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Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice.

ABSTRACT: Although primary cilia are well established as important sensory and signaling structures, their function in most tissues remains unknown. Obesity is a feature associated with some syndromes of cilia dysfunction, such as Bardet-Biedl syndrome (BBS) and Alström syndrome, as well as in several cilia mutant mouse models. Recent data indicate that obesity in BBS mutant mice is due to defects in leptin receptor trafficking and leptin resistance. Furthermore, induction of cilia loss in leptin-responsive proopiomelanocortin neurons results in obesity, implicating cilia on hypothalamic neurons in regulating feeding behavior. Here, we directly test the importance of the cilium as a mediator of the leptin response. In contrast to the current dogma, a longitudinal study of conditional Ift88 cilia mutant mice under different states of adiposity indicates that leptin resistance is present only when mutants are obese. Our studies show that caloric restriction leads to an altered anticipatory feeding behavior that temporarily abrogates the anorectic actions of leptin despite normalized circulating leptin levels. Interestingly, preobese Bbs4 mutant mice responded to the anorectic effects of leptin and did not display other phenotypes associated with defective leptin signaling. Furthermore, thermoregulation and activity measurements in cilia mutant mice are inconsistent with phenotypes previously observed in leptin deficient ob/ob mice. Collectively, these data indicate that cilia are not directly involved in leptin responses and that a defect in the leptin signaling axis is not the initiating event leading to hyperphagia and obesity associated with cilia dysfunction.

SUBMITTER: Berbari NF

PROVIDER: S-EPMC3651481 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice.

Berbari Nicolas F NF Pasek Raymond C RC Malarkey Erik B EB Yazdi S M Zaki SM McNair Andrew D AD Lewis Wesley R WR Nagy Tim R TR Kesterson Robert A RA Yoder Bradley K BK

Proceedings of the National Academy of Sciences of the United States of America 20130418 19

Although primary cilia are well established as important sensory and signaling structures, their function in most tissues remains unknown. Obesity is a feature associated with some syndromes of cilia dysfunction, such as Bardet-Biedl syndrome (BBS) and Alström syndrome, as well as in several cilia mutant mouse models. Recent data indicate that obesity in BBS mutant mice is due to defects in leptin receptor trafficking and leptin resistance. Furthermore, induction of cilia loss in leptin-responsi ...[more]

PMID: 23599282

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Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice.

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Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice.

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