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To investigate the role of glial cells in the regulation of glucoprivic responses in rats, a chemogenetic approach was used to activate astrocytes neighboring catecholamine (CA) neurons in the ventromedial medulla (VLM) where A1 and C1 CA cell groups overlap (A1/C1). Previous results indicate that activation of CA neurons in this region is necessary and sufficient for feeding and corticosterone release in response to glucoprivation. However, it is not known whether astrocyte neighbors of CA neurons contribute to glucoregulatory responses. Hence, we made nanoinjections of AAV5-GFAP-hM3D(Gq)-mCherry to selectively transfect astrocytes in the A1/C1 region with the excitatory designer receptor exclusively activated by designer drugs (DREADDs), hM3D (Gq). After allowing time for DREADD expression, we evaluated the rats for increased food intake and corticosterone release in response to low systemic doses of the antiglycolytic agent, 2-deoxy-D-glucose (2DG), alone and in combination with the hM3D (Gq) activator clozapine-N-oxide (CNO). We found that DREADD-transfected rats ate significantly more food when 2DG and CNO were coadministered than when either 2DG or CNO was injected alone. We also found that CNO significantly enhanced 2DG-induced FOS expression in the A1/C1 CA neurons, and that corticosterone release also was enhanced when CNO and 2DG were administered together. Importantly, CNO-induced activation of astrocytes in the absence of 2DG did not trigger food intake or corticosterone release. Our results indicate that during glucoprivation, activation of VLM astrocytes cells markedly increases the sensitivity or responsiveness of neighboring A1/C1 CA neurons to glucose deficit, suggesting a potentially important role for VLM astrocytes in glucoregulation. [ABSTRACT FROM AUTHOR]

We examined food intake in chronically maintained decerebrate rats in response to two anti-metabolic drugs known to stimulate food intake, 2-mercaptoacetate (MA) and 2-deoxy-o-glucose (2DG). MA reduces fatty acid oxidation, and 2DG reduces glucose utilization. Because previous work has shown that insulin-induced hypoglycemia increases food intake in decerebrate rats, we predicted that 2DG would have this same effect. MA-induced feeding requires vagal sensory neurons that terminate in the hindbrain. Cholecystokinin-induced suppression of feeding, which likewise requires vagal sensory neurons, has been shown to suppress food intake in decerebrate rats. Therefore, we predicted that MA's effects on feeding would also persist in decerebrate rats. In our experiments, the test diet (40% milk, diluted with water) was infused intraorally through a chronic cheek fistula. We found that sham controls consumed 258% and 230% of their baseline milk intake in response to 2DG and MA, respectively. Decerebrates consumed 239% of their baseline milk intake in response to 2DG, but did not increase their intake in response to MA. Because decerebration separates the hindbrain from the forebrain, these results indicate that 2DG-induced glucoprivation is capable of acting within the hindbrain to activate fundamental reflex circuitry for consummatory feeding responses, as shown previously for hypoglycemia. In contrast, MA affects food consumption only after forebrain processing of MA-induced vagal afferent signals and in the presence of intact ascending and descending neural pathways. glucoprivic feeding; lipoprivic feeding; consummatory feeding responses; vagus nerve; hindbrain

Leptin reduces body fat selectively, sparing body protein. Accordingly, during chronic leptin administration, food intake is suppressed, and body weight is reduced until body fat is depleted. Body weight then stabilizes at this fat-depleted nadir, while food intake returns to normal caloric levels, presumably in defense of energy and nutritional homeostasis. This model of leptin treatment offers the opportunity to examine controls of food intake that are independent of leptin's actions, and provides a window for examining the nature of feeding controls in a 'fatless' animal. Here we evaluate macronutrient selection during this fat-depleted phase of leptin treatment. Adult, male Sprague-Dawley rats were maintained on standard pelleted rodent chow and given daily lateral ventricular injections of leptin or vehicle solution until body weight reached the nadir point and food intake returned to normal levels. Injections were then continued for 8 days, during which rats self-selected their daily diet from separate sources of carbohydrate, protein, and fat. Macronutrient choice differed profoundly in leptin and control rats. Leptin rats exhibited a dramatic increase in protein intake, whereas controls exhibited a strong carbohydrate preference. Fat intake did not differ between groups at any time during the 8-day test. Despite these dramatic differences in macronutrient selection, total daily caloric intake did not differ between groups except on day 2. Thus controls of food intake related to ongoing metabolic and nutritional requirements may supersede the negative feedback signals related to body fat stores. macronutrient choice; homeostasis; lipoprivation; white adipose tissue; dual X-ray absorptiometry

