Region-specific leptin resistance within the hypothalamus of diet-induced obese mice.
Leptin resistance in diet-induced obese (DIO) mice is characterized by elevated serum leptin and a decreased response to exogenous leptin and is caused by unknown defects in the central nervous system. Leptin normally acts on several brain nuclei, but a detailed description of leptin resistance within individual brain regions has not been reported. We first mapped leptin-responsive cells in brains from DIO mice using phospho-signal transducer and activator of transcription (P-STAT3) immunohistochemistry. After 16 wk of high-fat-diet feeding, leptin-activated P-STAT3 staining within the arcuate nucleus (ARC) was dramatically decreased. In contrast, other hypothalamic and extrahypothalamic nuclei remained leptin sensitive. Reduced leptin-induced P-STAT3 in the ARC could also be detected after 4 wk and as early as 6 d of a high-fat diet. To examine potential mechanisms for leptin-resistant STAT3 activation in the ARC of DIO mice, we measured mRNA levels of candidate signaling molecules in the leptin receptor-STAT3 pathway. We found that the level of suppressor of cytokine signaling 3 (SOCS-3), an inhibitor of leptin signaling, is specifically increased in the ARC of DIO mice. The study suggests that the ARC is selectively leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus. Defects in leptin action in the ARC may play a role in the pathogenesis of leptin-resistant obesity.
Division of Endocrinology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Heike
H
Münzberg
Jeffrey S
JS
Flier
Christian
C
Bjørbaek
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D001835:Body Weight / Q000502:physiology; D004041:Dietary Fats / Q000494:pharmacology; D004302:Dorsomedial Hypothalamic Nucleus / Q000378:metabolism; D004435:Eating / Q000502:physiology; D006963:Hyperphagia / Q000378:metabolism; D020738:Leptin / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism
D004041:Dietary Fats; D020738:Leptin; D012333:RNA, Messenger; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors