Harvey J. Grill

The neuroanatomical axis for control of energy balance.

The hypothalamic feeding-center model, articulated in the 1950s, held that the hypothalamus contains the interoceptors sensitive to blood-borne correlates of available or stored fuels as well as the integrative substrates that process metabolic and visceral afferent signals and issue commands to brainstem mechanisms for the production of ingestive behavior. A number of findings reviewed here, however, indicate that sensory and integrative functions are distributed across a central control axis that includes critical substrates in the basal forebrain as well as in the caudal brainstem. First, the interoceptors relevant to energy balance are distributed more widely than had been previously thought, with a prominent brainstem complement of leptin and insulin receptors, glucose-sensing mechanisms, and neuropeptide mediators. The physiological relevance of this multiple representation is suggested by the demonstration that similar behavioral effects can be obtained independently by stimulation of respective forebrain and brainstem subpopulations of the same receptor types (e.g., leptin, CRH, and melanocortin). The classical hypothalamic model is also challenged by the integrative achievements of the chronically maintained, supracollicular decerebrate rat. Decerebrate and neurologically intact rats show similar discriminative responses to taste stimuli and are similarly sensitive to intake-inhibitory feedback from the gut. Thus, the caudal brainstem, in neural isolation from forebrain influence, is sufficient to mediate ingestive responses to a range of visceral afferent signals. The decerebrate rat, however, does not show a hyperphagic response to food deprivation, suggesting that interactions between forebrain and brainstem are necessary for the behavioral response to systemic/ metabolic correlates of deprivation in the neurologically intact rat. At the same time, however, there is evidence suggesting that hypothalamic-neuroendocrine responses to fasting depend on pathways ascending from brainstem. Results reviewed are consistent with a distributionist (as opposed to hierarchical) model for the control of energy balance that emphasizes: (i) control mechanisms endemic to hypothalamus and brainstem that drive their unique effector systems on the basis of local interoceptive, and in the brainstem case, visceral, afferent inputs and (ii) a set of uni- and bidirectional interactions that coordinate adaptive neuroendocrine, autonomic, and behavioral responses to changes in metabolic status.

Quality of acquired responses to tastes by Rattus norvegicus depends on type of associated discomfort.

Rats were trained to avoid a sugar solution through pairing with LiCl toxicosis (upper gastrointestinal tract discomfort), shock (peripheral pain), or high levels of lactose (lower gastrointestinal tract discomfort). Among animals matched for strength of avoidance of the sugar solution, only the LiCl group showed orofacial responses (e.g., gaping) indicative of distaste; the other groups continued to show positive orofacial responses to the sugar solution. These results, in conjunction with recent results on humans, are interpreted to represent a distinction between food rejection based primarily on unpalatability (distaste) and food rejection based primarily on anticipated negative consequences of ingestion (danger). The results also support the hypothesis that upper gastrointestinal distress (most probably nausea) plays a special role in negative palatability shifts (acquired distastes). These results have implications for the understanding of predispositions in learning and suggest important differences in the quality (readout) of different types of associations. Prior research, by relying on intake measures alone, was insensitive to the differences revealed here by monitoring a wider range of responses.

Gustatory cortex in the rat. I. Physiological properties and cytoarchitecture

The precise cytoarchitectural localization of taste-elicited cortical responses in the rat was studied using a combination of anatomical and physiological techniques. Multi-unit responses to tongue tactile, thermal and gustatory stimuli were recorded along 97 electrode penetrations positioned parallel to the lateral convexity of the brain and marking lesions were placed at the sites of transitions in these functional properties. Lesions made at sites that received different sensory inputs were consistently located within different cytoarchitectural subdivisions. In this manner, taste cortex in the rat was localized to the agranular insular cytoarchitectural region, in contrast to its traditional assignation to granular insular cortex. Instead, tongue temperature was found to be represented in the cortical area previously termed gustatory, i.e., in ventral granular cortex where layer IV attenuates.

Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance.

