Programming and regulation of metabolic homeostasis by HDAC11
Open accessAbstract
Histone deacetylases (HDACs) are enzymes that regulate protein functions by catalyzing the removal of acetyl and acyl groups from lysine residues. They play pivotal roles in governing cell behaviors and are indispensable in numerous biological processes. HDAC11, the last identified and sole member of class IV HDACs, was reported over a decade ago. However, its physiological function remains poorly understood. Here, we report that HDAC11 knockout mice are resistant to high-fat diet-induced obesity and metabolic syndrome, suggesting that HDAC11 functions as a crucial metabolic regulator. Depletion of HDAC11 significantly enhanced insulin sensitivity and glucose tolerance, attenuated hypercholesterolemia, and decreased hepatosteatosis and liver damage. Mechanistically, HDAC11 deficiency boosts energy expenditure through promoting thermogenic capacity, which attributes to the elevation of uncoupling protein 1 (UCP1) expression and activity in brown adipose tissue. Moreover, loss of HDAC11 activates the adiponectin-AdipoR-AMPK pathway in the liver, which may contribute to a reversal in hepatosteatosis. Overall, our findings distinguish HDAC11 as a novel regulator of obesity, with potentially important implications for obesity-related disease treatment.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mice with Hdac11 knockout show no significant abnormalities.
“To add further mystery to HDAC11, mice Hdac11 -/-show no significant abnormalities (Huang et al., 2017;Sun et al., 2018;Yue et al., 2020).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Sun et al., 2018
In high-fat fed mice, deletion of Hdac11 prevents obesity, insulin resistance and glucose intolerance by increasing energy expenditure through improved thermogenic capacity.
“In high-fat fed mice, deletion of Hdac11 prevents obesity, insulin resistance and glucose intolerance by increasing energy expenditure through improved thermogenic capacity (Sun et al., 2018).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Sun et al., 2018
These mice reduce white adipose tissue deposition.
“In contrast, these mice reduce white adipose tissue deposition.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Sun et al., 2018
Loss of Hdac11 promotes brown adipose tissue accumulation and function.
“In addition, loss of Hdac11 promotes brown adipose tissue accumulation and function.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Sun et al., 2018
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Identification and Importance of Brown Adipose Tissue in Adult Humans
Cypess, A. M., Lehman, S., Williams, G., Tal, I., Rodman, D., Goldfine, A. B., Kuo, F. C., Palmer, E. L., Tseng, Y.-H., Doria, A., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810780 · Cited by 4,399 · see citing works
Yamauchi, T., Kamon, J., Minokoshi, Y., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S., Ueki, K., et al. (2002) · Nature Medicine · doi:10.1038/nm788 · Cited by 4,238 · see citing works
Erasers of Histone Acetylation: The Histone Deacetylase EnzymesPreprint
Seto, E., & Yoshida, M. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a018713 · Cited by 2,019 · see citing works
Self-citationYamauchi, T., Nio, Y., Maki, T., Kobayashi, M., Takazawa, T., Iwabu, M., Okada-Iwabu, M., Kawamoto, S., Kubota, N., Kubota, T., et al. (2007) · Nature Medicine · doi:10.1038/nm1557 · Cited by 1,396 · see citing works
Purushotham, A., Schug, T. T., Xu, Q., Surapureddi, S., Guo, X., & Li, X. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.02.006 · Cited by 1,112 · see citing works
Fullerton, M. D., Galic, S., Marcinko, K., Sikkema, S., Pulinilkunnil, T., Chen, Z.-P., O'Neill, H. M., Ford, R. J., Palanivel, R., O'Brien, M., et al. (2013) · Nature Medicine · doi:10.1038/nm.3372 · Cited by 893 · see citing works
AMPK activators: mechanisms of action and physiological activities
Kim, J., Yang, G., Kim, Y., Kim, J., & Ha, J. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.16 · Cited by 817 · see citing works
A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity
Okada-Iwabu, M., Yamauchi, T., Iwabu, M., Honma, T., Hamagami, K.-I., Matsuda, K., Yamaguchi, M., Tanabe, H., Kimura-Someya, T., Shirouzu, M., et al. (2013) · Nature · doi:10.1038/nature12656 · Cited by 757 · see citing works
A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism
Feng, D., Liu, T., Sun, Z., Bugge, A., Mullican, S. E., Alenghat, T., Liu, X. S., & Lazar, M. A. (2011) · Science · doi:10.1126/science.1198125 · Cited by 701 · see citing works
Kopecky, J., Clarke, G., Enerbäck, S., Spiegelman, B., & Kozak, L. P. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118363 · Cited by 553 · see citing works