Glucose is required for brain energy metabolism. Decerebration, aqueduct occlusion, and cannula mapping studies have established that glucose-sensing cells capable of eliciting feeding and adrenal medullary responses to glucoprivation are localized in the hindbrain. Glucoprivation also evokes corticosterone and glucagon secretion, but the location of receptors mediating these responses is unknown. To determine whether glucoreceptive sites controlling these responses are present in the hindbrain, we administered the antiglycolytic agent, 5-D-thioglucose (5TG, 24 [micro]g in 200 nl) into brain stem sites through implanted cannulas and examined plasma concentrations of corticosterone and glucagon. Both hindbrain and hypothalamic sites were tested. Blood was collected remotely from intra-atrial catheters at 0, 30, 60, 90, 120, 180, and 240 min after 5TG or control injection. Caudal hindbrain 5TG injections potently increased circulating corticosterone and glucagon concentrations. For corticosterone, the mean peak response (maximum concentration minus time 0 concentration) elicited at positive sites (23 of 40 sites) was 391 ng/ml (SE = 16). For glucagon, the mean peak response at positive sites (27 of 40 sites) was 46 pg/ml (SE = 6). Glucoprivically evoked glucagon secretion was abolished by the ganglionic blocker, hexamethonium, but not by adrenal denervation. Six of twenty-five hypothalamic sites were positive for corticosterone secretion, yielding plasma levels of 279 [+ or -] 23 ng/ml, but none of the hypothalamic injection sites elevated glucagon concentrations. Results demonstrate that receptor cells responsive to glucose deficit and capable of increasing corticosterone and glucagon concentrations exist within the hindbrain, thus further delineating central glucoregulatory neural circuitry. 5-thioglucose; hypothalamus; glucoregulation; glucoreceptors doi: 10.1152/ajpregu.00777.2006.

To better understand the involvement of hindbrain catecholamine neurons in hypovolemia-induced secretion of AVP, we injected antidopamine [beta]-hydroxylase saporin (DSAP) or unconjugated saporin (SAP) control solution into the hypothalamic paraventricular nucleus (PVH) of anesthetized rats to retrogradely lesion catecholamine neurons innervating magnocellular areas of the hypothalamus. Subsequently, hypotensive hypovolemia was induced by remote blood withdrawal (4.5 ml, 1 ml/min) using an intra-atrial catheter. Blood was sampled at 2, 5, 20, and 50 min after onset of blood withdrawal. The AVP response was severely impaired by DSAP. Peak responses at 50 min were 51 pg/ml in SAP control and 17 pg/ml in DSAP-lesioned rats, indicating the importance of catecholamine neurons for this response. We also measured AVP responses to osmotic challenge induced by administration of hypertonic saline (1 M, 15 ml/kg, sc) and to insulin-induced hypoglycemia. Osmotic challenge increased AVP levels, but the response was not impaired by DSAP, indicating that AVP neurons were not damaged by the DSAP injection. Insulin-induced hypoglycemia did not increase AVP levels in either DSAP- or SAP-treated rats. However, the same dose of insulin increased food intake and corticosterone secretion in SAP controls, and these responses were profoundly impaired by DSAP. Thus catecholamine neurons are required for both the AVP response to hypotensive hypovolemia and for feeding and corticosterone responses to hypoglycemia. Lack of an AVP response to insulin-induced hypoglycemia in intact rats therefore indicates that responses to hypovolemia and hypoglycemia are mediated by different catecholamine neurons under distinct sensory controls. arginine vasopressin; norepinephrine; epinephrine; anti-dopamine beta-hydroxylase saporin; osmotic challenge; corticosterone; glucoprivation; insulin

Catecholamine (CA) neurons within the A1 and C1 cell groups in the ventrolateral medulla (VLM) potently increase food intake when activated by glucose deficit. In contrast, CA neurons in the A2 cell group of the dorsomedial medulla are required for reduction of food intake by cholecystokinin (CCK), a peptide that promotes satiation. Thus dorsal and ventral medullary CA neurons are activated by divergent metabolic conditions and mediate opposing behavioral responses. Acute glucose deficit is a life-threatening condition, and increased feeding is a key response that facilitates survival of this emergency. Thus, during glucose deficit, responses to satiation signals, like CCK, must be suppressed to ensure glucorestoration. Here we test the hypothesis that activation of VLM CA neurons inhibits dorsomedial CA neurons that participate in satiation. We found that glucose deficit produced by the antiglycolytic glucose analog, 2-deoxy-D-glucose, attenuated reduction of food intake by CCK. Moreover, glucose deficit increased c-Fos expression by A1 and C1 neurons while reducing CCK-induced c-Fos expression in A2 neurons. We also selectively activated A1/C1 neurons in TH-Cre+ transgenic rats in which A1/C1 neurons were transfected with a Cre-dependent designer receptor exclusively activated by a designer drug (DREADD). Selective activation of A1/C1 neurons using the DREADD agonist, clozapine-N-oxide, attenuated reduction of food intake by CCK and prevented CCK-induced c-Fos expression in A2 CA neurons, even under normoglycemic conditions. Results support the hypothesis that activation of ventral CA neurons attenuates satiety by inhibiting dorsal medullary A2 CA neurons. This mechanism may ensure that satiation does not terminate feeding before restoration of normoglycemia. [ABSTRACT FROM AUTHOR]