Adipocyte-specific deletion of Dbc1 does not recapitulate healthy obesity phenotype but suggests regulation of inflammation signaling

Leonardo Santos; Rafael Sebastián Fort; Geraldine Schlapp; Karina Cal; Valentina Perez-Torrado; Maria Noel Meikle; Ana Paula Mulet; Camila Espasandín; Camila Chiesa; José R. Sotelo-Silveira; Jose M. Verdes; Paola Contreras; Aldo J. Calliari; Martina Crispo; Jose L. Badano; Carlos Escande

doi:10.1371/journal.pone.0322732

Peer Review History

Original SubmissionSeptember 13, 2024
13 Sep 2024 Author Response https://doi.org/10.1371/journal.pone.0322732.r001
21 Oct 2024 Decision Letter - Chien-Feng Li, Editor PONE-D-24-40711Adipocyte-specific deletion of Dbc1 does not recapitulate healthy obesity phenotype but suggests regulation of inflammation signalingPLOS ONE Dear Dr. Escande, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Dec 05 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors present their findings from characterization of mature adipocyte specific knockout of Dbc1. Unexpectedly, no difference is observed in wildtype and cAT-dbc1 KO animals on normal chow or HFD except for enhanced immune signaling in KO adipocytes. The findings though new and important in context to the data on the whole body knockout mice, can be distilled into a short report rather than a primary research article. Most of the data on cAT-dbc1 KO mouse generation can be supplemental. RNA seq data on major immune genes should be validated by qPCR. Methods must clearly show the number of mice used in each experiment. There are some minor errors of grammar, line formatting, etc. Reviewer #2: The transcription factor Deleted in Breast Cancer 1 (DBC1) has previously been shown to regulate obesity and aging-related processes in preclinical models, with murine global Dbc1 KO causing morbid obesity but protecting against liver steatosis, insulin resistance and atherosclerosis. This makes DBC1 a promising therapeutic target. In this study the authors generated an adipocyte-specific Dbc1 KO model to assess whether the putatively beneficial effects of global Dbc1 KO are attributable to adipocyte Dbc1 KO. Deletion of Dbc1 in mature adipocytes had no effect on weight gain, glucose tolerance nor other markers of metabolic dysregulation, regardless of sex, however. This is the central finding of this study, and although it is essentially a “negative” finding this is a clear and valuable answer to the question posed. Dbc1 KO adipocytes were, however, reported to display an mRNA expression profile consistent with increased inflammation, although the magnitude of this was not very impressive, and the finding was not pursued in more detail. In summary, this study adds new and useful information regarding the metabolic role of adipocyte Dbc1. In several places the drafting of the manuscript could also be included. Major Comments 1. The manuscript states that “In previous studies, we and others showed that whole-body Dbc1 knockout mice do not develop obesity when fed a regular chow diet” (L291-293) but later states that “Our previous work, in mice with mixed genetic background, showed that whole-body Dbc1 KO mice develop morbid obesity with prevention of fatty-acid spillover and metabolic damage” (L314-316). Can this be reconciled? Presumably it relates to diet? 2. Fig 1: In Panel D, top, the immunoblot shows a clear decrease of Dbdc1 protein expression in Cre+ whole eWAT and iWAT and corresponding isolated adipocytes, suggesting successful deletion of Dbc1 in mature adipocytes. However, expression of Dbdc1 in isolated SVF seems increased compared to related whole fat tissue, particularly in the last lane, possibly indicating compensatory upregulation in SV cells from Cre+ fat tissue. Can the authors quantify the blot and clarify this? 3. Dbc1 knockout (KO) adipocytes show upregulation of several inflammatory pathways (Fig 6D). Particularly noticeable are the enriched terms related to cytokine production and NF-kB activity. This may indicate the adipose tissue is inflamed in KO mice, but this requires substantial further characterisation if much is to be made of this observation. As noted above, the negative metabolic findings are perhaps the most important outcome of the study. Minor comments 1. The layouts of figure legends, and panel labelling are not very clear. As an example, in L267-289, the illustration jumps back and forward or repeats description of the same things. 2. Nomenclature for the mouse strain is sometimes inconsistent: cAT-Dbc1 KO vs Dbcloxp/loxp Cre +/- (L291- 301). Also, can the panel be given more detailed labels to indicate sex. 3. L352-358 appears to have a half sentence that is hard to follow 4. L297: change “had no affectation of” to “did not affect” and “glucose management” to “glucose homeostasis” ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0322732.r002
