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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]
Citations
Cites
Weight-Reducing Effects of the Plasma Protein Encoded by the obese Gene
Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D., Lallone, R. L., Burley, S. K., & Friedman, J. M. (1995) · Science · doi:10.1126/science.7624777 · Cited by 4,451
Effects of the obese Gene Product on Body Weight Regulation in ob / ob Mice
Pelleymounter, M. A., Cullen, M. J., Baker, M. B., Hecht, R., Winters, D., Boone, T., & Collins, F. (1995) · Science · doi:10.1126/science.7624776 · Cited by 4,017
Campfield, L. A., Smith, F. J., Guisez, Y., Devos, R., & Burn, P. (1995) · Science · doi:10.1126/science.7624778 · Cited by 3,243
STAT3 signalling is required for leptin regulation of energy balance but not reproduction
Bates, S. H., Stearns, W. H., Dundon, T. A., Schubert, M., Tso, A. W. K., Wang, Y., Banks, A. S., Lavery, H. J., Haq, A. K., Maratos-Flier, E., et al. (2003) · Nature · doi:10.1038/nature01388 · Cited by 1,010
Receptor-mediated regional sympathetic nerve activation by leptin.
Haynes, W. G., Morgan, D. A., Walsh, S. A., Mark, A. L., & Sivitz, W. I. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119532 · Cited by 979
Self-citationAgouti-related peptide–expressing neurons are mandatory for feeding
Gropp, E., Shanabrough, M., Borók, E., Xu, A. W., Janoschek, R., Buch, T., Plum, L., Balthasar, N., Hampel, B., Waisman, A., et al. (2005) · Nature Neuroscience · doi:10.1038/nn1548 · Cited by 800
Self-citationFei, H., Okano, H. J., Li, C., Lee, G.-H., Zhao, C., Darnell, R., & Friedman, J. M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.13.7001 · Cited by 766
Insulin Action in AgRP-Expressing Neurons Is Required for Suppression of Hepatic Glucose Production
Könner, A. C., Janoschek, R., Plum, L., Jordan, S. D., Rother, E., Ma, X., Xu, C., Enriori, P., Hampel, B., Barsh, G. S., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.004 · Cited by 695
Self-citationRole for neuronal insulin resistance in neurodegenerative diseases
Schubert, M., Gautam, D., Surjo, D., Ueki, K., Baudler, S., Schubert, D., Kondo, T., Alber, J., Galldiks, N., Küstermann, E., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308724101 · Cited by 659
Self-citationWidespread recombinase expression using FLPeR (Flipper) mice
Farley, F. W., Soriano, P. M., Steffen, L. S., & Dymecki, S. M. (2000) · genesis · doi:10.1002/1526-968x(200011/12)28:3/4 · Cited by 602
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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
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“Additionally, phosphatase and tensin homolog (PTEN) and tyrosine phosphatase epsilon (RPTPe) are also suggested to be involved in the development of leptin resistance [155–158].”
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“However, there is mounting evidence that the central nervous system (CNS) control of WAT browning is also important (Plum et al., 2007; Ruan et al., 2014; Williams et al., 2014).”
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Belgardt, B., & Brüning, J. C. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05799.x · Cited by 287
Self-citationLeptin as a key regulator of the adipose organ
Picó, C., Palou, M., Pomar, C. A., Rodríguez, A. M., & Palou, A. (2021) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-021-09687-5 · Cited by 304
Butler, A. A., & Kozak, L. P. (2010) · Diabetes · doi:10.2337/db09-1471 · Cited by 265
“Wt Mc4r Ob 0 10 20 30 40 50 60 (51) (10) (19)”
BackgroundInfluentialAdvances in understanding the interrelations between leptin resistance and obesity
Pan, H., Guo, J., & Su, Z. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.04.003 · Cited by 257
“Leptinstimulated activation of hypothalamic phosphatidylinositol-3-kinase (PI3K) is impaired in DIO [80], and the pharmacological inhibition of PI3K activity blocks the anorectic effect of leptin [81,82], while chronic activation of the hypothalamic PI3K pathway by ObR neuron-targeted deletion of the PIP3 phosphatase…”
BackgroundHormone and glucose signalling in POMC and AgRP neurons
Belgardt, B., Okamura, T., & Brüning, J. C. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.179192 · Cited by 257
“…upon leptin binding activate the signal cascade intracellularly) induces changes in white adipose tissue (WAT) energy expenditure and leanness in mice (Plum et al. 2007), whereas in rats, central leptin action depends on intact PI3K signalling to inhibit lipogenesis in WAT (Buettner et al. 2008).”
