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1、Dear Editor,We have studied the valuable comments from you, the assistant editor andreviewers carefully, and tried our best to revise the manuscript. The point to pointresponds to the reviewers comments are listed as following:Responds to the reviewers comments:Reviewer 1Comment1:inpage3,line40,wefe
2、drats.changedtoratswerefedwith.Response:According to the reviewers comment, we have corrected the sentence.Furthermore,wehavehadthemanuscript polishedwithaprofessionalassistanceinwriting.Comment2:page25.Thestyleofreference40isnotright(usinginitialsforthefirstnames).Since this paper has been publishe
3、d, the volume and page Nos should beprovided.Response:Thank you for your careful work. We have added the volume and pagenumbers for reference40.Reviewer 2Comment:I would like to thank the authors for their efforts in addressing thecriticisms with additional experiments. The one criticism that they d
4、id not addresswasrelatingtoenergyexpenditure asthereasonthattheanimalsonthelowcalciumdiet gained more weight. While I understand that performing this experiment will notaffecttheconclusionofthismanuscript,Idobelievethatthispointcouldbediscussedin the Discussionsection.Response:Thankyouforyourvaluabl
5、eadvice.Basedonthepreviousrevision,wefurtheraddresstherelationshipbetweenlowcalciumdietandenergyexpenditureinthe section of discussion according to your thoughtful comments.Reviewer 3Comment 1: In the text you often write: “As previously described”. Unless that paperisfrom your lab or oneof themetho
6、d paper co-authors ison thepresent MS this isnotquitepropersincethestatementinfersmethoddevelopmentfromyourlab.Therearenumerousinstanceslikethatinthemethodssection;theseshouldallbechanged“according to those described by.”Response:Wearesorryforthislanguagemistake.Wehavecarefullycorrectedthisphrasethr
7、oughoutthemanuscriptaccordingtoyourcomment.Comment 2: There are still some wording, sentence structure and grammatical issueseven in this basically well put together MS. For example, while authors may havebeen excited about the data you cannot start a sentence with “Excitedly” in line 418 or“Whateve
8、r” in line 395.Response: Thank youverymuch topointoutthesentence structure and grammaticalissues in our manuscript. According to the comments from you and the editors, wepolishedthemanuscriptwithaprofessionalassistanceinwriting,conscientiously.Comment3: Inmy view abig omissionin this work isignoring
9、 the anabolic sideof lipid metabolism as well as thermogenesis issues. For example all animalsconsumedthesameamountoffeedbutwehadextrafatstorageinthelowCadietgroups.Sowheredidtheextraenergygo?Zemeletal(citation34)insimilarworkindicatethatincreasedthermogenesisonthehighCadietexplainsthedissipationofd
10、ietary energy. Further even though Zemel et al (#34) indicated lipogenesis wasenhancedin the low Ca diets that was in 2000 and you should have monitoredexpression of FAS and UCP either as mRNA abundance or actual FAS/UCPchanges via proteomics or blotting techniques. In any case these controls aremis
11、sing hereand not emphasizedintheMS.Casual reading ofthis paper wouldlead to the conclusion that the dietary Ca effect on fat deposition isstrictly a functionof increased or decreased lipolysis.While lipolysis appears to be a major player,lipogenesisandthermogenesiscannotbeignoredforcompleteness.InFi
12、g8youalso show a decline in cAMP for the low Ca diet. Well beta agonists or cAMPenhancers regulate transcription of adipose and liver FAS (in rats (J BiolChem271:2307, 1996) and recently with large animal models (Hausman et al J AnimalScience87:1218, 2009 and Halsey et alJ Animal Science 89: 1011, 2
13、011). In additioncAMPlevelscouldhavebeenmonitored.IreallydonotlikethelastsentenceintheAbstract line 47-50 where you state that “low calcium diet-induced increase in fatmass was due to enhancedlipogenesismediated by an upregulatedCaSRsignaling pathway” Your results here show no such thing, this is a
14、completelyfalse statement based on data herein. Correct. You show that high Ca dietsenhance lipolysis and low Ca diets are antilipolytic. You did not monitor lipidanabolismhereatall.Seealsoline255-257andlines333-335ofyourMS.Response: Thank you for your valuable and thoughtful comments. As you sugges
15、tedthatthe anabolic side oflipid metabolism as wellas thermogenesis issues should bemonitored.Wereally agreewith yourviewpoints. Inthepresent study, wedid findthatlowcalciumdietincreasedthemRNAleveloffattyacidsynthase(FAS)inwhiteadipose tissue. Furthermore, the FAS mRNA level were also increased in
