Immunotoxic destruction of distinct catecholamine subgroups produces selective impairment of glucoregulatory responses and neuronal activation

Abstract

The toxin-antibody complex anti-d(beta)h-saporin (DSAP) selectively destroys d(beta)h-containing catecholamine neurons. To test the role of specific catecholamine neurons in glucoregulatory feeding and adrenal medullary secretion, we injected DSAP, unconjugated saporin (SAP), or saline bilaterally into the paraventricular nucleus of the hypothalamus (PVH) or spinal cord (T2-T4) and subsequently tested rats for 2-deoxy-D-glucose (2DG)-induced feeding and blood glucose responses. Injections of DSAP into the PVH abolished 2DG-induced feeding, but not hyperglycemia. 2DG-induced Fos expression was profoundly reduced or abolished in the PVH, but not in the adrenal medulla. The PVH DSAP injections caused a nearly complete loss of tyrosine hydroxylase immunoreactive (TH-ir) neurons in the area of A1/C1 overlap and severe reduction of A2, C2, C3 (primarily the periventricular portion), and A6 cell groups. Spinal cord DSAP blocked 2DG-induced hyperglycemia but not feeding. 2DG-induced Fos-ir was abolished in the adrenal medulla but not in the PVH. Spinal cord DSAP caused a nearly complete loss of TH-ir in cell groups A5, A7, subcoeruleus, and retrofacial C1 and a partial destruction of C3 (primarily the ventral portion) and A6. Saline and SAP control injections did not cause deficits in 2DG-induced feeding, hyperglycemia, or Fos expression and did not damage catecholamine neurons. DSAP eliminated d(beta)h immunoreactivity but did not cause significant nonspecific damage at injection sites. The results demonstrate that hindbrain catecholamine neurons are essential components of the circuitry for glucoprivic control of feeding and adrenal medullary secretion and indicate that these responses are mediated by different subpopulations of catecholamine neurons.

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

“…In addition, injections of 5-thio-glucose in different hypothalamic nuclei failed to induce a glucoregulatory response, whereas its injection into the NTS and the basolateral medulla region containing the A1/C1 catecholaminergic neurons, which project to different sites of the hypothalamus, induced a strong response. [54][55][56] Also, in decerebrated rats, the hyperglycemic response to an intraperitoneal injection of 2-DG is preserved, 57 and c-fos immunostaining revealed that the activated neurons are present in the NTS, the dorsal motor nucleus of the vagus and the catecholaminergic neurons of the basolateral medulla. 58 Thus, hypoglycemia can be detected at several sites, the hepatoportal vein area, the brainstem and the hypothalamus.…”

“…Furthermore, food intake can be stimulated by direct injections of 5-thio-glucose into the basolateral medulla, the dorsal motor nucleus of the vagus and the NTS, 54 where glucose-sensitive catecholaminergic neurons are located, which project to the hypothalamus, in particular the PVN and the AN. 55,58 Immunotoxin destruction of these neurons showed their role in the feeding response to the 2-DG glucoprivic signal 56 and in the regulation of NPY and Agrp expression. 55 A role for central Glut2 expression in feeding regulation has been suggested by experiments in which its expression was decreased by the injection of antisense oligonucleotides in the AN.…”

Catecholaminergic Control of Mitogen-Activated Protein Kinase Signaling in Paraventricular Neuroendocrine NeuronsIn VivoandIn Vitro: A Proposed Role during Glycemic Challenges

“…Establishing these linkages requires, in part, identifying afferents signaling the PVH during glycemic challenge and the neurotransmitter(s) involved in such signaling. Ritter et al (2001) identified an essential afferent pathway by showing that selectively destroying PVH afferents originating from hindbrain CA cell groups impaired the feeding and PVH responses to 2-DG or insulin challenges (elevated CRH hnRNA, Fos mRNA, and circulating corticosterone) but not those occurring basally or from forced-swim challenge (Ritter et al, 2003). These lesions also impair PVH phospho-ERK1/2 responses to insulin (Rapp et al, 2006).…”

The Neuroanatomical Axis for Control of Energy Balance

“…Thus, for example, Ob-Rb is coexpressed with AgRP in arcuate neurons, whereas the caudal brainstem contains no AgRP perikarya. Similarly, research indicates (38,147,149) that glucose interoceptors are coextensive with, or coexpressed within, norepinephrine and epinephrine neurons in the DVC and VLM, whereas cell bodies for these catecholamines are not found in forebrain. Determination of the neurotransmitter phenotypes of the neurons sensitive to blood-borne correlates of metabolic state begins the discussion taken up in the next section, addressing the transmission of interoceptive information to other substrates, nearby and distant, involved in energy balance.…”

“…Biogenic amine neurons, therefore, represent an element in a pathway, endemic to the caudal brainstem, with potent effects on ingestive behavior. Under physiological conditions, these neurons may receive signals arising from brainstem interoceptors (33,147,205). But because of direct and indirect descending pathways from hypothalamus to these neurons, a possibly critical role for basal forebrain interoceptors or integrative mechanisms can never be ruled out.…”