期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 117, 期 5, 页码 1354-1360出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI30688
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资金
- NIDDK NIH HHS [R01 DK057768, R01 DK056731, DK 57768, R37 DK056731, DK 56731] Funding Source: Medline
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 and-adiposity effects of leptin, especially in females, potentially contributing to leptin insensitivity in obesity.
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