Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function
Marie Björnholm, … , Christian Bjørbaek, Martin G. Myers Jr.
Marie Björnholm, … , Christian Bjørbaek, Martin G. Myers Jr.
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1354-1360. https://doi.org/10.1172/JCI30688.
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Research Article Metabolism

Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function

Abstract

The adipose-derived hormone, leptin, acts via its receptor (LRb) to convey the status of body energy stores to the brain, decreasing feeding and potentiating neuroendocrine energy expenditure. The failure of high levels of leptin in most obese individuals to promote weight loss defines a state of diminished responsiveness to increased leptin, termed leptin resistance. Leptin stimulates the phosphorylation of several tyrosine residues on LRb to mediate leptin action. We homologously replaced LRb in mice with a receptor with a mutation in one of these sites (Tyr985) in order to examine its role in leptin action and signal attenuation in vivo. Mice homozygous for this mutation are neuroendocrinologically normal, but females demonstrate decreased feeding, decreased expression of orexigenic neuropeptides, protection from high-fat diet–induced obesity, and increased leptin sensitivity in a sex-biased manner. Thus, leptin activates autoinhibitory signals via LRb Tyr985 to attenuate the anti-adiposity effects of leptin, especially in females, potentially contributing to leptin insensitivity in obesity.

Authors

Marie Björnholm, Heike Münzberg, Rebecca L. Leshan, Eneida C. Villanueva, Sarah H. Bates, Gwendolyn W. Louis, Justin C. Jones, Ryoko Ishida-Takahashi, Christian Bjørbaek, Martin G. Myers Jr.

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Figure 3

Decreased body weight and feeding in l/l females during HF feeding.

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Decreased body weight and feeding in l/l females during HF feeding. ...
(A–D) C57BL/6 female (A and B) and male (C and D) +/+, l/+, and l/l animals were provided NC (A and C) or HF (B and D) diets from the age of 5 weeks and weighed weekly until 12 weeks of age. All values represent mean ± SEM. ANOVA and repeated measures ANOVA, P = NS, except for #P < 0.02 for l/l versus other groups where indicated. (E) Weight gained per female mouse from 5–12 weeks of age on each diet. (F) Food intake for first week of divergent diet for female mice of the indicated genotype. *P < 0.05, **P < 0.01 versus +/+ animals, by ANOVA.