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Regulation of Hypothalamic Proopiomelanocortin mRNA by Leptin in ob/ob Mice
Abstract
The hormone leptin acts on the brain to regulate feeding, metabolism, and reproduction; however, its cellular targets and molecular mechanisms of action remain to be fully elucidated. The melanocortins, which are derived from the precursor proopiomelanocortin (POMC), are also implicated in the physiological regulation of body weight. POMC-containing neurons express the leptin receptor, and thus it is conceivable that the POMC gene itself may be part of the signaling pathway involved in leptin's action on the brain. Using in situ hybridization and computerized image analysis, we tested the hypothesis that the POMC gene is a target for regulation by leptin by comparing cellular levels of POMC mRNA in the hypothalamus among groups of leptin-deficient (ob/ob) mice, leptin-treated ob/ob mice, and wild-type controls. POMC mRNA levels were significantly reduced throughout the arcuate nucleus in vehicle-treated ob/ob mice relative to wild-type controls, whereas POMC mRNA levels in leptin-treated ob/ob mice were indistinguishable from wild-type controls. These observations suggest that one or more products of POMC serve as an integrative link between leptin and the central mechanisms governing body weight regulation and reproduction.
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“HA-ObRb/Pomc-Cre/Leprdb/db mice had modestly increased hypothalamic POMC mRNA (Figure 6A) consistent with a role of leptin signaling to stimulate Pomc gene expression (Munzberg et al., 2003; Thornton et al., 1997).”
From Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons (2009) · cites this paper as Thornton et al., 1997
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“Indeed, the melanocortin system is suppressed in leptin-deficient ob/ob mice (39, 40), which show hyperphagia as well as infertility.”
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“…be consistent with the previous reports that a decreased leptin signal lowers pro-opiomelanocortin (POMC) mRNA levels in ARC (Schwartz et al. 1997; Thornton et al. 1997; Mizuno et al. 1998), and also that ARC–POMC neurons senda-MSH-immunoreactive fibres to the MPOA (Leranth et al. 1988; Thind &…”
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“Exogenous leptin administration not only reverses these changes in ob/ob mice (16, 41, 43, 55), but also blunts the increases in NPY and AGRP mRNA levels and the decrease in POMC mRNA levels induced by food deprivation (42, 51, 59, 62).”
BackgroundObesity therapy: altering the energy intake-and-expenditure balance sheet
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“Conditions that are associated with an increased drive to consume food, such as fasting or leptin deficiency, are accompanied by reduced expression of POMC in the ARCUATE NUCLEUS”
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“Thus hypothalamic POMC and CART mRNA levels are 50% and 15% lower in ob/ob mice than in lean counterparts respectively ( Thornton et al., 1997, Schwartz et al., 1997, Mizuno et al., 1998 and Duan et al., 2007).”
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“Complementary to these effects were findings by our (Schwartz et al., 1997; van Dijk et al., 1999) and other groups (Thornton et al., 1997) that leptin stimulates proopiomelanocortin (POMC; precursor peptide from which a-MSH is cleaved) synthesis in neuronal cell bodies of the arcuate hypothalamic…”
BackgroundPACAP Neurons in the Hypothalamic Ventromedial Nucleus Are Targets of Central Leptin Signaling
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BackgroundRho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling
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“Furthermore, animals with deficiencies in leptin or leptin-signaling pathways have elevated AGRP mRNA but reduced POMC mRNA in the arcuate nucleus (26, 43, 46).”
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“The following areas were included in the analysis: Arc, DMN and PeN.”
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“Other mechanisms, mediating the actions of leptin on food intake, may involve the products of pro-opiomelanocortin gene (Cheung et al., 1997a; Thornton et al., 1997).”
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“ventricular injection of leptin increases mRNA levels of POMC in the Arc of ob/ob mice (30, 33), and the leptin receptor is colocalized with POMC-containing neurons in the Arc (5, 15).”
BackgroundThe neuroanatomical function of leptin in the hypothalamus
van Swieten, M. M. H., Pandit, R., Adan, R. A. H., & Plasse, G. (2014) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2014.05.004 · Cited by 87
“Leptin directly activates POMC/ CART neurons to enhance POMC- (Thornton et al., 1997) and CART mRNA expression (Kristensen et al.”
BackgroundAcute leptin deficiency, leptin resistance, and the physiologic response to leptin withdrawal
Montez, J. M., Soukas, A. A., Asilmaz, E., Fayzikhodjaeva, G., Fantuzzi, G., & Friedman, J. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409530102 · Cited by 78
Neuroanatomical Framework of the Metabolic Control of Reproduction
Hill, J. W., & Elias, C. F. (2018) · Physiological Reviews · doi:10.1152/physrev.00033.2017 · Cited by 80
“In conditions of negative energy balance, such as fasting, POMC mRNA expression drops, and the opposite is seen when energy is abundant (445, 489, 498).”
BackgroundImplications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction
Antonio Zorzano, A., & Claret, M. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00101 · Cited by 83
“Leptin exerts its anorexigenic effects by increasing Pomc expression and processing into α-MSH (Schwartz et al., 1997; Thornton et al., 1997; Mizuno et al., 1998), and by inhibiting bothNpy and AgRP transcription (Stephens et al., 1995; Schwartz et al., 1996; Mizuno and Mobbs, 1999).”
