A major role for perifornical orexin neurons in the control of glucose metabolism in rats.
OBJECTIVE
The hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats.


METHODS
We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies.


RESULTS
Hypothalamic disinhibition of neuronal activity by the gamma-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone-containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes.


CONCLUSIONS
Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis.
Yi
Chun-Xia
CX
Department of Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands. c.yi@nin.knaw.nl
Serlie
Mireille J
MJ
Ackermans
Mariette T
MT
Foppen
Ewout
E
Buijs
Ruud M
RM
Sauerwein
Hans P
HP
Fliers
Eric
E
Kalsbeek
Andries
A
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005937:Glucaric Acid / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006946:Hyperinsulinism / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D007276:Injections, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000294:innervation / Q000378:metabolism; D008297:Male; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D064446:Orexin Receptors; D000068797:Orexins; D017764:Parasympathectomy; D010275:Parasympathetic Nervous System / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013562:Sympathectomy; D013564:Sympathetic Nervous System / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018756:GABA Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D005680:gamma-Aminobutyric Acid; D005937:Glucaric Acid; D001640:Bicuculline