Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function.
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.
Björnholm
Marie
M
Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.
Münzberg
Heike
H
Leshan
Rebecca L
RL
Villanueva
Eneida C
EC
Bates
Sarah H
SH
Louis
Gwendolyn W
GW
Jones
Justin C
JC
Ishida-Takahashi
Ryoko
R
Bjørbaek
Christian
C
Myers
Martin G
MG
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D004703:Endocrine System / Q000502:physiology*; D005260:Female; D020738:Leptin / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D054411:Receptors, Leptin; D012680:Sensitivity and Specificity; D012737:Sex Factors; D015398:Signal Transduction / Q000235:genetics*; D013851:Thinness / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D014443:Tyrosine / Q000235:genetics
D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D014443:Tyrosine