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Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62
Open accessAbstract
Signaling cascades that control adipogenesis are essential in the regulation of body weight and obesity. The adaptor p62 controls pathways that modulate cell differentiation. We report here that p62(-/-) mice develop mature-onset obesity, leptin resistance, as well as impaired glucose and insulin intolerance. The metabolic rate was significantly reduced in p62(-/-) nonobese mice, which displayed increased mRNA levels of PPAR-gamma and reduced levels of UCP-1 in adipose tissue. Basal activity of ERK was enhanced in fat from nonobese mutant mice. Embryo fibroblasts from p62(-/-) mice differentiated better than the wild-type controls into adipocytes, which was abrogated by pharmacological inhibition of the ERK pathway. p62 is induced during adipocyte differentiation and inhibits ERK activation by direct interaction. We propose that p62 normally antagonizes basal ERK activity and adipocyte differentiation and that its loss leads to the hyperactivation of ERK that favors adipogenesis and obesity.
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“sqstm1-knockout mice display reduced numbers of osteoclasts as well as cognitive impairment and anxiety, associated with hyperphosphorylated MAPT/tau and neurofibrillary tangles [134–136].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [136]
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“Loss in mice of p62, a protein important for the efficiency of autophagy, results in mature-onset obesity and leptin resistance, as well as metabolic abnormalities (Rodriguez et al., 2006).”
Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice.
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“Although p62 deficiency was associated with adulthood-onset obesity and diabetes as reported recently (Rodriguez et al., 2006), no apparent abnormality was noted in the p62deleted liver (Figure S7).”
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Metadata
- Authors
- Rodriguez, A., Durán, A., Selloum, M., Champy, M.-F., Diez-Guerra, F. J., Flores, J. M., Serrano, M., Auwerx, J., Diaz-Meco, M. T., & Moscat, J.
- Affiliations
- Phénotypage et ingénierie précliniques des systèmes d’organismes modèles (FR)
- Universidad Complutense de Madrid (ES)
- Spanish National Cancer Research Centre (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Corresponding author
- Moscat, Jorge
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2006-03
- Volume
- 3
- Issue
- 3
- Pages
- 211-222
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2096738869
- Cited by
- 290
- References
- 34
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 8 · 2023: 3 · 2022: 14 · 2021: 19 · 2020: 14 · 2019: 14 · 2018: 24 · 2017: 17 · 2016: 19 · 2015: 14 · 2014: 22 · 2013: 26 · 2012: 21
- FWCI
- 9.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- p62, insulin resistance, leptin resistance, adipogenesis, ERK signaling, PPARγ, UCP1, metabolic rate, adipose tissue, impaired glucose tolerance
- MeSH terms
- Adipose Tissue, Animals, Diabetes Mellitus, Type 2, Embryo, Mammalian, Fibroblasts, HeLa Cells, Humans, Insulin Resistance, RNA, Messenger, Transcription Factors, Signal Transduction, Adipocytes, Mice, Knockout, 3T3-L1 Cells, Extracellular Signal-Regulated MAP Kinases, Adipogenesis, Mice, Transcription Factor TFIIH
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