The physiological control of eating: signals, neurons, and networks.

During the past 30 yr, investigating the physiology of eating behaviors has generated a truly vast literature. This is fueled in part by a dramatic increase in obesity and its comorbidities that has coincided with an ever increasing sophistication of genetically based manipulations. These techniques have produced results with a remarkable degree of cell specificity, particularly at the cell signaling level, and have played a lead role in advancing the field.

The Medullary Targets of Neurally Conveyed Sensory Information from the Rat Hepatic Portal and Superior Mesenteric Veins.

Vagal and spinal sensory endings in the wall of the hepatic portal and superior mesenteric veins (PMV) provide the brain with chemosensory information important for energy balance and other functions. To determine their medullary neuronal targets, we injected the transsynaptic anterograde viral tracer HSV-1 H129-772 (H129) into the PMV wall or left nodose ganglion (LNG) of male rats, followed by immunohistochemistry (IHC) and high-resolution imaging. We also determined the chemical phenotype of H129-infected neurons, and potential vagal and spinal axon terminal appositions in the dorsal motor nucleus of the vagus (DMX) and the nucleus of the solitary tract (NTS).

Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats.

Endogenous intestinal glucagon-like peptide-1 (GLP-1) controls satiation and glucose metabolism via vagal afferent neurons (VANs). Recently, VANs have received increasing attention for their role in brown adipose tissue (BAT) thermogenesis. It is, however, unclear whether VAN GLP-1 receptor (GLP-1R) signaling affects BAT thermogenesis and energy expenditure (EE) and whether this VAN mechanism contributes to energy balance.

Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity.

Objective: Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate energy balance by controlling sympathetic outflow and BAT function.

Methods: We investigate this possibility in adult male rats by using direct administration of GLP-1 (0.

Catecholaminergic projections into an interconnected forebrain network control the sensitivity of male rats to diet-induced obesity.

Hindbrain catecholamine neurons convey gut-derived metabolic signals to an interconnected neuronal network in the hypothalamus and adjacent forebrain. These neurons are critical for short-term glycemic control, glucocorticoid and glucoprivic feeding responses, and glucagon-like peptide 1 (GLP-1) signaling. Here we investigate whether these pathways also contribute to long-term energy homeostasis by controlling obesogenic sensitivity to a high-fat/high-sucrose choice (HFSC) diet.

MAP kinases couple hindbrain-derived catecholamine signals to hypothalamic adrenocortical control mechanisms during glycemia-related challenges.

Physiological responses to hypoglycemia, hyperinsulinemia, and hyperglycemia include a critical adrenocortical component that is initiated by hypothalamic control of the anterior pituitary and adrenal cortex. These adrenocortical responses ensure appropriate long-term glucocorticoid-mediated modifications to metabolism. Despite the importance of these mechanisms to disease processes, how hypothalamic afferent pathways engage the intracellular mechanisms that initiate adrenocortical responses to glycemia-related challenges are unknown.

Salt-inducible kinase is involved in the regulation of corticotropin-releasing hormone transcription in hypothalamic neurons in rats.

Activation of CRH transcription requires phosphorylation of cAMP response element-binding protein (CREB) and translocation of the CREB coactivator, transducer of regulated CREB activity (TORC) from cytoplasm to nucleus. In basal conditions, transcription is low because TORC remains in the cytoplasm, inactivated by phosphorylation through Ser/Thr protein kinases of the AMP-dependent protein kinases (AMPK) family, including salt-inducible kinase (SIK). To determine which kinase is responsible for TORC phosphorylation in CRH neurons, we measured SIK1 and SIK2 mRNA in the hypothalamic paraventricular nucleus of rats by in situ hybridization.

The distribution of messenger RNAs encoding the three isoforms of the transducer of regulated cAMP responsive element binding protein activity in the rat forebrain.

Increasing evidence indicates that the cAMP responsive element binding protein (CREB)-dependent transcriptional activation of a number of genes requires the CREB co-activator: transducer of regulated CREB activity (TORC). Because of the central importance of CREB in many brain functions, we examined the topographic distribution of TORC1, 2, and 3 mRNAs in specific regions of the rat forebrain. In situ hybridisation analysis revealed that TORC1 is the most abundant isoform in most forebrain structures, followed by TORC2 and TORC3.

A role for the forebrain in mediating time-of-day differences in glucocorticoid counterregulatory responses to hypoglycemia in rats.

The time of day influences the magnitude of ACTH and corticosterone responses to hypoglycemia. However, little is known about the mechanisms that impart these time-of-day differences on neuroendocrine CRH neurons in the hypothalamic paraventricular nucleus (PVH). Rats received 0-3 U/kg insulin (or 0.

Catecholaminergic control of mitogen-activated protein kinase signaling in paraventricular neuroendocrine neurons in vivo and in vitro: a proposed role during glycemic challenges.

Paraventricular hypothalamic (PVH) corticotropin-releasing hormone (CRH) neuroendocrine neurons mount neurosecretory and transcriptional responses to glycemic challenges [intravenous 2-deoxyglucose (2-DG) or insulin]. Although these responses require signals from intact afferents originating from hindbrain CA (catecholaminergic) neurons, the identity of these signals and the mechanisms by which they are transduced by PVH neurons during glycemic challenge remain unclear. Here, we tested whether the prototypical catecholamine, norepinephrine (NE), can reproduce PVH neuroendocrine responses to glycemic challenge.

Rapid and preferential activation of Fos protein in hypocretin/orexin neurons following the reversal of dehydration-anorexia.

Dehydration (DE)-anorexia is stimulated by chronic consumption of hypertonic saline. Spontaneous nocturnal food intake is markedly reduced with this treatment but is rapidly reversed upon the return of drinking water. Here we examined the neurons in the lateral hypothalamic area (LHA) of chronically dehydrated rats for their peptidergic phenotype, colocalization, and activation profiles following the rapid reversal of anorexia.

Hypoglycemic detection at the portal vein is mediated by capsaicin-sensitive primary sensory neurons.

To elucidate the type of spinal afferent involved in hypoglycemic detection at the portal vein, we considered the potential role of capsaicin-sensitive primary sensory neurons. Specifically, we examined the effect of capsaicin-induced ablation of portal vein afferents on the sympathoadrenal response to hypoglycemia. Under anesthesia, the portal vein was isolated in rats and either capsaicin (CAP) or the vehicle (CON) solution applied topically.

Activation in neural networks controlling ingestive behaviors: what does it mean, and how do we map and measure it?

Over the past thirty years many of different methods have been developed that use markers to track or image the activity of the neurons within the central networks that control ingestive behaviors. The ultimate goal of these experiments is to identify the location of neurons that participate in the response to an identified stimulus, and more widely to define the structure and function of the networks that control specific aspects of ingestive behavior. Some of these markers depend upon the rapid accumulation of proteins, while others reflect altered energy metabolism as neurons change their firing rates.

Comparison of melanin-concentrating hormone and hypocretin/orexin mRNA expression patterns in a new parceling scheme of the lateral hypothalamic zone.

A high-resolution spatial distribution analysis of hypothalamic neurons expressing melanin-concentrating hormone or hypocretin/orexin was performed in adult male rats with in situ hybridization cytochemistry. For the analysis, a new parcellation of the lateral zone with some two-dozen regions was used, and distributions were plotted on 15 transverse reference levels through the hypothalamus. Qualitatively the results confirm earlier, much lower resolution mapping studies, although some discrepancies are clarified.

Corticotropin-releasing hormone and arginine vasopressin gene transcription in the hypothalamic paraventricular nucleus of unstressed rats: daily rhythms and their interactions with corticosterone.

To drive the daily ACTH secretory rhythm from anterior pituitary corticotropes signals from the circadian clock schedule CRH and, to lesser extent, arginine vasopressin (AVP) release from neuroendocrine terminals. In turn, releasable pools of CRH and AVP in neuroendocrine terminals are sustained by synthetic mechanisms in the medial parvicellular paraventricular nucleus, a critical component of which involves transcribing primary (heteronuclear (hn)) RNA transcripts from their cognate genes. To determine the fundamental daily patterns of ACTH secretagogue gene transcription in unstressed rats, we measured CRH and AVP hnRNA levels at 1- to 4-h intervals throughout the day using in situ hybridization.

Immunotoxin lesion of hypothalamically projecting norepinephrine and epinephrine neurons differentially affects circadian and stressor-stimulated corticosterone secretion.

Hindbrain norepinephrine (NE) and epinephrine (E) neurons play a pivotal role in the central distribution of sensory signals derived from the internal environment. Their projections influence the various secretory patterns of the hypothalamo-pituitary-adrenal axis and are essential for feeding and adrenal medullary responses to glucoprivation. NE and E terminals in the paraventricular nucleus of the hypothalamus (PVH) and associated hindbrain cell bodies can be virtually eliminated by PVH microinjection of a retrogradely transported conjugate of saporin (SAP, a ribosomal toxin) and a monoclonal antibody against dopamine beta-hydroxylase (dbetah), i.

Interactions between heterotypic stressors and corticosterone reveal integrative mechanisms for controlling corticotropin-releasing hormone gene expression in the rat paraventricular nucleus.

Although the convergence of neural and humoral afferent information onto paraventricular neuroendocrine corticotropin-releasing hormone (CRH) neurons is a major determinant for adaptive stress responses, the underlying integrative mechanisms are poorly understood. To dissect the relative contributions made by neural afferents and corticosterone to these processes, we determined how the concurrent application of two heterotypic physiological stressors, chronic dehydration (produced by drinking hypertonic saline) and sustained hypovolemia (produced by subcutaneous injections of polyethylene glycol), is interpreted by the synthetic and secretory activity of CRH neurons using in situ hybridization and plasma ACTH measurements. These two stressors are encoded by relatively simple, distinct, and well defined sets of neural afferents to CRH neurons.