Signaling through Tyr985 of leptin receptor as an age/diet-dependent switch in the regulation of energy balance.
Leptin regulates energy homeostasis through central activation of multiple signaling pathways mediated by Ob-Rb, the long form of leptin receptor. Leptin resistance underlies the pathogenic development of obesity, which is closely associated with environmental factors. To further understand the physiological function of leptin signaling mechanisms, we generated a knock-in line of mice (Y985F) expressing a mutant Ob-Rb with a phenylalanine substitution for Tyr985, one of the three intracellular tyrosines that mediate leptin's signaling actions. Surprisingly, whereas young homozygous Y985F animals were slightly leaner, they exhibit adult-onset or diet-induced obesity. Importantly, both age-dependent and diet-induced deterioration of energy balance was paralleled with pronounced leptin resistance, which was largely attributable to attenuation of leptin-responsive hypothalamic STAT3 activation as well as prominently elevated expression of hypothalamic SOCS3, a key negative regulator of leptin signaling. Thus, these results unmask distinct binary roles for Try985-mediated signaling in energy metabolism, acting as an age/diet-dependent regulatory switch to counteract age-associated or diet-induced obesity.
You
Jia
J
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, China.
Yu
Yue
Y
Jiang
Lei
L
Li
Wenxia
W
Yu
Xinxin
X
Gonzalez
Lety
L
Yang
Guoqing
G
Ke
Zunji
Z
Li
Wenjun
W
Li
Cai
C
Liu
Yong
Y
D000375:Aging / Q000502:physiology*; D000818:Animals; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism; D004435:Eating; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*
D004041:Dietary Fats; D009479:Neuropeptides; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine