Sodium Appetite Research Articles

Aldosterone-induced salt appetite requires HSD2 neurons.

Excessive aldosterone production increases the risk of heart disease, stroke, dementia, and death. Aldosterone increases both sodium retention and sodium consumption, and increased sodium consumption may worsen end-organ damage in patients with aldosteronism. Preventing this increase could improve outcomes, but the behavioral mechanisms of aldosterone-induced sodium appetite remain unclear. In rodents, we previously identified aldosterone-sensitive neurons, which express the mineralocorticoid receptor and its pre-receptor regulator, 11-beta-hydroxysteroid dehydrogenase 2 (HSD2). In the present study, we identified HSD2 neurons in the human brain, then used a mouse model to evaluate their role in aldosterone-induced salt intake. First, we confirmed that dietary sodium deprivation increases aldosterone production, salt intake, and HSD2 neuron activity. Next, we showed that continuous chemogenetic stimulation of HSD2 neurons causes a large and specific increase in salt intake. Finally, we use dose-response studies and genetically targeted ablation of HSD2 neurons to show that these neurons are necessary for aldosterone-induced salt intake. Identifying HSD2 neurons in the human brain and establishing their necessity for aldosterone-induced salt intake in mice improves our understanding of appetitive circuits and highlights this small cell population as a therapeutic target for moderating dietary sodium.

Removing interoceptive input from the kidney to the brain reduces salt appetite in DOCA hypertensive rats

Removing interoceptive input from the kidney to the brain reduces salt appetite in DOCA hypertensive rats

Chlorthalidone-Induced Salt Appetite Is Prevented by Afferent Renal Denervation

Chlorthalidone-Induced Salt Appetite Is Prevented by Afferent Renal Denervation

Control of sodium appetite by hindbrain aldosterone-sensitive neurons

Mineralocorticoids play a key role in hydromineral balance by regulating sodium retention and potassium wasting. Through favoring sodium, mineralocorticoids can cause hypertension from fluid overload under conditions of hyperaldosteronism, such as aldosterone-secreting tumors. An often-overlooked mechanism by which aldosterone functions to increase sodium is through stimulation of salt appetite. To drive sodium intake, aldosterone targets neurons in the hindbrain which uniquely express 11β-hydroxysteroid dehydrogenase type 2 (HSD2). This enzyme is a necessary precondition for aldosterone-sensing cells as it metabolizes glucocorticoids – preventing their activation of the mineralocorticoid receptor. In this review, we will consider the role of hindbrain HSD2 neurons in regulating sodium appetite by discussing HSD2 expression in the brain, regulation of hindbrain HSD2 neuron activity, and the circuitry mediating the effects of these aldosterone-sensitive neurons. Reducing the activity of hindbrain HSD2 neurons may be a viable strategy to reduce sodium intake and cardiovascular risk, particularly for conditions of hyperaldosteronism.

Role of Dorsal Raphe Serotonergic Neurons in the Regulation of Sodium Appetite

An animal with sodium deficiency develops sodium appetite which drives it to consume more sodium. A lot of studies have been performed to understand how sodium depletion may lead to the development of sodium appetite, but there are still unanswered questions. In particular, while the relationship between serotonin receptors and sodium appetite has been identified in previous studies, it is still unclear how serotonergic neurons control sodium appetite in response to sodium depletion. In this study, we focused on serotonergic neurons in the dorsal raphe nucleus (DRN) which releases more than 50% of serotonin in the brain. We found that DRN serotonergic neurons are activated in response to sodium depletion. In addition, we found evidence that angiotensin II is a key molecule herein to evoke sodium appetite in sodium depletion. Our results provide refined insight how sodium appetite develops in sodium depletion. This work was supported by grants from Samsung Science & Technology Foundation (SSTF-BA1901-11) to Jong-Woo Sohn. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex differences in the regulation of salt appetite in Spontaneously Hypertensive Rats after loss of interoceptive input from the kidney

The average American consumes 3,400 mg/day of sodium, 1000mg over the American Heart Association’s recommended maximum daily allowance. Excessive salt intake accelerates the progression of many diseases including hypertension, congestive heart failure, and chronic kidney disease. Reducing sodium intake has beneficial effects on a population level and in at risk patients. In previous studies we have shown that afferent renal nerves are involved in the regulation of sodium intake in DOCA hypertensive rats. Like DOCA hypertensive rats, Spontaneously Hypertensive rats (SHR) are a model with increased salt appetite. Here, we tested the hypothesis that afferent renal nerves regulate sodium intake in SHR. Secondarily, it is well documented that estrogens modulate salt intake. To examine the effect of sex on sodium intake we compared salt-appetite between male and female SHR. Bilateral afferent renal denervation (ARDN) was performed using the periaxonal application of 33mM capsaicin. In sham rats the renal arteries were isolated but not treated. Mean arterial blood pressure (MAP) was assessed using radiotelemetry, with the catheter implanted in the femoral artery. Four groups of rats were studied: male SHR-sham (n=9), female SHR-sham (n=3), male SHR+ARDN (n=8) and female SHR+ARDN (n=4). All rats were given ad libitum access to two bottles, one containing dH2O and the other containing 1.8% NaCl. The bottle position was rotated, and fluid intake was recorded daily for 21-days. ARDN caused a significant reduction in 1.8% intake in female but not male SHR rats (p=0.02, female SHR-sham v female SHR-ARDN, p>0.99 male SHR v male SHR-ARDN). This effect was specific for saline intake, water intake was not altered by ARDN in the female SHR (p=0.3). The female SHR drank more saline than male SHR when normalized to body weight (p=0.04 female SHR-sham v male SHR-sham). MAP was not reduced by ARDN in the male SHR (p=0.39), and ongoing studies are examining MAP in response to ARDN in female SHR. The data presented demonstrate for the first time that ARDN decreases salt appetite in female but not male SHR. We also found that baseline saline intake was higher in female SHR than male SHR. In future studies we will examine the renal mechanisms underlying these sex differences. Together, these data suggest that reduced sodium intake may offer an additional therapeutic benefit of renal denervation in female patients with hypertension and cardiovascular disease. LE is funded by R01HL152166; ACV is funded by FAPESP. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Medium-chain triglyceride-specific appetite is regulated by the β-oxidation of medium-chain fatty acids in the liver.

Most studies on fat appetite have focused on long-chain triglycerides (LCTs) due to their obesogenic properties. Medium-chain triglycerides (MCTs), conversely, exhibit antiobesogenic effects; however, the regulation of MCT intake remains elusive. Here, we demonstrate that mice can distinguish between MCTs and LCTs, and the specific appetite for MCTs is governed by hepatic β-oxidation. We generated liver-specific medium-chain acyl-CoA dehydrogenase (MCAD)-deficient (MCADL-/-) mice and analyzed their preference for MCT and LCT solutions using glyceryl trioctanoate (C8-TG), glyceryl tridecanoate (C10-TG), corn oil, and lard oil in two-bottle choice tests conducted over 8 days. In addition, we used lick microstructure analyses to evaluate the palatability and appetite for MCT and LCT solutions. Finally, we measured the expression levels of genes associated with fat ingestion (Galanin, Qrfp, and Nmu) in the hypothalamus 2 h after oral gavage of fat. Compared with control mice, MCADL-/- mice exhibited a significantly reduced preference for MCT solutions, with no alteration in the preference for LCTs. Lick analysis revealed that MCADL-/- mice displayed a significantly decreased appetite for MCT solutions only while the palatability of both MCT and LCT solutions remained unaffected. Hypothalamic Galanin expression in control mice was elevated by oral gavage of C8-TG but not by LCTs, and this response was abrogated in MCADL-/- mice. In summary, our data suggest that hepatic β-oxidation is required for MCT-specific appetite but not for LCT-specific appetite. The induction of hypothalamic galanin upon MCT ingestion, dependent on hepatic β-oxidation, could be involved in the regulation of MCT-specific appetite.NEW & NOTEWORTHY Whether and how medium-chain triglyceride (MCT) intake is regulated remains unknown. Here, we showed that mice can discriminate between MCTs and LCTs. Hepatic β-oxidation participates in MCT-specific appetite, and hypothalamic galanin may be one of the factors that regulate MCT intake. Because of the antiobesity effects of MCTs, studying MCT-specific appetite may help combat obesity by promoting the intake of MCTs instead of LCTs.

