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The Journal of Neuroscience, January 3, 2007, 27(1):69-74; doi:10.1523/JNEUROSCI.3168-06.2007

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Behavioral/Systems/Cognitive
Appropriate Inhibition of Orexigenic Hypothalamic Arcuate Nucleus Neurons Independently of Leptin Receptor/STAT3 Signaling

Heike Münzberg,¹ Erin E. Jobst,² Sarah H. Bates,¹ Justin Jones,¹ Eneida Villanueva,¹ Rebecca Leshan,¹ Marie Björnholm,¹ Joel Elmquist,³ Mark Sleeman,⁴ Michael A. Cowley,² and Martin G. Myers, Jr¹

¹Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, ²Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97239, ³Department of Medicine/Endocrinology, Harvard Medical School, Boston, Massachusetts 02215, and ⁴Obesity and Diabetes Research, Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591

Correspondence should be addressed to Dr. Martin G. Myers Jr, Division of Metabolism, Endocrinology, and Diabetes, Departments of Internal Medicine and Physiology, University of Michigan Medical School, 1150 West Medical Center Drive, 4240 MSRB 3, Ann Arbor, MI 48109-0638. Email: mgmyers{at}umich.edu

Leptin directly suppresses the activity of orexigenic neurons in the hypothalamic arcuate nucleus (ARC). We examined c-Fos-like immunoreactivity (CFLIR) as a marker of ARC neuronal activity in db/db mice devoid of the signaling form of the leptin receptor (LRb) and s/s mice that express LRb^S1138 [which is defective for STAT3 (signal transducer and activator of transcription) signaling]. Both db/db and s/s animals are hyperphagic and obese. This analysis revealed that CFLIR in agouti related peptide-expressing orexigenic ARC neurons is basally elevated in db/db but not s/s mice. Consistent with these observations, electrophysiologic evaluation of a small number of neurons in s/s animals suggested that leptin appropriately suppresses the frequency of IPSCs on ARC proopiomelanocortin (POMC) neurons that are mediated by the release of GABA from orexigenic ARC neurons. CFLIR in POMC neurons of s/s mice was also increased compared with db/db animals. Thus, these data suggest that, although LRbSTAT3 signaling is crucial for the regulation of feeding, it is not required for the acute or chronic regulation of orexigenic ARC neurons, and the activation of STAT3-mediated transcription by leptin is not required for the appropriate development of leptin responsiveness in these neurons.

Key words: leptin; signaling; AgRP; c-Fos; arcuate nucleus; hypothalamus; STAT3

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Received July 25, 2006; revised Nov. 15, 2006; accepted Nov. 15, 2006.

Correspondence should be addressed to Dr. Martin G. Myers Jr, Division of Metabolism, Endocrinology, and Diabetes, Departments of Internal Medicine and Physiology, University of Michigan Medical School, 1150 West Medical Center Drive, 4240 MSRB 3, Ann Arbor, MI 48109-0638. Email: mgmyers{at}umich.edu

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