p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity
Open accessAbstract
Insulin resistance is a key factor in the etiology of type 2 diabetes. Insulin-stimulated glucose uptake is mediated by the glucose transporter 4 (GLUT4), which is expressed mainly in skeletal muscle and adipose tissue. Insulin-stimulated translocation of GLUT4 from its intracellular compartment to the plasma membrane is regulated by small guanosine triphosphate hydrolases (GTPases) and is essential for the maintenance of normal glucose homeostasis. Here we show that the p75 neurotrophin receptor (p75(NTR)) is a regulator of glucose uptake and insulin resistance. p75(NTR) knockout mice show increased insulin sensitivity on normal chow diet, independent of changes in body weight. Euglycemic-hyperinsulinemic clamp studies demonstrate that deletion of the p75(NTR) gene increases the insulin-stimulated glucose disposal rate and suppression of hepatic glucose production. Genetic depletion or shRNA knockdown of p75(NTR) in adipocytes or myoblasts increases insulin-stimulated glucose uptake and GLUT4 translocation. Conversely, overexpression of p75(NTR) in adipocytes decreases insulin-stimulated glucose transport. In adipocytes, p75(NTR) forms a complex with the Rab5 family GTPases Rab5 and Rab31 that regulate GLUT4 trafficking. Rab5 and Rab31 directly interact with p75(NTR) primarily via helix 4 of the p75(NTR) death domain. Adipocytes from p75(NTR) knockout mice show increased Rab5 and decreased Rab31 activities, and dominant negative Rab5 rescues the increase in glucose uptake seen in p75(NTR) knockout adipocytes. Our results identify p75(NTR) as a unique player in glucose metabolism and suggest that signaling from p75(NTR) to Rab5 family GTPases may represent a unique therapeutic target for insulin resistance and diabetes.
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p75NTR knockout mice show increased insulin sensitivity.
“Indeed, p75NTR KO-mice show an increased insulin sensitivity [31].”
From Circadian control of glucose metabolism (2014) · cites this paper as [31]
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- Authors
- Baeza-Raja, B., Li, P., Le Moan, N., Sachs, B. D., Schachtrup, C., Davalos, D., Vagena, E., Bridges, D., Kim, C., Saltiel, A. R., Olefsky, J. M., & Akassoglou, K.
- Affiliations
- University of California, San Francisco (US)
- University of California San Diego (US)
- Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158;
- Duke University (US)
- University of Freiburg (DE)
- University of Michigan (US)
- Baylor College of Medicine (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-03-28
- Volume
- 109
- Issue
- 15
- Pages
- 5838-5843
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3326459
- OpenAlex
- W2049672215
- Cited by
- 53
- References
- 36
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 9 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 1 · 2016: 5 · 2015: 4 · 2014: 2 · 2013: 3 · 2012: 1
- FWCI
- 1.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM090161, T32GM007752, R01GM090161)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, DK 074868, DK 033651, T32DK007494, R01DK061618, R37DK033651, R24DK090962, DK061618, P01DK074868, DK090962, R01DK033651, P30DK063720, P30DK020572, P30DK026743, P30DK063491)
- National Institute of Neurological Disorders and Stroke (NS051470, R01NS051470)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD012303)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- p75 neurotrophin receptor, insulin resistance, glucose homeostasis, insulin-stimulated glucose uptake, GLUT4 translocation, Rab5, RAB31, GTPase, adipocytes, hepatic glucose production, type 2 diabetes, death domain, glucose transport
- MeSH terms
- Amino Acid Sequence, Animals, Body Weight, Glucose, Homeostasis, Humans, Insulin Resistance, Molecular Sequence Data, Protein Binding, Protein Structure, Tertiary, Adipocytes, Muscle, Skeletal, rab GTP-Binding Proteins, rab5 GTP-Binding Proteins, Receptor, Nerve Growth Factor, Protein Transport, Muscle Cells, Glucose Transporter Type 4, Mice, HEK293 Cells
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