Revision 1
7 Mar 2025 Author Response We would like to thank the reviewers for their comments and detailed review of the manuscript. Their feedback has been helpful in enhancing our work. We are now submitting a revised version of the manuscript, which we believe addresses all the points raised by the reviewers. In this revised version, we have corrected all minor issues identified. Additionally, we have performed new experiments to validate and further strengthen the transcriptomic data that further support our original data. Please see below for responses to the reviewers, including corrections, comments, an improved discussion. These changes enhance the clarity and rigor of the manuscript. Thank you for considering our revised manuscript for publication in Plos One.. Point by point response to the reviewer's comments: Reviewer #1: The authors present their findings from characterization of mature adipocyte specific knockout of Dbc1. Unexpectedly, no difference is observed in wildtype and cAT-dbc1 KO animals on normal chow or HFD except for enhanced immune signaling in KO adipocytes. The findings though new and important in context to the data on the whole body knockout mice, can be distilled into a short report rather than a primary research article. Most of the data on cAT-dbc1 KO mouse generation can be supplemental. RNA seq data on major immune genes should be validated by qPCR. Response: We agree with the reviewer that RNA seq data on major immune genes as well as the original RNA seq data set should be validated as a whole, by qPCR. Therefore, we conducted qPCR analysis of several of the genes found involved in the reported pathways. Thus, we completed the study by including: a) genes not directly related to the main inflammatory pathway here reported, but found either significantly up or down regulated; b) genes belonging to canonical inflammatory pathways whose expression levels were found unchanged in our original RNAseq analysis. As expected, the gene expression levels found in the qPCR analysis closely correlated with those present in the seq data set. Importantly, because the strategy used for the transcriptome analysis (Gene Set Enrichment Analysis, GSEA), privileges the occurrence of minor but general changes in given metabolic pathways instead high changes in a minor set of genes to assign significant changes, qPCR analysis yielded subtle but consistent changes in several genes belonging to the reported inflammatory via. This information is now included in a supplementary figure (figure S5). Reviewer: Methods must clearly show the number of mice used in each experiment. There are some minor errors of grammar, line formatting, etc. Response: The number of mice used in each experiment is now clearly stated in the Methods section. Grammar error and line formatting were corrected. Reviewer #2 Reviewer: The transcription factor Deleted in Breast Cancer 1 (DBC1) has previously been shown to regulate obesity and aging-related processes in preclinical models, with murine globalDbc1 KO causing morbid obesity but protecting against liver steatosis, insulin resistance and atherosclerosis. This makes DBC1 a promising therapeutic target. In this study the authors generated an adipocyte-specific Dbc1 KO model to assess whether the putatively beneficial effects of global Dbc1 KO are attributable to adipocyte Dbc1 KO. Deletion of Dbc1 in mature adipocytes had no effect on weight gain, glucose tolerance nor other markers of metabolic dysregulation, regardless of sex, however. This is the central finding of this study, and although it is essentially a “negative” finding this is a clear and valuable answer to the question posed. Dbc1 KO adipocytes were, however, reported to display an mRNA expression profile consistent with increased inflammation, although the magnitude of this was not very impressive, and the finding was not pursued in more detail. In summary, this study adds new and useful information regarding the metabolic role of adipocyte Dbc1. In several places the drafting of the manuscript could also be included. Major Comments The manuscript states that “In previous studies, we and others showed that whole-body Dbc1knockout mice do not develop obesity when fed a regular chow diet” (L291-293) but later states that “Our previous work, in mice with mixed genetic background, showed that whole-body Dbc1 KO mice develop morbid obesity with prevention of fatty-acid spillover and metabolic damage” (L314-316). Can this be reconciled? Presumably it relates to diet? Response: As pointed out by the reviewer, the effect of morbid but “healthy” obesity developed by Dbc1 KO mice only occurs when mice are fed with high-fat diet. This apparent inconsistency arises because we omitted to clearly state that animals that get obese but without fatty acid spillover and metabolic disorders were those fed a high fat diet.