New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.

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Central nervous system control of food intake

The novel neuropeptides called hypocretins (orexins) have recently been identified as being localized exclusively in cell bodies in a subregion of the tuberal part of the hypothalamus. The structure of the hypocretins, their accumulation in vesicles of axon terminals, and their excitatory effect on cultured hypothalamic neurons suggest that the hypocretins function in intercellular communication. To characterize these peptides further and to help understand what physiological functions they may serve, we undertook an immunohistochemical study to examine the distribution of preprohypocretin-immunoreactive neurons and fibers in the rat brain. Preprohypocretin-positive neurons were found in the perifornical nucleus and in the dorsal and lateral hypothalamic areas. These cells were distinct from those that express melanin-concentrating hormone. Although they represent a restricted group of cells, their projections were widely distributed in the brain. We observed labeled fibers throughout the hypothalamus. The densest extrahypothalamic projection was found in the locus coeruleus. Fibers were also seen in the septal nuclei, the bed nucleus of the stria terminalis, the paraventricular and reuniens nuclei of the thalamus, the zona incerta, the subthalamic nucleus, the central gray, the substantia nigra, the raphe nuclei, the parabrachial area, the medullary reticular formation, and the nucleus of the solitary tract. Less prominent projections were found in cortical regions, central and anterior amygdaloid nuclei, and the olfactory bulb. These results suggest that hypocretins are likely to have a role in physiological functions in addition to food intake such as regulation of blood pressure, the neuroendocrine system, body temperature, and the sleep–waking cycle.

https://www.jneurosci.org/content/jneuro/18/23/9996.full.pdf

Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems

http://www.columbia.edu/cu/biology/courses/w3004/recitation7.pdf

The Cloned Capsaicin Receptor Integrates Multiple Pain-Producing Stimuli

The survival and well-being of all species requires appropriate physiological responses to environmental and homeostatic challenges. The re-establishment and maintenance of homeostasis entails the coordinated activation and control of neuroendocrine and autonomic stress systems. These collective stress responses are mediated by largely overlapping circuits in the limbic forebrain, the hypothalamus and the brainstem, so that the respective contributions of the neuroendocrine and autonomic systems are tuned in accordance with stressor modality and intensity. Limbic regions that are responsible for regulating stress responses intersect with circuits that are responsible for memory and reward, providing a means to tailor the stress response with respect to prior experience and anticipated outcomes.

Neural regulation of endocrine and autonomic stress responses.

EVOLUTION: Of Mice . . .

Localization of hindbrain glucoreceptive sites controlling food intake and blood glucose.

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.

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

Subgroups of hindbrain catecholamine neurons are selectively activated by 2-deoxy-d-glucose induced metabolic challenge

Absence of lithium-induced taste aversion after area postrema lesion

This experiment examined the role of subdiaphragmatic vagal sensory neurons in feeding stimulated by pharmacological blockade of fatty-acid oxidation (lipoprivic feeding) and glucose utilization (glucoprivic feeding). Rats prepared by surgical transection of the subdiaphragmatic vagal trunk or aspiration lesion of the vagal sensory terminal fields in the area postrema-nucleus of the solitary tract (AP-NTS) were maintained and tested on a fat-supplemented, high carbohydrate diet. Fatty-acid oxidation was blocked with mercaptoacetate (MA, 400 and 600 mumol/kg ip) and glucose utilization was blocked with 2-deoxy-D-glucose (2-DG, 100 and 200 mg/kg sc). On test days, rats were injected with MA, 2-DG, or saline, and feeding was measured hourly for 6 h beginning immediately after injection. We found that both subdiaphragmatic vagotomy and AP-NTS lesions abolished lipoprivic feeding. In contrast, glucoprivic feeding was abolished by AP-NTS lesions but not by subdiaphragmatic vagotomy. These results indicate that lipoprivic feeding requires intact subdiaphragmatic vagal sensory neurons that terminate in the AP-NTS region. Glucoprivic feeding is not vagally mediated but also requires a neural substate within the AP-NTS region.

Sue Ritter

Papers

Localization of hindbrain glucoreceptive sites controlling food intake and blood glucose.

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

Subgroups of hindbrain catecholamine neurons are selectively activated by 2-deoxy-d-glucose induced metabolic challenge

Absence of lithium-induced taste aversion after area postrema lesion

Vagal sensory neurons are required for lipoprivic but not glucoprivic feeding in rats