Chain length-specific properties of ceramides
Grösch, S., Schiffmann, S., & Geißlinger, G. (2011) · Progress in Lipid Research · doi:10.1016/j.plipres.2011.11.001 · Cited by 484 · see citing works
Role of Disulfide Bonds in Acrp30/Adiponectin Structure and Signaling Specificity
Tsao, T., Tomás, E., Murrey, H. E., Hug, C., Lee, D. H., Ruderman, N. B., Heuser, J. E., & Lodish, H. F. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m309469200 · Cited by 473 · see citing works
A rapid spectrophotometric assay for carnitine palmitoyltransferase
BIEBER, L. L., Abraham, T., & Helmrath, T. A. (1972) · Analytical Biochemistry · doi:10.1016/0003-2697(72)90061-9 · Cited by 376 · see citing works
The rate of oxygen utilization by cells
Wagner, B. A., Venkataraman, S., & Buettner, G. R. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.05.024 · Cited by 364 · see citing works
Adipokines in nonalcoholic fatty liver disease
Pοlyzos, S. A., Kountouras, J., & Mantzoros, C. S. (2015) · Metabolism · doi:10.1016/j.metabol.2015.11.006 · Cited by 359 · see citing works
Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration
Sun, Z., Miller, R. A., Patel, R. T., Chen, J., Dhir, R., Wang, H., Zhang, D., Graham, M. J., Unterman, T. G., Shulman, G. I., et al. (2012) · Nature Medicine · doi:10.1038/nm.2744 · Cited by 335 · see citing works
Reduced thermogenesis in obesity
Jung, R. T., Shetty, P. S., James, W. P. T., Barrand, M. A., & Callingham, B. A. (1979) · Nature · doi:10.1038/279322a0 · Cited by 296 · see citing works
Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice
Li, B., Nolte, L. A., Ju, J.-S., Ho Han, D., Coleman, T., Holloszy, J. O., & Semenkovich, C. F. (2000) · Nature Medicine · doi:10.1038/80450 · Cited by 291 · see citing works
Opposing Effects of Adiponectin Receptors 1 and 2 on Energy Metabolism
Bjursell, M., Ahnmark, A., Bohlooly‐Y, M., William‐Olsson, L., Rhedin, M., Peng, X., Ploj, K., Gerdin, A.-K., Arnerup, G., Elmgren, A., et al. (2007) · Diabetes · doi:10.2337/db06-1432 · Cited by 277 · see citing works
Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks
Knutson, S. K., Chyla, B. J., Amann, J. M., Bhaskara, S., Huppert, S. S., & Hiebert, S. W. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.51 · Cited by 271 · see citing works
Adipokines and Non-Alcoholic Fatty Liver Disease: Multiple Interactions
Adolph, T. E., Grander, C., Grabherr, F., & Tilg, H. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081649 · Cited by 243 · see citing works
Biddinger, S. B., Almind, K., Miyazaki, M., Kokkotou, E. G., Ntambi, J. M., & Kahn, C. R. (2005) · Diabetes · doi:10.2337/diabetes.54.5.1314 · Cited by 231 · see citing works
(2010) · doi:10.1074/jbc.m110.168039 · Cited by 207 · see citing works
Gaidhu, M. P., Fediuc, S., Anthony, N. M., So, M., Mirpourian, M., Perry, R. L. S., & Ceddia, R. B. (2008) · Journal of Lipid Research · doi:10.1194/jlr.m800480-jlr200 · Cited by 200 · see citing works
Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge
Emmett, M. J., Lim, H., Jager, J., Richter, H. J., Adlanmérini, M., Peed, L. C., Briggs, E. R., Steger, D. J., Ma, T., Sims, C. A., et al. (2017) · Nature · doi:10.1038/nature22819 · Cited by 196 · see citing works
Regulation of SIRT6 protein levels by nutrient availability
Kanfi, Y., Shalman, R., Peshti, V., Pilosof, S. N., Gozlan, Y. M., Pearson, K. J., Lerrer, B., Moazed, D., Marine, J., de Cabo, R., et al. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.01.019 · Cited by 187 · see citing works
Down-regulation of Histone Deacetylases Stimulates Adipocyte Differentiation
Yoo, E. J., Chung, J.-J., Choe, S. S., Kim, K. H., & Kim, J. B. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m508982200 · Cited by 184 · see citing works
Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity
Schwer, B., Schumacher, B., Lombard, D. B., Xiao, C., Kurtev, M. V., Gao, J., Schneider, J. I., Chai, H., Bronson, R. T., Tsai, L., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016306107 · Cited by 176 · see citing works
Histone deacetylase 11 is a fatty-acid deacylase
Kutil, Z., Novakova, Z., Meleshin, M., Mikesova, J., Schutkowski, M., & Barinka, C. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.7b00942 · Cited by 174 · see citing works
Laliotis, G. P., Bizelis, I., & Rogdakis, E. (2010) · Current Genomics · doi:10.2174/138920210791110960 · Cited by 152 · see citing works
Structure and Function of Carnitine Acyltransferases
Jogl, G., Hsiao, Y., & Tong, L. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1320.002 · Cited by 140 · see citing works
Tian, Y., Wong, V. W., Wong, G. L., Yang, W., Sun, H., Shen, J., TONG, J. H. M., Go, M. Y. Y., Cheung, Y. S., Lai, P. B. S., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-3786 · Cited by 134 · see citing works