…The corrected sentence now state “… whole-body Dbc1 KO mice fed with high fat diet for 20 weeks, develop morbid obesity with prevention of fatty-acid spillover and metabolic damage.” (L344-346) We thank the reviewer for pointing out this error. Reviewer: Fig 1: In Panel D, top, the immunoblot shows a clear decrease of Dbdc1 protein expression in Cre+ whole eWAT and iWAT and corresponding isolated adipocytes, suggesting successful deletion of Dbc1 in mature adipocytes. However, expression of Dbdc1 in isolated SVF seems increased compared to related whole fat tissue, particularly in the last lane, possibly indicating compensatory upregulation in SV cells from Cre+ fat tissue. Can the authors quantify the blot and clarify this? Response: We quantified the expression of Dbc1 in the SVF by western blot and found that there is no increase in Dbc1 expression in isolated SVF of Cre+ mice. This fact is now briefly mentioned at the end of the section “Generation of Dbc1LoxP/LoxP conditional mice by CRISPR/Cas9 and adipocyte-specific deletion” (L316-319) and depicted in figure S1. We thank the reviewer for pointing out this important detail. Reviewer: Dbc1 knockout (KO) adipocytes show upregulation of several inflammatory pathways (Fig 6D). Particularly noticeable are the enriched terms related to cytokine production and NF-kB activity. This may indicate the adipose tissue is inflamed in KO mice, but this requires substantial further characterisation if much is to be made of this observation. As noted above, the negative metabolic findings are perhaps the most important outcome of the study. Response: We agree about the need for a deeper characterization of these findings. To evaluate the consistency of the original RNA seq data as a whole, we have now included qPCR analysis to confirm the expression of several key genes belonging to differentially regulated inflammatory pathways. Also, we completed the study by including: a) some additional genes not directly related to the main inflammatory pathway (but found either up or down regulated), b) genes belonging to canonical inflammatory pathways whose expression levels were found unchanged in our original RNAseq dataset. As a result, we found that the expression levels of selected genes found in the qPCR analysis, closely correlated with most of those present in the seq data set. This information is now included in a supplementary figure (figure S5). Minor comments Reviewer: The layouts of figure legends, and panel labelling are not very clear. As an example, in L267-289, the illustration jumps back and forward or repeats description of the same things. Response: We revised panel labeling and figure legends. Some text passages were rewritten as well as some figures rearranged. The changes are highlighted in red. Reviewer: Nomenclature for the mouse strain is sometimes inconsistent: cAT-Dbc1 KO vs Dbcloxp/loxp Cre +/- (L291- 301). Also, can the panel be given more detailed labels to indicate sex. Response: We replaced “cAT-Dbc1 KO” with “Dbc1LoxP/LoxP;CRE” throughout the text to designate the mouse adipocyte conditional Dbc1 KO strain. Reviewer: L352-358 appears to have a half sentence that is hard to follow. Response: Response: The text was reviewed and rewritten for clarity (L384-388). The revised paragraph is as follows: "Histological analysis of liver samples confirmed the presence of steatosis, as expected in the diet-induced obesity (DIO) condition (Fig. 5). Overall, Dbc1LoxP/LoxP;CRE KO mice did not show significant differences in weight gain, glucose management, or liver and kidney function compared to controls under a high-fat diet treatment, indicating that adipocyte-specific Dbc1 deletion does not replicate the protective effects observed in whole-body Dbc1 knockout models." Reviewer: L297: change “had no affectation of” to “did not affect” and “glucose management” to “glucose homeostasis” Response: We accepted and incorporated these suggestions. Attachments Attachment Submitted filename: Point by point response to reviewers.docx https://doi.org/10.1371/journal.pone.0322732.r003
27 Mar 2025 Decision Letter - Chien-Feng Li, Editor Adipocyte-specific deletion of Dbc1 does not recapitulate healthy obesity phenotype but suggests regulation of inflammation signaling PONE-D-24-40711R1 Dear Dr. Escande, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Chien-Feng Li, M.D., Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #3: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #3: No ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #3: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #3: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No Reviewer #3: No ******** https://doi.org/10.1371/journal.pone.0322732.r004
Formally Accepted
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