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This version published online on July 22, 2004
Endocrinology, doi:10.1210/en.2004-0726
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Submitted on June 8, 2004
Accepted on July 16, 2004

Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced-Obese Mice

Heike Münzberg, Jeffrey S. Flier, and Christian Bjørbæk*

The Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston MA 02215

* To whom correspondence should be addressed. E-mail: cbjorbae{at}bidmc.harvard.edu.

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-STAT3 (signal-transducer-and-activator-of-transcription) immunohistochemistry. After 16 weeks of high-fat-diet (HFD) feeding, leptin-activated P-STAT3 staining within the arcuate nucleus (ARC) was dramatically decreased. In contrast, other hypothalamic and extra-hypothalamic nuclei remained leptin sensitive. Reduced leptin-induced P-STAT3 in the ARC could also be detected after 4 weeks and as early as six days of HFD. 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 (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 SOCS-3 in this hypothalamic nucleus. Defects in leptin action in the ARC may play a role in the pathogenesis of leptin-resistant obesity.
Key words: leptin resistance • obesity • hypothalamus • arcuate nucleus • STAT3 • SOCS-3




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