeptide, acts but amylin also has other binding sites in the central ner- principally in the hindbrain to decrease food intake and vous system that have not been thoroughly studied yet, has recently been shown to act as a neurotrophic factor such as the nucleus of the solitary tract (NTS), the lateral to control the development of area postrema → nucleus hypothalamic area (LHA), and the ventromedial (VMN) of the solitary tract and arcuate hypothalamic nucleus → and arcuate (ARC) hypothalamic nucleus (6–8). Recent data paraventricular nucleus axonal fiber outgrowth. Amylin is of whole brain imaging with fluorescently labeled rat amylin fi also able to activate ERK signaling speci cally in POMC in vivo confirmed its binding in the ARC and AP (9). The neurons independently of leptin. For investigation of the ARC has come into focus as a mediator of amylin’s effects physiological role of amylin signaling in POMC neurons, on energy expenditure (EE), its interactions with leptin the core component of the amylin receptor, calcitonin signaling pathways, and its developmental effects on ax- receptor (CTR), was depleted from POMC neurons using onal fiber outgrowth (6,10,11). The effects of amylin in an inducible mouse model. The loss of CTR in POMC adults are of interest because chronic amylin treatment has neurons leads to increased body weight gain, increased adiposity, and glucose intolerance in male knockout mice, a sizable effect on weight loss that cannot be solely explained METABOLISM characterized by decreased energy expenditure (EE) and by a reduction in food intake (12) and hypothalamic actions “ ” decreased expression of uncoupling protein 1 (UCP1) in might contribute to the leptin-sensitizing effect of amylin brown adipose tissue. Furthermore, a decreased spon- (13,14). taneous locomotor activity and absent thermogenic re- Our current hypothetical model of amylin signaling in action to the application of the amylin receptor agonist the ARC includes a direct effect of amylin on POMC neurons were observed in male and female mice. Together, these through ERK1/2 phosphorylation and an indirect effect on results show a significant physiological impact of amylin/ AgRP neurons through microglial IL-6 secretion (15). This calcitonin signaling in CTR-POMC neurons on energy study aims to investigate the direct physiological effect of metabolism and demonstrate the need for sex-specific endogenous amylin signaling on POMC neurons with a approaches in obesity research and potentially treatment. conditional genetic knockout (KO) model. The depletion of CTR specifically in POMC neurons with tamoxifen (Tx) induction after weaning aims to avoid early developmental Amylin is a pancreatic gut hormone that is co-released with effects of disturbed amylin signaling (15) and allows us to insulin by b-cells in response to meals (1). The main central test the hypothesis that amylin signaling in POMC neu- effect of amylin is an acute reduction of food intake that rons is critical for the control of EE. occurs after amylin binding to neurons in the area post- rema (AP) (2). The amylin receptor consists of a core cal- RESEARCH DESIGN AND METHODS citonin receptor (CTRA/B), which is coupled to receptor Animal Husbandry and Diet activity–modifying proteins (RAMP1–3) (3,4). These receptor Animals were kept in a temperature-controlled environ- components are expressed in single neurons of the AP (5), ment (21 6 2°C) on a 12:12 h light cycle with lights off at Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, © 2020 by the American Diabetes Association. Readers may use this article as Switzerland long as the work is properly cited, the use is educational and not for profit, and the Corresponding author: Christelle Le Foll, [email protected] work is not altered. More information is available at https://www.diabetesjournals .org/content/license. Received 27 August 2019 and accepted 28 February 2020 This article contains supplementary material online at https://diabetes.diabetesjournals .org/lookup/suppl/doi:10.2337/db19-0849/-/DC1. diabetes.diabetesjournals.org Coester and Associates 1111 1000 h. After weaning, they were separated by genotype Care, Basel, Switzerland) at the tail was measured before and group-housed with littermates or single-housed for and 15, 30, 45, 60, 90, and 120 min after gavage or injection. the Tx injections (16). Tx (cat. no. T5648; Sigma-Aldrich, In addition, baseline blood samples after a 2-h fast during the Merck KGaA, Darmstadt, Germany) was dissolved in pure study were obtained by tongue bleeding during a brief ethanol and mixed with corn oil (cat. no. C8267; Sigma- 30-s isoflurane anesthesia (2%). Insulin and leptin were Aldrich) for a final concentration