This Review highlights the processing and integration performed by hindbrain nuclei, focusing on the inputs received by nucleus tractus solitarius (NTS) neurons. These inputs include vagally mediated gastrointestinal satiation signals, blood-borne energy-related hormonal and nutrient signals, and descending neural signals from the forebrain. We propose that NTS (and hindbrain neurons, more broadly) integrate these multiple energy status signals and issue-output commands controlling the behavioral, autonomic, and endocrine responses that collectively govern energy balance. These hindbrain-mediated controls are neuroanatomically distributed; they involve endemic hindbrain neurons and circuits, hindbrain projections to peripheral circuits, and projections to and from midbrain and forebrain nuclei.

Peripheral and Central GLP-1 Receptor Populations Mediate the Anorectic Effects of Peripherally Administered GLP-1 Receptor Agonists, Liraglutide and Exendin-4

UNLABELLED The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists, exendin-4 and liraglutide, suppress food intake and body weight. The mediating site(s) of action for the anorectic effects produced by peripheral administration of these GLP-1R agonists are not known. Experiments addressed whether food intake suppression after i.p. delivery of exendin-4 and liraglutide is mediated exclusively by peripheral GLP-1R or also involves direct central nervous system (CNS) GLP-1R activation. Results showed that CNS delivery [third intracerebroventricular (3(rd) ICV)] of the GLP-1R antagonist exendin-(9-39) (100 μg), attenuated the intake suppression by i.p. liraglutide (10 μg) and exendin-4 (3 μg), particularly at 6 h and 24 h. Control experiments show that these findings appear to be based neither on the GLP-1R antagonist acting as a nonspecific competing orexigenic signal nor on blockade of peripheral GLP-1R via efflux of exendin-(9-39) to the periphery. To assess the contribution of GLP-1R expressed on subdiaphragmatic vagal afferents to the anorectic effects of liraglutide and exendin-4, food intake was compared in rats with complete subdiaphragmatic vagal deafferentation and surgical controls after i.p. delivery of the agonists. Both liraglutide and exendin-4 suppressed food intake at 3 h, 6 h, and 24 h for controls; for subdiaphragmatic vagal deafferentation rats higher doses of the GLP-1R agonists were needed for significant food intake suppression, which was observed at 6 h and 24 h after liraglutide and at 24 h after exendin-4. CONCLUSION Food intake suppression after peripheral administration of exendin-4 and liraglutide is mediated by activation of GLP-1R expressed on vagal afferents as well as direct CNS GLP-1R activation.

Sodium depletion enhances salt palatability in rats.

Sterotyped fixed action patterns (FAPs) are elicited in rats by oral infusions of taste solutions. These taste-elicited FAPs can be classified as either ingestive or aversive. They reflect the palatability of the taste and can be modified by learning and by the physiological state of the animal. These studies demonstrated that when the physiological state of the rat is altered by sodium depletion, the pattern of FAPs elicited by oral infusions of 0.5 M NaCl shifts from a mixture of ingestive and aversive components (while sodium replete) to exclusively ingestive ones (while sodium deplete). This shift in taste reactivity occurred the first time the rats were made sodium deplete. A similar shift was not observed to accompany infusions of 0.01 M HCl, a taste solution that also elicited mixed ingestive and aversive FAPs. This result suggests that the shift in response to NaCl is not due to a general change in ingestive bias or to a general taste deficit. On the basis of the change in FAPs, it is concluded that the palatability of highly concentrated salt solutions increases in sodium-deplete rats. Such a shift in salt palatability may be instrumental in directing the appetitive behavior of the animal.

Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation.

Medial nucleus tractus solitarius (mNTS) neurons express leptin receptors (LepRs), and intra-mNTS delivery of leptin reduces food intake and body weight. Here, the contribution of endogenous LepR signaling in mNTS neurons to energy balance control was examined. Knockdown of LepR in mNTS and area postrema (AP) neurons of rats (LepRKD) via adeno-associated virus short hairpin RNA-interference (AAV-shRNAi) resulted in significant hyperphagia for chow, high-fat, and sucrose diets, yielding increased body weight and adiposity. The chronic hyperphagia of mNTS/AP LepRKD rats is likely mediated by a reduction in leptin potentiation of gastrointestinal satiation signaling, as LepRKD rats showed decreased sensitivity to the intake-reducing effects of cholecystokinin. LepRKD rats showed increased basal AMP-kinase activity in mNTS/AP micropunches, and pharmacological data suggest that this increase provides a likely mechanism for their chronic hyperphagia. Overall these findings demonstrate that LepRs in mNTS and AP neurons are required for normal energy balance control.

