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Enhanced Leptin-Stimulated Pi3k Activation in the CNS Promotes White Adipose Tissue Transdifferentiation
Open accessAbstract
The contribution of different leptin-induced signaling pathways in control of energy homeostasis is only partly understood. Here we show that selective Pten ablation in leptin-sensitive neurons (Pten(DeltaObRb)) results in enhanced Pi3k activation in these cells and reduces adiposity by increasing energy expenditure. White adipose tissue (WAT) of Pten(DeltaObRb) mice shows characteristics of brown adipose tissue (BAT), reflected by increased mitochondrial content and Ucp1 expression resulting from enhanced leptin-stimulated sympathetic nerve activity (SNA) in WAT. In contrast, leptin-deficient ob/ob-Pten(DeltaObRb) mice exhibit unaltered body weight and WAT morphology compared to ob/ob mice, pointing to a pivotal role of endogenous leptin in control of WAT transdifferentiation. Leanness of Pten(DeltaObRb) mice is accompanied by enhanced sensitivity to insulin in skeletal muscle. These data provide direct genetic evidence that leptin-stimulated Pi3k signaling in the CNS regulates energy expenditure via activation of SNA to perigonadal WAT leading to BAT-like differentiation of WAT.
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“Selective PTEN ablation in leptin-expressing neurons results in a phenotype characterized by reduced adiposity and increased energy expenditure due, at least in part, to increased fatty acid oxidation in WAT (144)”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [144]
In the citing paper
“associated with increased sympathetic nerve activity to WAT and leading to a remodeling of WAT to take on characteristics of BAT, including increased mitochondrial content and UCP1 expression (144).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [144]
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“For example, increased lipolysis in gonadal WAT is associated with elevated sympathetic inputs (Plum et al., 2007), while the expanded gonadal WAT is found to have decreased sympathetic inputs (Ramadori et al., 2010).”
BackgroundJordan, S. D., Krüger, M., Willmes, D. M., Redemann, N., Wunderlich, F. T., Brönneke, H. S., Merkwirth, C., Kashkar, H., Olkkonen, V. M., Böttger, T., et al. (2011) · Nature Cell Biology · doi:10.1038/ncb2211 · Cited by 531
“Dissected white- and brown-adipose-tissue samples were incubated in fixation solution containing 4p paraformaldehyde at 4 °C overnight, embedded in paraffin and sliced according to a previously described standard protoco”
MethodSelf-citationRecent advances in understanding leptin signaling and leptin resistance
Morris, D. L., & Rui, L. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00274.2009 · Cited by 484
Structure, production and signaling of leptin
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Self-citationSignaling pathways in obesity: mechanisms and therapeutic interventions
Wen, X., Zhang, B., Wu, B., Xiao, H., Li, Z., Li, R., Xu, X., & Li, T. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01149-x · Cited by 490
“In contrast, PTEN knockout in hypothalamic leptin-sensitive neurons increases PI3K activity and leads to browning of WAT and weight loss.(132) A possible explanation is that systemic overexpression of PTEN exerts opposing effects in both the central and peripheral systems, but is more potent in the latter.”
Background
Metadata
- Authors
- Plum, L., Rother, E., Münzberg, H., Wunderlich, F. T., Morgan, D. A., Hampel, B., Shanabrough, M., Janoschek, R., Könner, A. C., Alber, J., Suzuki, A., Krone, W., Horvath, T. L., Rahmouni, K., & Brüning, J. C.
- Affiliations
- University of Cologne (DE)
- University of Michigan (US)
- University of Iowa (US)
- Yale University (US)
- Akita University (JP)
- Corresponding author
- Brüning, Jens C.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2007-12
- Volume
- 6
- Issue
- 6
- Pages
- 431-445
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2160824260
- Cited by
- 138
- References
- 34
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 7 · 2023: 2 · 2022: 4 · 2021: 13 · 2020: 8 · 2019: 5 · 2018: 8 · 2017: 8 · 2016: 9 · 2015: 6 · 2014: 13 · 2013: 8 · 2012: 11
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bundesministerium für Bildung und Forschung
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin, PI3K signaling, PTEN, white adipose tissue, energy expenditure, sympathetic activity, leptin receptor neurons, ob/ob mice, insulin sensitivity, skeletal muscle, mitochondrial content, UCP1, energy homeostasis
- MeSH terms
- Animals, Adipose Tissue, Brown, Central Nervous System, Enzyme Activation, Glucose, Mice, Mutant Strains, Mice, Obese, Mice, Transgenic, Thinness, Signal Transduction, Mice, Knockout, Phosphatidylinositol 3-Kinases, Leptin, PTEN Phosphohydrolase, Mice, Adipose Tissue, White, Cell Transdifferentiation
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