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Ramadori, G., Fujikawa, T., Fukuda, M., Anderson, J. G., Morgan, D. A., Mostoslavsky, R., Stuart, R. C., Perelló, M., Vianna, C. R., Nillni, E. A., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.05.010 · Cited by 226
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Könner, A. C., Klöckener, T., & Brüning, J. C. (2009) · Physiology & Behavior · doi:10.1016/j.physbeh.2009.03.027 · Cited by 230
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German, J., Kim, F., Schwartz, G. J., Havel, P. J., Rhodes, C. J., Schwartz, M. W., & Morton, G. J. (2009) · Endocrinology · doi:10.1210/en.2009-0445 · Cited by 164
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Belgardt, B., Husch, A., Rother, E., Ernst, M. B., Wunderlich, F. T., Hampel, B., Klöckener, T., Alessi, D. R., Kloppenburg, P., & Brüning, J. C. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.01.006 · Cited by 159
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Harlan, S. M., Guo, D., Morgan, D. A., Fernandes‐Santos, C., & Rahmouni, K. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.02.017 · Cited by 103
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BackgroundBell, B. B., Harlan, S. M., Morgan, D., Guo, D., Cui, H.-X., & Rahmouni, K. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.12.006 · Cited by 77
Self-citationCentral Regulation of Metabolism by Protein Tyrosine Phosphatases
Tsou, R. C., & Bence, K. K. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2012.00192 · Cited by 87
Tanida, M., Yamamoto, N., Morgan, D., Kurata, Y., Shibamoto, T., & Rahmouni, K. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.1828-14.2015 · Cited by 68
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BackgroundInfluentialSahu, A. (2011) · Neuroendocrinology · doi:10.1159/000326785 · Cited by 74
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Self-citationKyriakou, E., Schmidt, S., Dodd, G. T., Pfuhlmann, K., Simonds, S. E., Lenhart, D., Geerlof, A., Schriever, S. C., Angelis, M. D., Schramm, K. ‐., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01224 · Cited by 74
Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine?
Genchi, V. A., D’Oria, R., Palma, G., Caccioppoli, C., Cignarelli, A., Natalicchio, A., Laviola, L., Giorgino, F., & Perrini, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126445 · Cited by 83
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Iskandar, K., Cao, Y., Hayashi, Y., Nakata, M., Takano, E., Yada, T., Zhang, C., Ogawa, W., Oki, M., Chua, S. C., et al. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00512.2009 · Cited by 67
Wang, L., Opland, D. M., Tsai, S. J., Luk, C. T., Schroer, S. A., Allison, M. B., Elia, A., Furlonger, C. L., Suzuki, A., Paige, C. J., et al. (2014) · Nature Medicine · doi:10.1038/nm.3527 · Cited by 67
Self-citationCai, R., Tang, G., Zhang, Q., Yong, W., Zhang, W., Xiao, J., Wei, C., He, C., Yang, G., & Pang, W. (2019) · Cells · doi:10.3390/cells8050477 · Cited by 65
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Qiu, J., Bosch, M. A., Meza, C., Navarro, U.-V., Nestor, C. C., Wagner, E. J., Rønnekleiv, O. K., & Kelly, M. J. (2017) · Endocrinology · doi:10.1210/en.2017-00793 · Cited by 64
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Donato, J., Frazão, R., & Elias, C. (2010) · Arquivos brasileiros de endocrinologia e metabologia · doi:10.1590/s0004-27302010000700002 · Cited by 53
Seoane‐Collazo, P., Martínez‐Sánchez, N., Milbank, E., & Contreras, C. (2020) · Nutrients · doi:10.3390/nu12020472 · Cited by 61
Imaging modalities for diagnosis and monitoring of cancer cachexia
Han, J., Harrison, L., Patzelt, L., Wu, M., Junker, D., Herzig, S., Díaz, M. B., & Karampinos, D. C. (2021) · EJNMMI Research · doi:10.1186/s13550-021-00834-2 · Cited by 57
“browning and to drive thermogenesis via sympathetic innervation of the adipose tissue [28].”
