Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels.
Proopiomelanocortin (POMC) neurons within the hypothalamic arcuate nucleus are vital anorexigenic neurons. Although both the leptin and insulin receptors are coupled to the activation of phosphatidylinositide 3 kinase (PI3K) in POMC neurons, they are thought to have disparate actions on POMC excitability. Using whole-cell recording and selective pharmacological tools, we have found that, similar to leptin, purified insulin depolarized POMC and adjacent kisspeptin neurons via activation of TRPC5 channels, which are highly expressed in these neurons. In contrast, insulin hyperpolarized and inhibited NPY/AgRP neurons via activation of KATP channels. Moreover, Zn(2+), which is found in insulin formulations at nanomolar concentrations, inhibited POMC neurons via activation of KATP channels. Finally, as predicted, insulin given intracerebroventrically robustly inhibited food intake and activated c-fos expression in arcuate POMC neurons. Our results show that purified insulin excites POMC neurons in the arcuate nucleus, which we propose is a major mechanism by which insulin regulates energy homeostasis.
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA.
Jian
J
Qiu
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA.
Chunguang
C
Zhang
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Amanda
A
Borgquist
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA.
Casey C
CC
Nestor
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA.
Arik W
AW
Smith
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA.
Martha A
MA
Bosch
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Stephen
S
Ku
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Edward J
EJ
Wagner
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA; Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA.
Oline K
OK
Rønnekleiv
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA; Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA. Electronic address: kellym@ohsu.edu.
Martin J
MJ
Kelly
D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D004435:Eating / Q000187:drug effects*; D006168:Guinea Pigs; D007328:Insulin / Q000494:pharmacology*; D054086:KATP Channels / Q000187:drug effects; D059648:Kisspeptins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009478:Neuropeptide Y / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology
D054369:Agouti-Related Protein; D007328:Insulin; D054086:KATP Channels; D059648:Kisspeptins; D009478:Neuropeptide Y; D016760:Proto-Oncogene Proteins c-fos; D050051:Transient Receptor Potential Channels; D011333:Pro-Opiomelanocortin; D015032:Zinc