Li, F., Wu, R., Cui, X., Zha, L., Yu, L., Shi, H., & Xue, B. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.677930 · Cited by 118 · see citing works
Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats
Lundh, M., Galbo, T., Poulsen, S. S., & Mandrup-Poulsen, T. R. (2015) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12470 · Cited by 101 · see citing works
Suppression of Adiponectin Gene Expression by Histone Deacetylase Inhibitor Valproic Acid
Qiao, L., Schaack, J. B., & Shao, J. (2005) · Endocrinology · doi:10.1210/en.2005-1030 · Cited by 85 · see citing works
Luque, R. M., Lin, Q., Córdoba-Chacón, J., Subbaiah, P. V., Buch, T., Waisman, A., Vankelecom, H., & Kineman, R. D. (2011) · PLoS ONE · doi:10.1371/journal.pone.0015767 · Cited by 73 · see citing works
Daquinag, A. C., Tseng, C., Salameh, A., Zhang, Y., Amaya‐Manzanares, F., Dadbin, A., Florez, F., Xu, Y., Tong, Q., & Kolonin, M. G. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.148 · Cited by 63 · see citing works
Ferrari, A., Fiorino, E., Longo, R., Barilla, S., Mitro, N., Cermenati, G., Giudici, M., Caruso, D., Mai, A., Guerrini, U., et al. (2016) · International Journal of Obesity · doi:10.1038/ijo.2016.191 · Cited by 50 · see citing works
Bivens, C. L. M., Thomas, W. J., & Stanley, B. G. (1998) · Brain Research · doi:10.1016/s0006-8993(97)01289-4 · Cited by 44 · see citing works
Regulation of adiponectin receptor expression in human liver and a hepatocyte cell line
Shimizu, A., Takamura, T., Matsuzawa, N., Nakamura, S., Nabemoto, S., Takeshita, Y., Misu, H., Kurita, S., Sakurai, M., Yokoyama, M., et al. (2007) · Metabolism · doi:10.1016/j.metabol.2007.06.013 · Cited by 43 · see citing works
Chatterjee, T. K., Basford, J. E., Yiew, K. H., Stepp, D. W., Hui, D. Y., & Weintraub, N. L. (2014) · Adipocyte · doi:10.4161/adip.28814 · Cited by 39 · see citing works
Bond, L. M., & Ntambi, J. M. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m078469 · Cited by 38 · see citing works
Bricambert, J., Favre, D., Brajkovic, S., Bonnefond, A., Boutry, R., Salvi, R., Plaisance, V., Chikri, M., Chinetti, G., Staels, B., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.09.011 · Cited by 32 · see citing works
Liu, Y., Sen, S. R., Wannaiampikul, S., Palanivel, R., Hoo, R. L. C., Isserlin, R., Bader, G. D., Tungtrongchitr, R., Deshaies, Y., Xu, A., et al. (2015) · Biochemical Journal · doi:10.1042/bj20141455 · Cited by 26 · see citing works
Commentary: Evolution of UCP1 Transcriptional Regulatory Elements Across the Mammalian Phylogeny
Fromme, T. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00978 · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms
Yue, L., Sharma, V., Horvat, N. P., Akuffo, A. A., Beatty, M. S., Murdun, C., Colin, C., Billington, J. M. R., Goodheart, W. E., Sahakian, E., et al. (2020) · Blood · doi:10.1182/blood.2019895326 · Cited by 67 · see citing works
HDACs and the epigenetic plasticity of cancer cells: target the complexity
Brancolini, C., Gagliano, T., & Minisini, M. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108190 · Cited by 55 · see citing works
Baselious, F., Robaa, D., & Sippl, W. (2023) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2023.107700 · Cited by 20 · see citing works
HDAC in obesity: A critical insight
Nijhawan, P., Behl, T., Khullar, G., Pal, G., Kandhwal, M., & Goyal, A. (2020) · Obesity Medicine · doi:10.1016/j.obmed.2020.100212 · Cited by 13 · see citing works
- Authors
- Sun, L., Marin de Evsikova, C., Bian, K., Achille, A., Telles, E., Pei, H., & Seto, E.
- Affiliations
- George Washington University (US)
- University of South Florida (US)
- Corresponding author
- Seto, Edward
- Venue
- EBioMedicine
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 33
- Pages
- 157-168
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC6085537
- OpenAlex
- W2810056186
- Cited by
- 125
- References
- 45
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 20 · 2023: 16 · 2022: 10 · 2021: 12 · 2020: 19 · 2019: 11 · 2018: 1
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Cancer Institute (P30CA076292)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- HDAC11, histone deacetylase, metabolic homeostasis, high-fat diet-induced obesity, metabolic syndrome, insulin sensitivity, glucose tolerance, hypercholesterolemia, hepatic steatosis, energy expenditure, brown adipose tissue, UCP1, adiponectin, AMPK, liver, knockout mice
- MeSH terms
- Uncoupling Protein 1, Animals, Disease Models, Animal, Energy Metabolism, Fatty Liver, Glucose Tolerance Test, Histone Deacetylases, Homeostasis, Insulin Resistance, Liver, Obesity, Signal Transduction, Up-Regulation, Thermogenesis, Metabolic Syndrome, Mice, Gene Knockout Techniques, Diet, High-Fat
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