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Unger, E. K., Piper, M. L., Olofsson, L. E., & Xu, A. W. (2009) · Endocrinology · doi:10.1210/en.2009-0711 · Cited by 50
Elevated Fra-1 expression causes severe lipodystrophy
Luther, J., Drießler, F., Megges, M., Heß, A., Herbort, B., Mandic, V., Zaiss, M. M., Reichardt, A., Zech, C., Tuckermann, J. P., et al. (2011) · Journal of Cell Science · doi:10.1242/jcs.079855 · Cited by 47
“S1D) and no difference in the ratio of BAT weight to body weight could be observed (supplementary material Fig.”
BackgroundInfluentialMetabolic actions of hypothalamic SIRT1
Coppari, R. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.01.002 · Cited by 47
“By engaging the sympathetic nervous system, these hypothalamic neurons enhance amount and activity of the calorie-burning brown adipocytes in several fat depots (25, 44), including the interscapular brown adipose tissue (iBAT; a prominent tissue located between the shoulder blades in rodents) and visceral and subcutan…”
BackgroundThermogenic adipocytes: From cells to physiology and medicine
Díaz, M. B., Herzig, S., & Vegiopoulos, A. (2014) · Metabolism · doi:10.1016/j.metabol.2014.07.002 · Cited by 45
“[63] Plum L, Rother E, Munzberg H, et al.”
BackgroundEvans, M. C., Lord, R. A., & Anderson, G. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179210 · Cited by 48
A chromatin perspective of adipogenesis
Musri, M. M., Gomis, R., & Párrizas, M. (2010) · Organogenesis · doi:10.4161/org.6.1.10226 · Cited by 44
Perino, A., Beretta, M., Kilić, A., Ghigo, A., Carnevale, D., Repetto, I. E., Braccini, L., Longo, D. L., Liebig‐Gonglach, M., Zaglia, T., et al. (2014) · Science Signaling · doi:10.1126/scisignal.2005485 · Cited by 43
“Although insulin and leptin signaling control central SNS outflow (19), both insulin- and leptin-dependent SNS activation of BAT does not depend on PI3K in the hypothalamus (70, 71).”
BackgroundLeptin-mediated ion channel regulation: PI3K pathways, physiological role, and therapeutic potential
Gavello, D., Carbone, E., & Carabelli, V. (2016) · Channels · doi:10.1080/19336950.2016.1164373 · Cited by 43
“A number of studies have highlighted the relevance of PI3K in leptin-activated pathways.(21,22) Hirsch and collaborators recently gave a complete overview of the different PI3K isoforms and their relationship to leptin and obesity.”
BackgroundPI3K signaling in the pathogenesis of obesity: The cause and the cure
Beretta, M., Bauer, M. W., & Hirsch, E. (2014) · Advances in Biological Regulation · doi:10.1016/j.jbior.2014.11.004 · Cited by 42
García-Galiano, D., Borges, B., Donato, J., Allen, S. J., Bellefontaine, N., Wang, M., Zhao, J. J., Kozloff, K., Hill, J. W., & Elias, C. (2017) · JCI Insight · doi:10.1172/jci.insight.96728 · Cited by 33
“Our findings indicate a dissociated role of distinct PI3K catalytic subunits downstream of leptin signaling, which has also been suggested by studies using chemically defined hypothalamic neurons (14, 20, 21).”