Brain sodium sensing for regulation of thirst, salt appetite, and blood pressure.

The brain possesses intricate mechanisms for monitoring sodium (Na) levels in body fluids. During prolonged dehydration, the brain detects variations in body fluids and produces sensations of thirst and aversions to salty tastes. At the core of these processes Nax , the brain's Na sensor, exists. Specialized neural nuclei, namely the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), which lack the blood-brain barrier, play pivotal roles. Within the glia enveloping the neurons in these regions, Nax collaborates with Na+ /K+ -ATPase and glycolytic enzymes to drive glycolysis in response to elevated Na levels. Lactate released from these glia cells activates nearby inhibitory neurons. The SFO hosts distinct types of angiotensin II-sensitive neurons encoding thirst and salt appetite, respectively. During dehydration, Nax -activated inhibitory neurons suppress salt-appetite neuron's activity, whereas salt deficiency reduces thirst neuron's activity through cholecystokinin. Prolonged dehydration increases the Na sensitivity of Nax via increased endothelin expression in the SFO. So far, patients with essential hypernatremia have been reported to lose thirst and antidiuretic hormone release due to Nax -targeting autoantibodies. Inflammation in the SFO underlies the symptoms. Furthermore, Nax activation in the OVLT, driven by Na retention, stimulates the sympathetic nervous system via acid-sensing ion channels, contributing to a blood pressure elevation.

Two parabrachial Cck neurons involved in the feedback control of thirst or salt appetite

Thirst and salt appetite are temporarily suppressed after water and salt ingestion, respectively, before absorption; however, the underlying neural mechanisms remain unclear. The parabrachial nucleus (PBN) is the relay center of ingestion signals from the digestive organs. We herein identify two distinct neuronal populations expressing cholecystokinin (Cck) mRNA in the lateral PBN that are activated in response to water and salt intake, respectively. The two Cck neurons in the dorsal-lateral compartment of the PBN project to the median preoptic nucleus and ventral part of the bed nucleus of the stria terminalis, respectively. The optogenetic stimulation of respective Cck neurons suppresses thirst or salt appetite under water- or salt-depleted conditions. The combination of optogenetics and invivo Ca2+ imaging during ingestion reveals that both Cck neurons control GABAergic neurons in their target nuclei. These findings provide the feedback mechanisms for the suppression of thirst and salt appetite after ingestion.

Accumbal μ-opioid receptors and salt taste-elicited hedonic responses in a rodent model of prenatal adversity, and their correlates using human functional genomics

Prenatal adversity is associated with behavioral obesogenic features such as preference for palatable foods. Salt appetite may play a role in the development of adiposity and its consequences in individuals exposed to prenatal adversity, and sodium consumption involves individual differences in accumbal µ-opioid receptors function. We investigated the hedonic responses to salt and the levels of µ-opioid receptors and tyrosine hydroxylase in the nucleus accumbens (Nacc) of pups from an animal model of prenatal dietary restriction. In children, we evaluated the interaction between fetal growth and the genetic background associated with the accumbal µ-opioid receptor gene (OPRM1) expression on sodium consumption during a snack test. Sprague-Dawley dams were randomly allocated from pregnancy day 10 to receive an ad libitum (Adlib) or a 50% restricted (FR) diet. The pups’ hedonic responses to a salt solution (NaCl 2%) or water were evaluated on the first day of life. FR and Adlib pups differ in their hedonic responses to salt, and there were decreased levels of accumbal µ-opioid and p-µ-opioid receptors in FR pups. In humans, a test meal and genotyping from buccal epithelial cells were performed in 270 children (38 intrauterine growth restricted—IUGR) at 4 years old from a Canadian prospective cohort (MAVAN). The OPRM1 genetic score predicted the sodium intake in IUGR children, but not in controls. The identification of mechanisms involved in the brain response to prenatal adversity and its consequences in behavioral phenotypes and risk for chronic diseases later in life is important for preventive and therapeutic purposes.

