Hindbrain catecholamine neurons control multiple glucoregulatory responses
Section snippets
Anti-dopamine β-hydroxylase saporin (DSAP) selectively lesions brain NE and E neurons
Anti-dopamine β-hydroxylase conjugated to saporin, which we refer to as DSAP, is an immunotoxin that can be used to selectively destroy NE and E neurons [13], [14], [15], [16]. It consists of a monoclonal antibody against dopamine β-hydroxylase (DBH), conjugated to the ribosomal toxin, saporin (SAP). The DSAP molecule is selectively internalized by E and NE neurons due to their unique expression of the catecholamine biosynthetic enzyme, DBH, which is exposed to the extracellular space during
DSAP-induced selective destruction of hindbrain catecholamine neurons abolishes specific glucoregulatory responses
In our initial studies [18], we found that PVH injections of DSAP abolished the feeding response to systemic glucoprivation induced by 2-deoxy-glucose (2DG), a glycolytic inhibitor [25] (Fig. 4), but did not impair the adrenal medullary hyperglycemic response to 2DG. The feeding deficit was highly selective, leaving deprivation-induced feeding and feeding in response to beta mercaptoacetate (MA)-induced lipoprivation intact. Injection into the spinal cord did not impair glucoprivic feeding, but
Hindbrain catecholamine neurons are necessary for the consummatory component of glucoprivic feeding
Appetitive behaviors and consummatory responses are distinct but closely integrated components of ingestion [26], [27]. Appetitive responses include complex motivated behaviors involved in searching for and ingesting food. Consummatory responses include reflexes necessary for accepting, chewing and swallowing food once it is in the mouth. Results from experiments using decerebrate rats [28] have shown that the forebrain is not required for glucoprivation-induced enhancement of consummatory
Hindbrain catecholamine neurons are functionally specialized
The fact that PVH DSAP injections impair or abolish glucoregulatory feeding, reproductive, adrenal medullary and corticosterone responses does not necessarily suggest that the same neurons mediate all of these responses, since functionally distinct neurons may have overlapping terminal beds and therefore be simultaneously lesioned by the DSAP injection. Moreover, the fact that PVH DSAP injections impair these responses does not necessarily indicate that catecholamine terminals in the PVH and
Hindbrain NPY neurons participate in glucoregulatory responses
One way to explore the division of labor between different populations of hindbrain catecholamine neurons is to isolate the functions of specific catecholamine subphenotypes, many of which have been identified already on the basis of co-expressed peptides and membrane receptors. We have made some progress in this regard by investigating the contribution to glucoprivic feeding of hindbrain catecholamine neurons that co-express NPY. Several lines of evidence suggest that NPY neurons are important
Glucoreceptor cells controlling systemic glucoregulatory responses are located in the hindbrain
Receptor cells that detect glucose deficit and elicit systemic glucoregulatory responses are either the catecholamine neurons themselves or are located in close proximity to them within the hindbrain. The most compelling evidence for this is the following: firstly, glucoprivic feeding and adrenal medullary responses are retained in decerebrate rats [28], [54]; secondly, acute cerebral aqueduct occlusion blocks both feeding and adrenal medullary responses to lateral ventricular but not 4th
Role of glucoprivation in the patterning of “daily meals”
There is no question that glucoprivation, when present, is a powerful stimulatory control of food intake. It can be activated despite large adipose stores. It can be activated even during periods of sustained and strongly suppressed food intake caused by chronic administration of exogenous leptin [85] and is not reduced under these conditions. Such demonstrations indicate the primacy of the brain's glucose requirement, as compared to body fat stores, as a control of appetite. Moreover, studies
Summary
Although catecholamine neuron participation in the control of food intake and autonomic and neuroendocrine responses has long been suspected, results of DSAP lesions have made it clear that hindbrain catecholamine neurons play specific and essential roles in eliciting a variety of responses to glucose deficit. The influence of these neurons extends across all levels of the neuroaxis to orchestrate responses of multiple complex systems. The degree to which individual hindbrain catecholamine
Acknowledgements
This work was supported by PHS grants R01 DK 40498 and NS 4552004 and by the Juvenile Diabetes Research Foundation International and the American Diabetes Association.
References (96)
Modulation of the feeding response to peripheral insulin, 2-deoxyglucose or 3-O-methyl glucose injection
Physiol Behav
(1972)- et al.
Insulin-induced elevation of hypothalamic norepinephrine turnover persists after glucorestoration unless feeding occurs
Brain Res
(1981) Effects of glucose and fat antimetabolites on norepinephrine turnover in rat hypothalamus and brainstem
Brain Res
(1992)- et al.
Subgroups of hindbrain catecholamine neurons are selectively activated by 2-deoxy-d-glucose induced metabolic challenge
Brain Res
(1998) - et al.
Localization of hindbrain glucoreceptive sites controlling food intake and blood glucose
Brain Res
(2000) - et al.
Central noradrenergic lesioning using anti-DBH-saporin: anatomical findings
Brain Res
(1996) - et al.
Neuronal lesioning with axonally transported toxins
J Neurosci Methods
(2000) - et al.
Noradrenergic lesioning with an anti-dopamine beta-hydroxylase immunotoxin
Brain Res
(1994) - et al.
