Sex difference in body weight gain and leptin signaling in hypocretin/orexin deficient mouse models.
Recent studies in human and animal models of narcolepsy have suggested that obesity in narcolepsy may be due to deficiency of hypocretin signaling, and is also under the influence of environmental factors and the genetic background. In the current study, using two hypocretin/orexin deficient narcoleptic mouse models (i.e. preproorexin knockout (KO) and orexin/ataxin-3 transgenic (TG) mice) with cross-sectional assessments, we have further analyzed factors affecting obesity. We found that both KO and TG narcoleptic mice with mixed genetic backgrounds (N4-5, 93.75-96.88% genetic composition of C57BL/6) tended to be heavier than wild type (WT) mice of 100-200 days old. The body weight of heterozygous mice was intermediate between those of KO and WT mice. Obesity was more prominent in females in both KO and TG narcoleptic mice and was associated with higher serum leptin levels, suggesting a partial leptin resistance. Obesity is less prominent in the congenic TG narcoleptic mice, but is still evident in females. Our results confirmed that hypocretin/orexin ligand deficiency is one of the critical factors for the obese tendency in narcolepsy. However, multiple factors are also likely to affect this phenotype, and a sex difference specific alteration of leptin-hypocretin signaling may be involved.
Fujiki
Nobuhiro
N
Center for Narcolepsy, Stanford Sleep Research Center, 701B Welch Rd., Palo Alto, CA 94304, United States.
Yoshida
Yasushi
Y
Zhang
Shengwen
S
Sakurai
Takeshi
T
Yanagisawa
Masashi
M
Nishino
Seiji
S
D000818:Animals; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D020738:Leptin / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D009290:Narcolepsy / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics*; D009765:Obesity / Q000209:etiology* / Q000378:metabolism; D000068797:Orexins; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology; D015430:Weight Gain
D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D009479:Neuropeptides; D000068797:Orexins