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dc.contributor.author
Chhabra, Kavaljit H.
dc.contributor.author
Adams, Jessica M.
dc.contributor.author
Jones, Graham L.
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Yamashita, Miho
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Schlapschy, Martin
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Skerra, Arne
dc.contributor.author
Rubinstein, Marcelo
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dc.contributor.author
Low, Malcolm J.
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dc.date.available
2018-04-03T20:57:54Z
dc.date.issued
2016-10
dc.identifier.citation
Chhabra, Kavaljit H.; Adams, Jessica M.; Jones, Graham L.; Yamashita, Miho; Schlapschy, Martin; et al.; Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity; Elsevier Gmbh; Molecular Metabolism; 5; 10; 10-2016; 869-881
dc.identifier.issn
2212-8778
dc.identifier.uri
http://hdl.handle.net/11336/40592
dc.description.abstract
Objective: A major challenge for obesity treatment is the maintenance of reduced body weight. Diet-induced obese mice are resistant to achieving normoweight once the obesogenic conditions are reversed, in part because lowered circulating leptin leads to a reduction in metabolic rate and a rebound of hyperphagia that defend the previously elevated body weight set point. Because hypothalamic POMC is a central leptin target, we investigated whether changes in circulating leptin modify Pomc expression to maintain normal energy balance in genetically predisposed obese mice. Methods: Mice with reversible Pomc silencing in the arcuate nucleus (ArcPomc−/−) become morbidly obese eating low-fat chow. We measured body composition, food intake, plasma leptin, and leptin sensitivity in ArcPomc−/− mice weight-matched to littermate controls by calorie restriction, either from weaning or after developing obesity. Pomc was reactivated by tamoxifen-dependent Cre recombinase transgenes. Long acting PASylated leptin was administered to weight-reduced ArcPomc−/− mice to mimic the super-elevated leptin levels of obese mice. Results: ArcPomc−/− mice had increased adiposity and leptin levels shortly after weaning. Despite chronic calorie restriction to achieve normoweight, ArcPomc−/− mice remained moderately hyperleptinemic and resistant to exogenous leptin's effects to reduce weight and food intake. However, subsequent Pomc reactivation in weight-matched ArcPomc−/− mice normalized plasma leptin, leptin sensitivity, adiposity, and food intake. In contrast, extreme hyperleptinemia induced by PASylated leptin blocked the full restoration of hypothalamic Pomc expression in calorie restricted ArcPomc−/− mice, which consequently regained 30% of their lost body weight and attained a metabolic steady state similar to that of tamoxifen treated obese ArcPomc−/− mice. Conclusions: Pomc reactivation in previously obese, calorie-restricted ArcPomc−/− mice normalized energy homeostasis, suggesting that their body weight set point was restored to control levels. In contrast, massively obese and hyperleptinemic ArcPomc−/− mice or those weight-matched and treated with PASylated leptin to maintain extreme hyperleptinemia prior to Pomc reactivation converged to an intermediate set point relative to lean control and obese ArcPomc−/− mice. We conclude that restoration of hypothalamic leptin sensitivity and Pomc expression is necessary for obese ArcPomc−/− mice to achieve and sustain normal metabolic homeostasis; whereas deficits in either parameter set a maladaptive allostatic balance that defends increased adiposity and body weight.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Elsevier Gmbh
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
Body Weight Set Point
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Hypothalamus
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Leptin
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Leptin Resistance
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Obesity
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Pasylation
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Pomc
dc.subject.classification
Otras Ciencias Biológicas
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-04-03T18:41:45Z
dc.journal.volume
5
dc.journal.number
10
dc.journal.pagination
869-881
dc.journal.pais
Alemania
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dc.description.fil
Fil: Chhabra, Kavaljit H.. University of Michigan; Estados Unidos
dc.description.fil
Fil: Adams, Jessica M.. University of Michigan; Estados Unidos
dc.description.fil
Fil: Jones, Graham L.. University of Michigan; Estados Unidos
dc.description.fil
Fil: Yamashita, Miho. University of Michigan; Estados Unidos
dc.description.fil
Fil: Schlapschy, Martin. Technische Universitat Munchen; Alemania
dc.description.fil
Fil: Skerra, Arne. Technische Universitat Munchen; Alemania
dc.description.fil
Fil: Rubinstein, Marcelo. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
dc.description.fil
Fil: Low, Malcolm J.. University of Michigan; Estados Unidos
dc.journal.title
Molecular Metabolism
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.molmet.2016.07.012
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S2212877816301144
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