Destruction of locus coeruleus neuronal perikarya after injection of anti-dopamine-B-hydroxylase immunotoxin into the olfactory bulb of the rat
Neurosci Lett
(1998) Production and regulation of ingestive consummatory behavior in the chronic decerebrate rat
Brain Res Bull
(1980)
The neuroanatomical axis for control of energy balance
Front Neuroendocrinol
Hindbrain catecholamine neurons mediate consummatory responses to glucoprivation
Physiol Behav
Inhibition of sympathetic preganglionic discharges by epinephrine and alpha-methylepinephrine
Brain Res
Neurotransmitter/neuropeptide interactions in the regulation of neurohypophyseal hormone release
Exp Neurol
Neuropeptide Y antibody attenuates 2-deoxy-d-glucose induced feeding in rats
Brain Res
Leptin activates hypothalamic CART neurons projecting to the spinal cord
Neuron
Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area
Neuron
d-glucose infusions into the basal ventromedial hypothalamus and feeding
Behav Brain Res
Glucose-sensing neurons: are they physiologically relevant?
Physiol Behav
Distribution of glucokinase, glucose transporter GLUT2, sulfonylurea receptor-1, glucagon-like peptide-1 receptor and neuropeptide Y messenger RNAs in rat brain by quantitative real time RT-PCR
Brain Res Mol Brain Res
Distribution and phenotype of neurons containing the ATP-sensitive K+ channel in rat brain
Brain Res
Fourth ventricular alloxan injection causes feeding but not hyperglycemia in rats
Brain Res
Intraventricular alloxan impairs feeding to both central and systemic glucoprivation
Physiol Behav
Alloxan-induced glucoprivic feeding deficits are blocked by d-glucose and amygdalin
Pharmacol Biochem Behav
Overlapping distribution of K(ATP) channel-forming Kir6.2 subunit and the sulfonylurea receptor SUR1 in rodent brain
FEBS Lett
Sulfonylurea binding sites associated with ATP-regulated K+ channels in the central nervous system: autoradiographic analysis of their distribution and ontogenesis, and of their localization in mutant mice cerebellum
Brain Res
Control of meal size by central noradrenergic action
Proc Natl Acad Sci U S A
Neurochemical regulation of feeding in the rat: facilitation by alpha-noradrenergic, but not dopaminergic, receptor stimulants
J Comp Physiol Psychol
Central adrenergic receptors and the regulation of hunger and thirst
Res Publ Assoc Res Nerv Ment Dis
Brain adrenergic system in the feeding response induced by 2-deoxy-d-glucose
Am J Physiol
Glucoregulatory feeding by rats after intraventricular 6-hydroxydopamine or lateral hypothalamic lesions
Science
Nigrostriatal bundle damage and the lateral hypothalamic syndrome
J Comp Physiol Psychol
Noradrenergic and GABAergic systems in the medial hypothalamus are activated during hypoglycemia
Am J Physiol Regul Integr Comp Physiol
Anti-dopamine beta-hydroxylase immunotoxin-induced sympathectomy in adult rats
J Pharmacol Exp Ther
Immunotoxic destruction of distinct catecholamine subgroups produces selective impairment of glucoregulatory responses and neuronal activation
J Comp Neurol
Localization of monoamines in the lower brain stem
Experientia
Demonstration and mapping of central neurons containing dopamine, noradrenaline, and 5-hydroxytryptamine and their reactions to psychopharmaca
Pharmacol Rev
Immunotoxin lesion of hypothalamically projecting norepinephrine and epinephrine neurons differentially affects circadian and stressor-stimulated corticosterone secretion
Endocrinology
Immunotoxic destruction of distinct catecholaminergic neuron populations disrupts the reproductive response to glucoprivation in female rats
Endocrinology
Immunolesion of norepinephrine and epinephrine afferents to medial hypothalamus alters basal and 2DG-induced NPY and AGRP mRNA expression in the arcuate nucleus
Endocrinology
Chemical dissection of brain glucoregulatory circuitry
Effects of 2-deoxy-d-glucose on carbohydrate metabolism: review of the literature and studies in the rat
Metabolism
Insulin elicits ingestion in decerebrate rats
Science
Dorsal medullary pathways subserving oromotor reflexes in the rat: implications for the central neural control of swallowing
J Comp Neurol
Origin and organization of brainstem catecholamine innervation in the rat
J Comp Neurol
Medullary visceral reflex circuits: local afferents to nucleus tractus solitarii synthesize catecholamines and project to thoracic spinal cord
J Comp Neurol
Regulation of sympathetic tone and arterial pressure by the rostral ventrolateral medulla after depletion of C1 cells in rats
Ann N Y Acad Sci
Lesions of the C1 catecholaminergic neurons of the ventrolateral medulla in rats using anti-DbetaH-saporin
Am J Physiol
Cited by (91)
Kobayashi Award 2019: The neuroendocrine regulation of the mammalian reproduction
2022, General and Comparative EndocrinologyEvidence of hypoglycemic anhedonia and modulation by bupropion in rats
2021, Pharmacology Biochemistry and BehaviorThromboxane A<inf>2</inf> in the paraventricular hypothalamic nucleus mediates glucoprivation-induced adrenomedullary outflow
2020, European Journal of PharmacologyHindbrain astrocytes and glucose counter-regulation
2019, Physiology and BehaviorHypothalamic POMC or MC4R deficiency impairs counterregulatory responses to hypoglycemia in mice
2019, Molecular Metabolism