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Targeting hypothalamic SIK3 to promote weight loss and improve glycemic control in mice.

Overview

Authors: Danise Ann Onda1, Chieh-Hsin Yang1, Callen Goldsmith2, Cait A. Beddows2, Rui Qi Teo2, Lei Zhang3, XiaoZhuo Yuan1, Yifei Zhu1, Man KS Lee4, Ashley J. Ovens5, Dingyi Yu6, Kei Sakamoto7, John W. Scott6,8, Andrew J. Murphy9, Noriyuki Tsumaki10, Herbert Herzog3, Garron T. Dodd2, Kim Loh1,11,12
ORCID iDs: Chieh-Hsin Yang, Cait A. Beddows, Rui Qi Teo, Ashley J. Ovens, Kei Sakamoto, John W. Scott, Andrew J. Murphy, Noriyuki Tsumaki, Herbert Herzog, Garron T. Dodd, Kim Loh
  1. Diabetes and Metabolic Disease, St. Vincent’s Institute of Medical Research, Fitzroy,Victoria, Australia
  2. Department of Anatomy and Physiology, The University of Melbourne, Melbourne,Victoria, Australia
  3. St Vincent’s Center for Applied Medical Research, Sydney, NSW Australia
  4. Division of Immunometabolism, Baker Heart and Diabetes Institute,Melbourne, Australia
  5. Protein Engineering in Immunity & Metabolism, St. Vincent’s Institute of Medical Research, Fitzroy,Victoria, Australia
  6. St. Vincent’s Institute of Medical Research, Fitzroy,Victoria, Australia
  7. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen,Copenhagen, Denmark
  8. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences,Melbourne Victoria, Australia
  9. Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Diabetes, Monash University, Melbourne, Australia; Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; Department of Medicine, University of Melbourne,Melbourne, Australia
  10. Department of Tissue Biochemistry, Graduate School of Medicine and Frontier Biosciences, Osaka University,Osaka, Japan
  11. Department of Medicine, University of Melbourne, Fitzroy,Victoria, Australia
  12. Mary MacKillop Institute for Health Research, Australian Catholic University,Victoria, Australia
Institutions: St Vincents Institute of Medical Research (Australia); The University of Melbourne (Australia); Baker Heart and Diabetes Institute (Australia); University of Copenhagen (Denmark); Monash University (Australia); The University of Osaka (Japan); Australian Catholic University (Australia)
Journal: Nature communications, volume 17, issue 1, article 8432
Dates: received 24 February 2025; accepted 18 May 2026; published online 2 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41467-026-73649-1 · PMID 42230648 · PMCID PMC13478199 · OpenAlex W7163201378
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials, Connectivity, Smoothing, state filtering, decompositions
Keywords: Hypothalamus, Obesity
MeSH: Hypothalamus*, Obesity*, Protein Serine-Threonine Kinases*, Weight Loss*, Adipose Tissue, White, Animals, Blood Glucose, Diet, High-Fat, Eating, Energy Metabolism, Histone Deacetylases, Insulin, Leptin, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Obese, Neurons, Neuropeptide Y, Signal Transduction, Transcription Factors (* major topic)
Topic: Regulation of Appetite and Obesity (Endocrine and Autonomic Systems, Neuroscience), according to OpenAlex
Funding: National Health and Medical Research Council (2019889); Australian Research Council (FT230100423)
Citations: not cited yet (Europe PMC); 122 references in the paper

Abstract

Salt-Inducible Kinase 3 (SIK3) has emerged as a key regulator of peripheral metabolism, however its cellular and molecular function in regulating body weight and energy metabolism, particularly in hypothalamic neurons, remains unclear and largely unexplored. Here, we demonstrate that SIK3 expression is elevated in the hypothalamus of obese mice. Inactivation of SIK3 specifically in orexigenic NPY neurons reduces food intake, increases energy expenditure, and enhances white adipose tissue browning, resulting in resistance to high-fat diet-induced obesity in mice. Pharmacological inhibition of SIK3 with the inhibitor GLPG3970 in diet-induced obese mice led to significant reductions in body weight and adiposity, primarily due to decreased energy intake, with notable improvements in metabolic health. These effects are linked to enhanced central leptin and insulin signaling, and the dephosphorylation and nuclear translocation of key transcriptional metabolic regulators, CRTC1 and HDAC5. These findings reveal a previously unidentified SIK3-mediated pathway that promotes positive energy balance and suggests SIK3 inhibition may offer therapeutic potential for treating obesity and metabolic disorders.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Code availability

This study did not generate any unique datasets or code.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information files. Source data underlying all figures are provided with this paper. Source data are provided in this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 18 authors, 2 keywords, 22 MeSH terms, 2 funders, 122 references.

Cite

This paper

Onda, D. A., Yang, C.-H., Goldsmith, C., Beddows, C. A., Teo, R. Q., Zhang, L., Yuan, X., Zhu, Y., Lee, M. K., Ovens, A. J., Yu, D., Sakamoto, K., Scott, J. W., Murphy, A. J., Tsumaki, N., Herzog, H., Dodd, G. T., & Loh, K. (2026). Targeting hypothalamic SIK3 to promote weight loss and improve glycemic control in mice. Nature communications, 17(1), 8432. https://doi.org/10.1038/s41467-026-73649-1

BibTeX

@article{onda2026targeting,
author = {Onda, Danise Ann and Yang, Chieh-Hsin and Goldsmith, Callen and Beddows, Cait A. and Teo, Rui Qi and Zhang, Lei and Yuan, XiaoZhuo and Zhu, Yifei and Lee, Man KS and Ovens, Ashley J. and Yu, Dingyi and Sakamoto, Kei and Scott, John W. and Murphy, Andrew J. and Tsumaki, Noriyuki and Herzog, Herbert and Dodd, Garron T. and Loh, Kim},
title = {{Targeting hypothalamic SIK3 to promote weight loss and improve glycemic control in mice}},
journal = {Nature communications},
year = {2026},
month = jun,
volume = {17},
number = {1},
pages = {8432},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/s41467-026-73649-1},
url = {https://doi.org/10.1038/s41467-026-73649-1},
pmid = {42230648},
pmcid = {PMC13478199}
}

RIS

TY - JOUR
AU - Onda, Danise Ann
AU - Yang, Chieh-Hsin
AU - Goldsmith, Callen
AU - Beddows, Cait A.
AU - Teo, Rui Qi
AU - Zhang, Lei
AU - Yuan, XiaoZhuo
AU - Zhu, Yifei
AU - Lee, Man KS
AU - Ovens, Ashley J.
AU - Yu, Dingyi
AU - Sakamoto, Kei
AU - Scott, John W.
AU - Murphy, Andrew J.
AU - Tsumaki, Noriyuki
AU - Herzog, Herbert
AU - Dodd, Garron T.
AU - Loh, Kim
TI - Targeting hypothalamic SIK3 to promote weight loss and improve glycemic control in mice
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/06/02
VL - 17
IS - 1
SP - 8432
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/s41467-026-73649-1
UR - https://doi.org/10.1038/s41467-026-73649-1
LA - en
ER -

CSL-JSON

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