Role of dorsal vagal motor nucleus orexin-receptor-1 in glycemic responses to acute versus repeated insulin administration

Paranjape, Sachin A.; Vavaiya, Kamlesh V.; Kale, Ajay; Briski, Karen P.

doi:10.1016/j.npep.2006.11.001

Cited by 16 publications

(11 citation statements)

References 14 publications

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“…Lateral hypothalamic area (LHA) orexin-A (ORX) neurons exhibit increased synaptic firing, cfos transcription, and preproorexin gene expression during nutrient shortage (10,11,20,37,56). ORX involvement in glucostasis is implied by evidence for orexin receptor-1-dependent blood glucose and glucagon secretory responses to acute and recurring hypoglycemia (46). The hypothalamic paraventricular nucleus (PVH) serves as the primary conduit for motor control of autonomic and neuroendocrine outflow.…”

mentioning

confidence: 99%

“…Exogenous OT elevates circulating glucose, glucagon, and corticosterone, in part by central actions, whereas OT receptor antagonism elicits hypoglycemia (3,4). Here, we used the hypoglycemia plus hindbrain lactate repletion model established in our laboratory (46) to address the hypothesis that hindbrain lactoprivation controls NPY, ORX, and OT gene and/or neuropeptide transmitter expression during hypoglycemia.…”

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confidence: 99%

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Hindbrain lactostasis regulates hypothalamic AMPK activity and metabolic neurotransmitter mRNA and protein responses to hypoglycemia

Gujar

Ibrahim

Tamrakar

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Nerve cell metabolic activity is monitored in multiple brain regions, including the hypothalamus and hindbrain dorsal vagal complex (DVC), but it is unclear if individual metabolosensory loci operate autonomously or interact to coordinate central nervous system (CNS) reactivity to energy imbalance. This research addressed the hypothesis that hypoglycemia-associated DVC lactoprivation stimulates hypothalamic AMPK activity and metabolic neurotransmitter expression. As DVC catecholaminergic neurons express biomarkers for metabolic monitoring, we investigated whether these cells are a source of lactate deficit signaling to the hypothalamus. Caudal fourth ventricle (CV4) infusion of the glucose metabolite l-lactate during insulin-induced hypoglycemia reversed changes in DVC A2 noradrenergic, arcuate neuropeptide Y (NPY) and pro-opiomelanocortin (POMC), and lateral hypothalamic orexin-A (ORX) neuronal AMPK activity, coincident with exacerbation of hypoglycemia. Hindbrain lactate repletion also blunted hypoglycemic upregulation of arcuate NPY mRNA and protein. This treatment did not alter hypoglycemic paraventricular oxytocin (OT) and lateral hypothalamic ORX mRNA profiles, but exacerbated or reversed adjustments in OT and ORX neuropeptide synthesis, respectively. CV4 delivery of the monocarboxylate transporter inhibitor, 4-CIN, increased A2 phosphoAMPK (pAMPK), elevated circulating glucose, and stimulated feeding, responses that were attenuated by 6-hydroxydopamine pretreatment. 4-CIN-infused rats exhibited increased (NPY, ORX neurons) or decreased (POMC neurons) pAMPK concurrent with hyperglycemia. These data show that hindbrain lactoprivic signaling regulates hypothalamic AMPK and key effector neurotransmitter responses to hypoglycemia. Evidence that A2 AMPK activity is lactate-dependent, and that DVC catecholamine cells are critical for lactoprivic control of glucose, feeding, and hypothalamic AMPK, implies A2 derivation of this metabolic regulatory stimulus.

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confidence: 99%

mentioning

confidence: 99%

Hindbrain lactostasis regulates hypothalamic AMPK activity and metabolic neurotransmitter mRNA and protein responses to hypoglycemia

Gujar

Ibrahim

Tamrakar

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…This suggests that orexin-A neurons in the LHA participating in the regulation of gastric motility. Research indicates that postprandial-like motility pattern induced by orexin-A was abolished by atropine and vagotomy [10] . Thus, we speculate that exogenous orexin-A may act on the LHA to regulate gastric motility via the vagus pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The evidences suggest that central orexin-A plays a role in gastrointestinal motility through the vagal pathways [9]. Orexin-A excites the gastric-projecting vagal motor neurons [9].OXR1 is highly expressed in the dorsal motor nucleus of vagus (DMV) [10]. Administration of orexin-A into the DMV increased intragastric pressure and antral motility in anesthetized rats [11], the effects induced by orexin-A were attenuated by vagotomy [12].However, it is not clear whether hypothalamus administered orexin-A modulates the gastric motility in conscious rats.…”

Section: Introductionmentioning

confidence: 99%

Extrinsic Orexin-A in Lateral Hypothalamic Area Regulates Gastric Motility in Rats