Distributed Neural Control of Energy Balance: Contributions from Hindbrain and Hypothalamus

Data are reviewed that support the hypothesis that the neural control of energy expenditure is distributed among several brain sites. This view contrasts with that expressed most commonly in literature, that a single site—the arcuate hypothalamic nucleus—receives and integrates signals of relevance to energy status assessment and engages the effector circuits that orchestrate responses that maintain energy balance. The data reviewed support a contribution from medullary neurons, including those of the nucleus of the solitary tract, in the integration of signals of relevance to energy balance and in the issuing of commands to local behavioral and autonomic effectors. Experimental evidence is discussed that supports the following specific conclusions: hindbrain neurons integrate oral and gastrointestinal signals and issue commands to local motor circuits that control meal size; leptins effect on food intake may be mediated, in part, by a direct action on the hindbrain neurons that respond to gastric distention; deprivation signals, such as the fall in leptin level, affect gene expression outside of the hypothalamus with reductions in proglucagon and proopiomelanocortin message seen in nucleus of the solitary tract‐rich tissue; and that hindbrain neurons contribute to the control of energy expenditure seen with food deprivation and increases in expenditure after cold exposure or starvation. Future work is needed to define how the nucleus of the solitary tract and arcuate nodes of the central energy balance control network interact to collectively, or separately, influence specific aspects of energy balance control in the intact brain.

Endogenous hindbrain glucagon-like peptide-1 receptor activation contributes to the control of food intake by mediating gastric satiation signaling.

Exogenous activation of central nervous system glucagon-like peptide-1 (GLP-1) receptors (GLP-1Rs) reduces food intake. Experiments addressed whether endogenous central GLP-1R activity is involved in the control of normal feeding and examined which gastrointestinal satiation signals contribute to this control. Given that nucleus tractus solitarius (NTS) neurons are the source of central GLP-1, that caudal brainstem circuits mediate the intake suppression triggered by exogenous hindbrain GLP-1R activation, and that these neurons process gastrointestinal vagal signals, the role of endogenous hindbrain GLP-1R activation to intake control was the focus of the analysis. Food intake increased with GLP-1R antagonist [Exendin-(9-39) (Ex-9)] [10 microg, fourth intracerebroventricular (icv)] delivery to overnight food-deprived rats after ingestion of 9 ml Ensure diet. Direct medial NTS injection of a ventricle subthreshold dose (1.0 microg) of Ex-9 increased food intake and established the contribution of this GLP-1R population to the effect observed with ventricular administration. To determine whether satiation signals of gastric vs. intestinal origin drive the GLP-1R-mediated NTS effect on food intake, two experiments were performed in overnight-fasted rats. In one, Ensure was infused intraduodenally (0.4 ml/min for 20 min); in another, the stomach was distended (9 ml SILASTIC brand balloon) for 15 min before fourth icv Ex-9. The intake suppression by duodenal nutrient infusion was not affected by GLP-1R blockade, but the feeding suppression after gastric distension was significantly attenuated by fourth icv Ex-9. We conclude that endogenous NTS GLP-1R activation driven by gastric satiation signals contributes to the control of normal feeding.

Central Gustatory Lesions: II. Effects on Sodium Appetite, Taste Aversion Learning, and Feeding Behaviors

Intake and taste reactivity tests were used to determine the effects of bilateral lesions of the gustatory portions of the nucleus of the solitary tract (NST), the parabrachial nucleus (PBN), and the ventral posteromedial nucleus of the thalamus (VPMpc) on several complex ingestive behaviors. In the 1st experiment, lesions of the PBN and the NST blocked, and VPMpc lesions impaired, the behavioral expression of salt appetite. In the 2nd experiment, alanine was paired with injections of LiCl. Control rats as well as rats with NST and VPMpc lesions acquired the taste aversion, but rats with PBN lesions did not. In the 3rd experiment, all animals increased their food intake after injections of 2 U/kg insulin and 250 mg/kg 2-deoxy-D-glucose, and their food intake was suppressed after nutritive stomach loads.