InfluentialNeuroanatomical determinants of the sympathetic nerve responses evoked by leptin
Harlan, S. M., & Rahmouni, K. (2012) · Clinical Autonomic Research · doi:10.1007/s10286-012-0168-4 · Cited by 39
Self-citationNeurocircuits integrating hormone and nutrient signaling in control of glucose metabolism
Rother, E., Könner, A. C., & Brüning, J. C. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00685.2007 · Cited by 38
Self-citationHuang, Y., He, Z., Gao, Y., Lieu, L., Yao, T. S., Sun, J. M., Liu, T., Javadi, C. S., Box, M., Afrin, S., et al. (2018) · Journal of the Endocrine Society · doi:10.1210/js.2018-00061 · Cited by 35
“In particular, overactivation of PI3K signaling in LepR-positive cells resulted in a lean phenotype coincident with browning of white adipose tissue [32].”
BackgroundRother, E., Belgardt, B., Tsaousidou, E., Hampel, B., Waisman, A., Myers, M. G., & Brüning, J. C. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206147109 · Cited by 33
“4), washed extensively to remove cryoprotectant, and then stained using previously described standard protocols (27, 37, 38).”
MethodSelf-citationDubois, E., Jacoby, M., Blockmans, M., Pernot, E., Schiffmann, S. N., Foukas, L. C., Henquin, J., Vanhaesebroeck, B., Erneux, C., & Schurmans, S. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2012.06.012 · Cited by 32
Kim, E., Lim, S.-M., Kim, M., Yoo, S., & Kim, Y. (2017) · Nutrients · doi:10.3390/nu9101049 · Cited by 33
“In particular, PI3K and ERK pathways are downstream of leptin in thermogenesis [75,76].”
History and future of leptin: Discovery, regulation and signaling
Münzberg, H., Heymsfield, S. B., Berthoud, H., & Morrison, C. D. (2024) · Metabolism · doi:10.1016/j.metabol.2024.156026 · Cited by 37
Self-citationImpact of adipokines and myokines on fat browning
Rodríguez, A., Catalán, V., Ramírez, B., Unamuno, X., Portincasa, P., Gómez‐Ambrosi, J., Frühbeck, G., & Becerril, S. (2020) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-020-00736-2 · Cited by 31
“Central leptin administration activates WAT differentiation towards a BAT-like phenotype through the activation of the sympathetic nerve activity in BAT [105].”
BackgroundKoch, C. E., Ganjam, G. K., Steger, J., Legler, K., Stöhr, S., Schumacher, D., Hoggard, N., Heldmaier, G., & Tups, A. (2012) · British Journal Of Nutrition · doi:10.1017/s0007114512003005 · Cited by 30
PI3K signaling: A key pathway in the control of sympathetic traffic and arterial pressure by leptin
Harlan, S. M., & Rahmouni, K. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2013.03.004 · Cited by 30
“Several downstream mechanisms that would explain the involvement of PI3K signaling in mediating the metabolic effects of leptin have been suggested, including its activation of phosphodiesterase-3B which can then interact with STAT3 [24] or through inactivation of FoxO-1 transcription factor that stimulate POMC neuron…”
Self-citationGao, Y.-X., Li, J., Zhang, Z., Zhang, R., Pollock, A., & Sun, T. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1618-y · Cited by 27
Whole-Body and Hepatic Insulin Resistance in Obese Children
Ibarra‐Reynoso, L. D. R., Pisarchyk, L., Pérez-Luque, E. L., Garay‐Sevilla, M. E., & Malacara, J. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113576 · Cited by 27
“tissue [34] thus controlling lipogenesis [35].”
Metlakunta, A. S., Sahu, M., Yasukawa, H., Dhillon, S. S., Belsham, D. D., Yoshimura, A., & Sahu, A. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00794.2010 · Cited by 27
“(34, 35) have shown that whereas selective activation of the PI3K/Akt pathway in ObRb-expressing neurons by ObRb-specific inactivation of the Pten gene results in a lean phenotype; Pten inactivation in POMC neurons, which increases PIP3, leads to leptin-resistant hyperphagia and obesity.”