of 100 mg/mL. Mice were measured (Meso Scale Discovery, Rockville, MD). injected at 4 weeks old with a dose of 150 mg/g or corn oil Telemetric Sensors, Indirect Calorimetry, and Body for 5 days. A first cohort of mice was fed standard chow Composition Measurements (65% carbohydrate, 22% protein, and 12.5% fat as per- TA-F10 sensors for body temperature and activity mea- cent of total energy content, cat. no. 3430; Provimi Kliba, surements (Data Sciences International, New Brighton, MN) Kaiseraugst, Switzerland), and two separate cohorts were were implanted intraperitoneally under brief isoflurane fed a high-fat diet (HFD) (35% carbohydrate, 20% protein, anesthesia (2%). Treatment with nonsteroidal anti- and 45% fat as percent of total energy content, cat. no. inflammatory agents (2 mg/kg subcutaneous [s.c.] Metacam) D12451; Research Diets, New Brunswick, NJ) ad libitum. The and antibiotics (7.5 mg/kg s.c. Baytril 2.5%) before surgery animals were kept in an enriched environment in wood chip and during the following 5 days was provided while the mice bedding with cardboard houses and tissues as nesting ma- recovered.Subsequently,miceweresinglehousedina terial. The Veterinary Office of the Canton of Zurich, Zurich, 16-cage PhenoMaster indirect calorimetry system (TSE Switzerland, approved allanimalprocedures. Systems, Bad Homburg, Germany) (18). After 1 week of POMC-creCTR Mice adaptation, data were collected at baseline or following POMC-cre:ERT2 (C57BL/6J;129X1/SvJ-Tg(Pomc-cre/ERT2) a 12- h fast and injection with saline or sCT (10 mg/kg i.p.). #Jke; MGI:5569339) (16) (kindly provided by Joel Elmquist, From these values, EE and respiratory exchange ratio (RER) fl fl UT Southwestern), CTR / (Calcr,tm1(fl).; MGI:5751436) were calculated based on equations of Weir (20). Body mass (frozen sperm kindly provided by Drs. Jean-Pierre David composition from L1 to L4 was performed using a computed and Thorsten Shinke, University Medical Center Hamburg) tomography scan (Quantum GX microCT; PerkinElmer, (17). The crossing resulted in two groups of mice: POMC- Waltham, MA). Lean and fat mass (FM) were quantified as fl fl fl fl WT 3 CTR / (POMC-WTCTR) and POMC-Cre 3 CTR / previously validated (21). Analyze 12.0 software (Analyze- (POMC-CreCTR). For confirmation of the genetic model, Direct, Overland Park, KS) was used to quantify visceral Ai14 reporter mice [B6.Cg-Gt(ROSA)26Sor,tm14(CAG- and subcutaneous fat volume in the computed tomography fl fl tdTomato)Hze./J(#007914)]werebredwithCTR / POMC- images. EE data were corrected for individual lean body CreERT2 mice. Each mouse was genotyped using previously mass (LBM) (in grams) and FM (in grams) using the fol- published primers (17). lowing equation: LBM 1 0.2 FM, as recommended by Even and Nadkarni (22). Effect of Amylin, sCT, and Leptin on Food Intake Mice were single housed in BioDAQ cages (Research Diets), Mouse Perfusion and following 7 days of acclimation, mice were fasted for For assessment of phosphorylated (p)ERK signaling, mice 12 h during the light phase. At dark onset mice were were fasted for 12 h and at dark onset were injected with m injected intraperitoneally (i.p.) with amylin (50, 500 mg/kg) saline or amylin (50 g/kg i.p.) as previously described (cat. no. H-9475; Bachem, Bubendorf, Switzerland), salmon (15). For assessment of pSTAT3 signaling, mice were fasted calcitonin (sCT) (10 mg/kg) (cat. no. 4033011.0001; Bachem) for 2 h and at dark onset were injected with saline or leptin or saline (NaCl 0.9%) in a crossover design and food was (5 mg/kg i.p.) (23). The brains were frozen in hexane on 2 m returned. Using the same paradigm described above, dry ice, stored at 80°C, cut in 25 m sections (Leica a separate cohort of mice was also tested for anorectic Biosystems, Wetzlar, Germany), mounted on Superfrost fi response to leptin (5 mg/kg i.p.) (PeproTech, London, Plus slides (Thermo Fisher Scienti c, Reinach, Switzerland), U.K.). Food intake was recorded for the following 24 h, and stored in cryoprotectant (50% 0.02 mol/L potassium and the mice could rest for two more days before the next phosphate buffered saline (KPBS), 30% ethylene glycol, 2 injection. Baseline food intake was calculated by averag- 20% glycerol) at 20°C until staining. ing food intake over a 3-day period prior to injections. Immunohistochemistry Meal pattern criteria were an intermeal interval of 600 s and a minimal meal of 0.02 g (18). Male and female food POMC-pERK Double Staining intake data were pooled, since no differences were ob- For pretreatment, sections were demasked in 0.5% NaOH 1 served between sexes (19). 1% H2O2 in KPBS and incubated in 0.3% glycine in KPBS.
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