Luo¹

2015

ijSciences

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Abstract:The orexin neuropeptide family consists of orexin-A and orexin-B, which are coded from the same prepro-mRNA. Although peripherally administered orexin-A abolishes small intestinal interdigestive contractions in rats, it still remains unclear whether orexin-A of lateral hypothalamic area(LHA) effects on the gastric motility in rats. We selected Wistar rats as our subjects. A stainless-steel injection cannula was implanted unilaterally into the LHA. A force transducer was embedmented into the stomach to record circular muscle contractiontions in freely moving conscious rats. The gastric motility was monitored by administration of ghrelin into LHA. The changes of amplitude of constriction and frequency of gastric motility were monitored in conscious rats by a transducer. Subdiaphragmatic vagotomy was performed to elucidate the neural pathways of orexin-A. After microinjection of orexin-A into LHA 5-20 min later, Orexin-A dose-dependently increased the amplitude of contraction and accelerated frequency of gastric motility in the stomach. The effect of orexin-A on promoting the amplitude and frequency of gastric contraction disappeared after 0.5μg orexin-A +6.0μg SB-334867 mixture was microinjection into LHA. However, there was no significant changes of amplitude and frequency of gastric contraction while injection of orexin-A receptor antagonists SB-334867 alone. The stimulatory effect of orexin-A on gastric motility was abolished by subdiaphragmatic vagotomy. It is suggested that exogenous orexin-A of LHA may promote gastric motility, the effect may be accomplished through the LHA-vagus pathway.

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“…Eight days before the study, female rats were bilaterally OVX and stereotaxically implanted with 26-gauge stainless steel double guide cannulas (Plastics One, Inc., Roanoke, Va., USA) aimed 1.0 mm dorsal to either the ARH (C235G-0.8 SPC; coordinates: 8.8 mm ventral to skull surface, 0.4 mm lateral to midline, and 3.3 mm posterior to bregma), or the ventrolateral VMH (C235G-1.5 SPC; coordinates: 8.8 mm ventral to skull surface, 0.7 mm lateral to midline, and 3.3 mm posterior to bregma), under ketamine/xylazine anesthesia, as previously described [24]. The same animals were implanted with i.v.…”

Section: Methodsmentioning

confidence: 99%

Site-Specific Effects of Intracranial Estradiol Administration on Recurrent Insulin-Induced Hypoglycemia in the Ovariectomized Female Rat

Nedungadi

Briski²

2012

Neuroendocrinology

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Clinical and experimental studies reveal gender differences in susceptibility to dampening effects of precedent hypoglycemia on recurrent insulin-induced hypoglycemia (RIIH). Recent studies implicate the ovarian steroid, estradiol, in the regulation of RIIH, since systemic replacement of this hormone at basal estrous cycle levels maintains glucose profiles during serial insulin dosing and prevents RIIH-associated reductions in neuronal activation in key metabolic structures in the ovariectomized female rat brain. The present study investigated the hypothesis that these effects are achieved, in part, by estrogenic action within the central nervous system, including glucoregulatory structures characterized by high estrogen receptor (ER) expression. Initial experiments evaluated the impact of global intracranial administration of estradiol on RIIH. Ovariectomized rats were treated by continuous infusion of graded doses of 17β-estradiol-3-benzoate (EB) or vehicle into the lateral ventricle (LV), and injected subcutaneously with 1 or 4 doses of the intermediate-release insulin, Humulin N (HN), 1 dose per day. Animals infused with 5 or 10 µg EB/day exhibited uniform glycemic responses to 1 versus 4 doses of insulin, whereas rescue from hypoglycemia was delayed during repetitive HN injection of rats infused with either vehicle or 1 µg EB/day. Recovery from both single and multiple bouts of hypoglycemia was more rapid in rats infused with the higher EB doses, compared to other groups. Mapping of ERα immunoreactivity in animals treated by LV infusion of EB revealed variable nuclear staining in ER-expressing metabolic loci typified by estrogen-dependent sustenance of neuronal reactivity to hypoglycemia, with highest levels of ERα immunoreactivity observed in the arcuate (ARH) and ventromedial (VMH) hypothalamic nuclei, and moderate labeling of the caudal hindbrain dorsal vagal complex. EB delivery to the caudal hindbrain via the caudal fourth ventricle resulted in dose-dependent effects on RIIH, since glycemic profiles were either unchanged or diminished relative to acute NH-induced hypoglycemia, in high versus low EB-treated animals, respectively. Bilateral administration of 1.0 µg EB into the ARH or VMH elicited disparate effects on acute and chronic HN-induced hypoglycemia. Intra-VMH EB delayed recovery from both acute and chronic hypoglycemia, compared to non-estradiol-treated controls. In contrast, neither that dose nor a 10-fold lower dosage of EB delivered to the ARH modified acute HN-induced hypoglycemia, but RIIH was either attenuated or enhanced, respectively, in animals treated by intra-ARH delivery of 1.0 versus 0.1 µg EB, respectively. These results suggest that whole brain exposure to elevated estradiol may promote outflow that truncates hypoglycemia and maintains glucose profiles during RIIH, whereas actions of relatively low hormone levels on the central nervous system may result in adaptive adjustments that result in lower blood glucose levels during recurring versus acute hypoglycemia. The data also imply...

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Role of dorsal vagal motor nucleus orexin-receptor-1 in glycemic responses to acute versus repeated insulin administration

Cited by 16 publications

References 14 publications

Hindbrain lactostasis regulates hypothalamic AMPK activity and metabolic neurotransmitter mRNA and protein responses to hypoglycemia

Hindbrain lactostasis regulates hypothalamic AMPK activity and metabolic neurotransmitter mRNA and protein responses to hypoglycemia

Extrinsic Orexin-A in Lateral Hypothalamic Area Regulates Gastric Motility in Rats

Site-Specific Effects of Intracranial Estradiol Administration on Recurrent Insulin-Induced Hypoglycemia in the Ovariectomized Female Rat

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