16、adipocytesafter treatment with 1,25-(OH)2D3in in-vitro experiments. However, the increasedFASmRNA levelswerenotaffectedbypreventingeitherthenuclearvitaminDreceptor (nVDR) or calcium-sensing receptor (CaSR), suggesting that FAS might notbeinvolvedintheCaSRpathway.Inaddition,wethoughtthatFASplayeditsr
17、oleinfattyacidsynthesis mainlyinliverpreviously.Besides,themanuscriptwasrequiredtorestrictnumberoftotalwordsandourpreviousfocuswasontheantilolyticroleofCaSRintheprocessoffataccumulation.SoweignoredtoprovidethedataofFASmRNAlevelsinthesubmittedmanuscript.Inthenewlysubmittedmanuscript,wehave provided t
18、he mRNA levels according to your helpful suggestion.We have reported the effects of dietary calcium on UCP2 mRNA levels inadiposetissueandUCP3inskeletalmuscleinourpreviousstudies(1,2).Thus,webelievedthatlow calcium dietledtodecreased thermogenesisin thepresentstudy.Itwas a pity that we did not measu
19、re the rat core temperature in those studies. TheUCP2mRNAlevelsinadipocyteswereobservedtobedecreasedaftertreatmentof1,25-(OH)2D3.ThiseffectwaspreventedbyusingnVDRCaSRgenesilencingbutnotby CaSR gene knockdown, suggesting that UCP2 was not involved in CaSR pathways.In the newly submitted manuscript, w
20、e have provided the UCP2 results.Thank you for your careful reading of our manuscript. We are very sorry for ourfaultstatementintheabstract.Wehavecorrecteditinthenewmanuscript.Comment4:ApointthatdoesnotemergewellfromthediscussionishowlowCaintakesresultinhigherintracellularCaconcentrationsandreallyth
21、eeffectsonfatdeposition in the cells in many ways are due to an increased intracellular Ca levelmediatedviaCaSRexpressionincreasesandtheeffectofVitD3onnVDRshowinFig8.TheauthorsmustremindreadersthatCalevelsinthebloodareunderhormonalregulation (Calcitonin, PTH and VitD3). Thus when diets low in Ca are
22、 consumedand blood Ca decline, PTH and VitD3 are called upon to mobilize bone Ca toreplenishthebloodCa.ThencoupledwithanincreaseinCaSRmoreCaactuallyisfoundinATdespitethefactthatmanywouldthinktheATCalevelshoulddecline.Thereasonisthattissue/circulatingCalevelsarenotdietdependedbutregulated.Thevastbone
23、storesofCawillprovideampleCahereespeciallyduringastudyofthislength. While authors address theseissues maybe could be presented in a lesscomplicated discussion.Response:Thank you for yourinstructive suggestions.We are sorry fornotdescribing the effect of low calcium diet on intracellular calcium conc
24、entrationsmediatedbyCaSR,aswellastheimpactof hormoneregulationonserum calciumlevelsclearly.Accordingtoyourhelpfuladvice,wehaverewrittenthesetwopartsinthe section of discussion. Thank you again.Comment 5: Not all citations are in JN styleResponse: We have careful recheck and corrected the style of th
25、e citations accordingto the requirement ofJN.Comment6:Abstractconclusiondiffersfromlines255-257and333-335;WHY?Response:Thank you for your careful reading of our manuscript. The conclusionfromlines255-257isabouttheeffectoflowcalciumdietonserumlevelsoffreefattyacids (FFAs) and lipids. We considered FF
26、A and glycerol as indicators of TGhydrolysis in adipose tissue. The low calcium diet caused decreased serum FFA andglycerollevelswithoutinfluencinglipoproteinlipase(LPL)activity,sowethoughtthelipolytic effect of adipose tissue to be suppressed by low calcium diet. The conclusionfrom lines 333-335 wa
27、s about the effect of 1,25-(OH)2D3whose levels were increasedunder low calcium conditions on lipolysis. We used the glycerol level as the indicatorofTGhydrolysisinadipocytes.Boththeinvivoandinvitroexperimentsshowedlowcalcium status caused an antilipolytic effect.Comment7:Line150-153.TheqRT-PCRmethod
28、ologyisnotatallunderstandableas you citeaTexasA&Mpublishedpaper.Thisiscompletely insufficient with thenewly established standards on gene expression via qRT-PCR. There is no mention ofefficienciesofamplificationsinthesedatanorhowtheuseofthereferencegenewasestablished etc. I think Pfaffl and Bustin h
29、ave recently written an article on this;please totally revise 150-153in line with what you did and applying thenewstandards.Response: Thank you very much. Because the JN restricts the number of total wordsof manuscript, we cited the Texas A&M published paper. In the newly submittedmanuscript, we des
30、cribe the detailed protocols in our lab.Comment 8: Line 179 on Not clear as in sentences talk about different AT cellsources etc.revise.Response: We are sorry for not addressing the adipose tissue cell sources clearly. Wehave rewritten themethods.Comment 9: Any previous documentable work with siRNA?
31、Response:Yes,wehavedocumentableworkwithsiRNAinourresearchteam.Theresults were published in the journal of Biochem Biophys Res Commun (3).Comment10:Line214.Culturedprimaryratadipocytesand SW872adipocytes Response:Thank you very much. According to your comment, we have had themanuscript polished and corrected the mistakes.