Leptin stimulates neuropeptide Y and cocaine amphetamine-regulated transcript coexpressing neuronal activity in the dorsomedial hypothalamus in diet-induced obese mice.
Neuropeptide Y (NPY) neurons in both the arcuate nucleus of the hypothalamus (ARH) and the dorsomedial hypothalamus (DMH) have been implicated in food intake and obesity. However, while ARH NPY is highly expressed in the lean animal, DMH NPY mRNA expression is observed only after diet-induced obesity (DIO). Furthermore, while ARH NPY neurons are inhibited by leptin, the effect of this adipokine on DMH NPY neurons is unknown. In this study we show that in contrast to the consistent expression in the ARH, DMH NPY mRNA expression was undetectable until after 10 weeks in mice fed a high-fat diet, and peaked at 20 weeks. Surprisingly, electrophysiological experiments demonstrated that leptin directly depolarized and increased the firing rate of DMH NPY neurons in DIO mice. To further differentiate the regulation of DMH and ARH NPY populations, fasting decreased expression of DMH NPY expression, while it increased ARH NPY expression. However, treatment with a leptin receptor antagonist failed to alter DMH NPY expression, indicating that leptin may not be the critical factor regulating mRNA expression. Importantly, we also demonstrated that DMH NPY neurons coexpress cocaine amphetamine-regulated transcript (CART); however, CART mRNA expression in the DMH peaked earlier in the progression of DIO. This study demonstrates novel and important findings. First, NPY and CART are coexpressed in the same neurons within the DMH, and second, leptin stimulates DMH NPY neurons. These studies suggest that during the progression of DIO, there is an unknown signal that drives the expression of the orexigenic NPY signal within the DMH, and that the chronic hyperleptinemia increases the activity of these NPY/CART neurons.
Division of Diabetes, Obesity and Metabolism and Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon 97006, and Monash Obesity and Diabetes Institute, Monash University, Clayton, Victoria, Australia 3800.
Shin J
SJ
Lee
Saurabh
S
Verma
Stephanie E
SE
Simonds
Melissa A
MA
Kirigiti
Paul
P
Kievit
Sarah R
SR
Lindsley
Alberto
A
Loche
M Susan
MS
Smith
Michael A
MA
Cowley
Kevin L
KL
Grove
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D007031:Hypothalamus / Q000187:drug effects* / Q000473:pathology; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000473:pathology*; D018408:Patch-Clamp Techniques; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D007328:Insulin; D020738:Leptin; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; C581199:leptin, Ala(39,40,41)-; D049452:Green Fluorescent Proteins