BackgroundEffects of fasting, leptin, and insulin on AGRP and POMC peptide release in the hypothalamus
Breen, T. L., Conwell, I. M., & Wardlaw, S. L. (2004) · Brain Research · doi:10.1016/j.brainres.2004.11.008 · Cited by 78
THE NEUROENDOCRINOLOGY OF CHILDHOOD OBESITY
Lustig, R. H. (2001) · Pediatric Clinics of North America · doi:10.1016/s0031-3955(05)70348-5 · Cited by 78
de Souza, F. S. J., Nasif, S., López-Leal, R., Levi, D. H., Low, M. J., & Rubinsten, M. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.10.114 · Cited by 75
“Part of the anorectic effect that leptin exerts on the central control of food intake is thought to be mediated by an increase in POMC expression (Schwartz et al., 1997; Thornton et al., 1997) and the activation of POMCneurons in”
Serum leptin level in women with idiopathic intracranial hypertension
Lampl, Y. (2002) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.72.5.642 · Cited by 78
Overview of human obesity and central mechanisms regulating energy homeostasis
Crowley, V. (2008) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1258/acb.2007.007193 · Cited by 78
Shimizu‐Albergine, M., Ippolito, D. L., & Beavo, J. A. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-04-01238.2001 · Cited by 76
“The dosage of leptin used was based on previous studies in which leptin (3–5 mg z kg 21 z d (21)) was subchronically injected in mice (Ahima et al., 1996; Schwartz et al., 1996; Thornton et al., 1997; Mizuno and Mobbs, 1999).”
MethodPerello, M., Stuart, R. C., & Nillni, E. A. (2006) · Endocrinology · doi:10.1210/en.2005-1533 · Cited by 74
Leptin and Leptin Receptor in Anterior Pituitary Function
Lloyd, R. V., Jin, L. G., Tsumanuma, I., Vidal, S., Kovács, K., Horváth, É., Scheithauer, B. W., Couce, M., & Burguera, B. G. (2001) · Pituitary · doi:10.1023/a:1012982626401 · Cited by 76
Arvaniti, K., Huang, Q., & Richard, D. (2001) · Neuroendocrinology · doi:10.1159/000054639 · Cited by 77
THE NEUROENDOCRINOLOGY OF OBESITY
Lustig, R. H. (2001) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(05)70211-5 · Cited by 73
Watanobe, H., & Habu, S. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-14-06265.2002 · Cited by 88
“…seems to be consistent with the reports that the ARC POMC neurons abundantly express leptin receptors (Cheung et al., 1997; Finn et al., 1998) and also that leptin upregulates POMC mRNA levels in the ARC (Schwartz et al., 1997; Thornton et al., 1997; Mizuno et al., 1998; Cowley et al., 2001).”
BackgroundResultNam, S.-Y., Kratzsch, J., Kim, K. W., Kim, K. R., Lim, S., & Marcus, C. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.10.7939 · Cited by 78
“In the arcuate nucleus, POMC neurons express the leptin receptor and POMC mRNA expression is positively regulated by leptin (13).”
Hypothalamic ER stress: A bridge between leptin resistance and obesity
Ramírez, S., & Claret, M. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.04.025 · Cited by 75
Candidate gene polymorphisms in eating disorders
Hinney, A., Remschmidt, H., & Hebebrand, J. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00812-8 · Cited by 70
N-acetylation of hypothalamic α-melanocyte-stimulating hormone and regulation by leptin
Guo, L., Münzberg, H., Stuart, R. C., Nillni, E. A., & Bjørbæk, C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403165101 · Cited by 71
Aja, S. M., Schwartz, G. J., Kuhar, M. J., & Moran, T. H. (2001) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2001.280.6.r1613 · Cited by 69
“CART production is decreased in leptin-deficient ob/ob mice after starvation and increased after leptin treatment (13, 19, 25, 33), and the fall in leptin with fasting results in a decrease in CART mRNA (1).”
BackgroundMode of leptin action in chicken hypothalamus
Dridi, S., Swennen, Q., Decuypere, E. M. P., & Buyse, J. G. (2005) · Brain Research · doi:10.1016/j.brainres.2005.04.034 · Cited by 71
Wardlaw, S. L. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.4.7388 · Cited by 75
The role of agouti-related protein in regulating body weight
Wilson, B. D., Ollmann, M. M., & Barsh, G. S. (1999) · Molecular Medicine Today · doi:10.1016/s1357-4310(99)01471-9 · Cited by 70
Nillni, E. A. (2007) · Endocrinology · doi:10.1210/en.2007-0173 · Cited by 70
Metadata
- Authors
- Thornton, J. E., Cheung, C. C., Clifton, D. K., & Steiner, R. A.
- Affiliations
- University of Washington (US)
- Corresponding author
- Clifton, Donald K.
- ORCID
- Steiner, Robert A.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1997-11-01
- Volume
- 138
- Issue
- 11
- Pages
- 5063-5066
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2064342369
- Cited by
- 437
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 5 · 2016: 7 · 2015: 12 · 2014: 9 · 2013: 12 · 2012: 9
- FWCI
- 12.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- ResearchWorks at the University of Washington (University of Washington) (submittedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD 27142, P50HD012629, R01HD027142, P50-HD-12629)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin, proopiomelanocortin, POMC mRNA, hypothalamus, arcuate nucleus, ob/ob mice, leptin receptor, melanocortin peptides, body weight regulation, reproduction, gene expression regulation
- MeSH terms
- Animals, Cell Count, Eating, Hypothalamus, Male, Mice, Mutant Strains, Neurons, Obesity, Pro-Opiomelanocortin, Proteins, RNA, Messenger, Leptin, Mice
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