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
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Research Article Endocrinology

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

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 7

The effect on body weight, food intake, and plasma corticosterone levels of corticosterone (Cort) replacement (25 μg/ml drinking water) in Pomc–/– and C57BL/6J Pomc+/+ mice starting at age 6–9 weeks.

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The effect on body weight, food intake, and plasma corticosterone levels...
Pomc+/+ mice (n = 20; 10 males and 10 females) were separated into 2 groups and received either water (n = 10) or corticosterone (n = 10) for 34 consecutive days. All Pomc–/– mice (n = 5; 3 males and 2 females) were first given corticosterone (days 1–16, filled circles), then water (days 16–25, open circles), and finally corticosterone again (days 25–34, filled circles). (A) Weight gain was significantly accelerated by corticosterone replacement in Pomc–/– mice but was unaltered in Pomc+/+ mice of either sex. (B) Average daily food intake measured over a 7-day period was increased in Pomc–/– mice (corticosterone versus water, **P = 0.01, paired t test) but was unchanged by corticosterone treatment in Pomc+/+ mice. (C) Plasma corticosterone levels obtained under stress-free conditions at 0800 and 2400 hours. Corticosterone was always less than 12.5 ng/ml (assay sensitivity) for Pomc–/– mice without replacement (data not shown).