PI3K and AKT at the Interface of Signaling and Metabolism
Solinas, G., & Becattini, B. (2022) · Current topics in microbiology and immunology · doi:10.1007/978-3-031-06566-8_13 · Cited by 27
Molecular pathways regulating the formation of brown‐like adipocytes in white adipose tissue
Fu, J., Li, Z., Zhang, H., Mao, Y., Wang, A., Wang, X., Zou, Z., & Zhang, X. (2014) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2600 · Cited by 29
“remodelling of WAT with increased mitochondrial content and UCP1 expression, resulting in increased energy expenditure and leanness [102].”
BackgroundInfluentialSympathetic Innervation of White Adipose Tissue: to Beige or Not to Beige?
Münzberg, H., Floyd, Z. E., & Chang, J. S. (2021) · Physiology · doi:10.1152/physiol.00038.2020 · Cited by 23
Self-citationLiu, J., Yang, X., Yu, S., & Zheng, R. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1286-1_7 · Cited by 25
Qiu, J., Bosch, M. A., Zhang, C., Rønnekleiv, O. K., & Kelly, M. J. (2019) · Neuroendocrinology · doi:10.1159/000501560 · Cited by 25
Zhang, D., Wu, W., Huang, X. S., Xu, K., Zheng, C. C., & Zhang, J. (2021) · BMC Genomics · doi:10.1186/s12864-020-07361-9 · Cited by 23
Inter-organ regulation of adipose tissue browning
Wang, S., & Yang, X. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2420-x · Cited by 23
Research on Sports Performance Prediction Based on BP Neural Network
Yang, S., Luo, L., & Tan, B. (2021) · Mobile Information Systems · doi:10.1155/2021/5578871 · Cited by 22
RetractedLeptin Downregulates Angulin-1 in Active Crohn’s Disease via STAT3
Hu, J.-C. E., Bojarski, C., Branchi, F., Fromm, M., & Krug, S. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217824 · Cited by 20
“In addition, the involvement of PI3K was exhibited during the regulation of energy consumption in the central nerve system [39].”
BackgroundLeptin, Acting at Central Level, Increases FGF21 Expression in White Adipose Tissue via PPARβ/δ
Mazuecos, L., Pintado, C., Rubio, B., Guisantes-Batán, E., Andrés, A., & Gallardo, N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094624 · Cited by 21
“In addition, in white adipose tissue, depending on the activation of POMC-positive hypothalamic neurons and the SNS, it has been widely reported that leptin (combined with insulin action) has the ability to promote the browning process as part of a metabolic reprogramming and nutritional adaptation of adipocytes, incr…”
BackgroundSenese, R., Cioffi, F., Matteis, R. D., Petito, G., de Lange, P., Silvestri, E., Lombardi, A., Moreno, M., Goglia, F., & Lanni, A. (2019) · Cells · doi:10.3390/cells8030256 · Cited by 21
Chida, D., Hashimoto, O., Kuwahara, M., Sagara, H., Osaka, T., Tsubone, H., & Iwakura, Y. (2008) · Diabetologia · doi:10.1007/s00125-008-1075-z · Cited by 20
“signalling in the CNS regulates energy expenditure via activation of the SNS, leading to BAT-like differentiation of WAT [ 40 ].”
BackgroundMesenchymal lineage cells and their importance in B lymphocyte niches
Green, A., Rudolph-Stringer, V., Chantry, A., Wu, J. Y., & Purton, L. (2017) · Bone · doi:10.1016/j.bone.2017.11.018 · Cited by 18
Zhang, X., Tang, L., Wang, X., Shen, C., Xiong, W., Shen, Y., Wan, Y.-H., Wu, Y., Wang, Y.-C., Zhang, H., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03634-7 · Cited by 18
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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