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Glucocorticoids exacerbate obesity and insulin resistance in neuron-specific proopiomelanocortin-deficient mice
James L. Smart, … , Virginie Tolle, Malcolm J. Low
James L. Smart, … , Virginie Tolle, Malcolm J. Low
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):495-505. https://doi.org/10.1172/JCI25243.
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Research Article Endocrinology Article has an altmetric score of 1

Glucocorticoids exacerbate obesity and insulin resistance in neuron-specific proopiomelanocortin-deficient mice

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Abstract

Null mutations of the proopiomelanocortin gene (Pomc–/–) cause obesity in humans and rodents, but the contributions of central versus pituitary POMC deficiency are not fully established. To elucidate these roles, we introduced a POMC transgene (Tg) that selectively restored peripheral melanocortin and corticosterone secretion in Pomc–/– mice. Rather than improving energy balance, the genetic replacement of pituitary POMC in Pomc–/–Tg+ mice aggravated their metabolic syndrome with increased caloric intake and feed efficiency, reduced oxygen consumption, increased subcutaneous, visceral, and hepatic fat, and severe insulin resistance. Pair-feeding of Pomc–/–Tg+ mice to the daily intake of lean controls normalized their rate of weight gain but did not abolish obesity, indicating that hyperphagia is a major but not sole determinant of the phenotype. Replacement of corticosterone in the drinking water of Pomc–/– mice recapitulated the hyperphagia, excess weight gain and fat accumulation, and hyperleptinemia characteristic of genetically rescued Pomc–/–Tg+ mice. These data demonstrate that CNS POMC peptides play a critical role in energy homeostasis that is not substituted by peripheral POMC. Restoration of pituitary POMC expression to create a de facto neuronal POMC deficiency exacerbated the development of obesity, largely via glucocorticoid modulation of appetite, metabolism, and energy partitioning.

Authors

James L. Smart, Virginie Tolle, Malcolm J. Low

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Figure 2

The effects of rescued pituitary POMC expression on body weight and length in the Pomc–/– background.

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The effects of rescued pituitary POMC expression on body weight and leng...
(A) Body weight curves for male and female Pomc+/+, Pomc+/–, and Pomc–/– mice with and without the pHalEx2* transgene (n = 9–44). Repeated-measures ANOVAs from 1 to 26 weeks old showed interactions between week and genotype for both sexes. Males: P < 0.0001, Pomc–/–, Pomc–/–Tg+, and Pomc+/–Tg+ compared with Pomc+/+ or Pomc+/+Tg+; P < 0.001, Pomc+/– compared with Pomc+/+ or Pomc+/+Tg+. Females: P < 0.0001, Pomc–/– and Pomc–/–Tg+ compared with Pomc+/+ or Pomc+/+Tg+. (B) Body lengths of males at age 44 ± 1.3 weeks and females at age 59 ± 2 weeks differed by genotype (F5,44 = 5.9, P < 0.0005, and F5,37 = 13.4, P < 0.0001, respectively). *P < 0.01, **P < 0.001, and ***P < 0.0001 compared with Pomc+/+.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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