RalA controls glucose homeostasis by regulating glucose uptake in brown fat
Open accessAbstract
Significance: The primary event in diabetes pathogenesis is the development of insulin resistance. Insulin is elevated during feeding and maintains blood glucose levels within a physiological range, largely by increasing glucose uptake in muscle and fat. Our laboratory has identified two components of insulin signaling, the protein RalA and its GAP complex RalGAP, which regulate glucose uptake by fat cells. Using genetic approaches and pharmacological inhibitors, we describe how these proteins influence glucose metabolism in mice. We discovered that RalA is essential for efficient insulin-stimulated glucose uptake in fat, while RalA activation via deletion of RalGAP dramatically increases glucose uptake into brown fat and improves glucose handling in mice (hence, protecting them from developing diabetes).
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RalA is transiently activated by insulin in brown adipocytes in response to short-term AKT activation.
“RalA is transiently activated by insulin in brown adipocytes in response to short-term AKT activation 46,47 .”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [46]
The Discussion (page unavailable) says insulin action represses RalGAP through AKT phosphorylation, causing RalA activation, and reports RalA activation in brown adipose tissue after feeding. It does not establish that the activation is transient or specifically follows short-term AKT activation in brown adipocytes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGLUT4 depends on general exocytic and endocytic pathways to regulate its surface levels.
“The reporter is based on the glucose transporter GLUT4 (Fig. 1A), which depends on general exocytic and endocytic pathways to regulate its surface levels (3, 19–21).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [20]
The paper’s discussion of glucose uptake in brown fat says insulin regulates GLUT4 trafficking to the plasma membrane through vesicle tethering and fusion, supporting the exocytic part of the claim. The section “RalA Activation Increases Plasma Membrane Glut4 in Brown Fat” mentions GLUT4 recycling, but our copy does not establish that general endocytic pathways regulate its surface levels. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRalA regulates vesicle tethering and fusion through interacting with exocyst.
“Ralbp1 binds to RalA, a small GTPase regulating vesicle tethering and fusion through interacting with exocyst (11, 20, 41–44).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [20]
Ralbp1 binds to RalA.
“Ralbp1 binds to RalA, a small GTPase regulating vesicle tethering and fusion through interacting with exocyst (11, 20, 41–44).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [20]
The paper’s section on Glut4 vesicle dynamics says RalA interacts with the exocyst proteins Sec5 and Exo84. Its discussion of RalGAPB concerns regulation of RalA activity, not Ralbp1. Searches for Ralbp1 and its alternative names found no passage in our copy stating that Ralbp1 binds RalA; RalGAPB should not be treated as Ralbp1. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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Cites
Adipocytes as regulators of energy balance and glucose homeostasis
Rosen, E. D., & Spiegelman, B. M. (2006) · Nature · doi:10.1038/nature05483 · Cited by 2,170 · cited 1× · see citing works
“RalGAP | GTPase | Ral inhibitors | Glut4 | insulin A adipose tissue accounts for only 10 to 15% of insulin-stimulated glucose uptake, it serves as a primary site for energy storage and coordinates systemic energy metabolism (1).”
BackgroundBrown adipose tissue activity controls triglyceride clearance
Bartelt, A., Bruns, O. T., Reimer, R., Hohenberg, H., Ittrich, H., Peldschus, K., Kaul, M. G., Tromsdorf, U. I., Weller, H., Waurisch, C., et al. (2011) · Nature Medicine · doi:10.1038/nm.2297 · Cited by 1,608 · cited 1× · see citing works
“Cold exposure substantially increases glucose uptake in BAT and, thus, may be responsible for disposal of up to three-fourths of ingested glucose in mice (15, 16).”
BackgroundATP-citrate lyase controls a glucose-to-acetate metabolic switch
Zhao, S., Torres, A., Henry, R. A., Trefely, S., Wallace, M., Lee, J. V., Carrer, A., Sengupta, A., Campbell, S. L., Kuo, Y.-M., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.09.069 · Cited by 394 · see citing works
Discovery and characterization of small molecules that target the GTPase Ral
Yan, C., Liu, D., Li, L., Wempe, M. F., Guin, S., Khanna, M., Meier, J., Hoffman, B., Owens, C., Wysoczynski, C. L., et al. (2014) · Nature · doi:10.1038/nature13713 · Cited by 150 · see citing works
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Insulin signaling in health and disease
Saltiel, A. R. (2021) · Journal of Clinical Investigation · doi:10.1172/jci142241 · Cited by 446 · see citing works
Self-citationTargeting Small GTPases and Their Prenylation in Diabetes Mellitus
Gendaszewska-Darmach, E., Garstka, M. A., & Błażewska, K. M. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00410 · Cited by 35 · see citing works
Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module
Wang, S., Chen, X., Crisman, L., Dou, X., Winborn, C. S., Wan, C., Puscher, H., Yin, Q., Kennedy, M. J., & Shen, J. (2023) · Science Advances · doi:10.1126/sciadv.ade2540 · Cited by 14 · see citing works
Self-citationDietary cholesterol activates a Ral-dependent pathway driving LDLR turnover
Feng, X., Zhang, S., Wang, Y., Kurlagunda, T., Sit, A., Jaishankar, P., Yang, P., Sakane, S., Park, S. Y., Wisessaowapak, C., et al. (2026) · Nature · doi:10.1038/s41586-026-10697-z · Cited by 2 · see citing works
Self-citation
- Authors
- Skorobogatko, Y., Dragan, M., Cordon, C., Reilly, S. M., Hung, C.-W., Xia, W., Zhao, P., Wallace, M., Lackey, D. E., Chen, X.-W., Osborn, O., Bogner-Strauss, J. G., Theodorescu, D., Metallo, C. M., Olefsky, J. M., & Saltiel, A. R.
- Affiliations
- University of Michigan (US)
- University of California San Diego (US)
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109;
- Institute of Biochemistry, Graz University of Technology, 8010 Graz, Austria;
- University of Colorado Anschutz (US)
- Corresponding author
- Saltiel, Alan R.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-06-18
- Volume
- 115
- Issue
- 30
- Pages
- 7819-7824
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6065037
- OpenAlex
- W2808562996
- Cited by
- 52
- References
- 4
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 11 · 2020: 11 · 2019: 5 · 2018: 2
- FWCI
- 4.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Foundation for the National Institutes of Health (DK076906, DK061618, DK060591, P30 DK063491)
- American Heart Association (19POST27740033)
- ADA Foundation (1-18-PDF-094)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- RalA, glucose homeostasis, glucose uptake, brown adipose tissue, insulin signaling, adipocytes, diet-induced obesity, metabolic disorders, small GTPases
- MeSH terms
- Animals, Adipose Tissue, Brown, Glucose, Homeostasis, Gene Deletion, Mice, Knockout, GTPase-Activating Proteins, ral GTP-Binding Proteins, 3T3-L1 Cells, Glucose Transporter Type 4, Mice
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