11β-Hydroxysteroid dehydrogenase and the brain: Not (yet) lost in translation.

11-beta-hydroxysteroid dehydrogenases (11β-HSDs) catalyse the conversion of active 11-hydroxy glucocorticoids (cortisol, corticosterone) and their inert 11-keto forms (cortisone, 11-dehydrocorticosterone). They were first reported in the body and brain 70 years ago, but only recently have they become of interest. 11β-HSD2 is a dehydrogenase, potently inactivating glucocorticoids. In the kidney, 11β-HSD2 generates the aldosterone-specificity of intrinsically non-selective mineralocorticoid receptors. 11β-HSD2 also protects the developing foetal brain and body from premature glucocorticoid exposure, which otherwise engenders the programming of neuropsychiatric and cardio-metabolic disease risks. In the adult CNS, 11β-HSD2 is confined to a part of the brain stem where it generates aldosterone-specific central control of salt appetite and perhaps blood pressure. 11β-HSD1 is a reductase, amplifying active glucocorticoid levels within brain cells, notably in the cortex, hippocampus and amygdala, paralleling its metabolic functions in peripheral tissues. 11β-HSD1 is elevated in the ageing rodent and, less certainly, human forebrain. Transgenic models show this rise contributes to age-related cognitive decline, at least in mice. 11β-HSD1 inhibition robustly improves memory in healthy and pathological ageing rodent models and is showing initial promising results in phase II studies of healthy elderly people. Larger trials are needed to confirm and clarify the magnitude of effect and define target populations. The next decade will be crucial in determining how this tale ends - in new treatments or disappointment.

Serotonergic regulation of appetite and sodium appetite.

Serotonin is a neurotransmitter that is synthesized and released from the brainstem raphe nuclei to affect many brain functions. It is well known that the activity of raphe serotonergic neurons is changed in response to the changes in feeding status to regulate appetite via the serotonin receptors. Likewise, changes in volume status are known to alter the activity of raphe serotonergic neurons and drugs targeting serotonin receptors were shown to affect sodium appetite. Therefore, the central serotonin system appears to regulate ingestion of both food and salt, although neural mechanisms that induce appetite in response to hunger and sodium appetite in response to volume depletion are largely distinct from each other. In this review, we discuss our current knowledge regarding the regulation of ingestion - appetite and sodium appetite - by the central serotonin system.

The psychological basis of hunger and its dysfunctions.

This article describes a new and emerging psychological perspective on hunger, together with the implications of that perspective, which is based upon learning and memory. Hunger is a psychological state characterized by a desire to eat. Historically, conceptions of hunger have largely been expressed in terms of physiology (eg, biological process X causes hunger). However, physiology neither offers a psychological account of hunger nor explains why memory impairment can eliminate hunger. Two forms of hunger are identified - specific and general. Specific hunger is for particular palatable foods. It involves recollecting episodic memories of eating that food, when an associated cue is encountered (eg, an advert). General hunger is a desire to eat triggered by temporal (eg, it is lunchtime) or interoceptive (eg, tummy rumble) cues. It involves semantic memory retrieval, which then augments the expected - remembered - pleasure for any food. Both hungers are supported by the medial temporal lobe memory system. Damage to this system can occur from eating a Western-style diet and, longer-term, from obesity and its consequences. Medial temporal lobe memory damage may cause deficits in specific hunger, but most especially in general hunger, resulting in little motivation to eat foods that the individual considers to be of low-to-moderate palatability, such as fruit and vegetables. The implications of this account for teaching people hunger, for how hunger is affected by diet, for public education, and pharmaceutical intervention, are discussed. Psychological concepts of hunger are widely used in nutritional practice. This article provides a new and emerging perspective on the psychological basis of hunger and its implications.

Sodium appetite and thirst do not require angiotensinogen production in astrocytes or hepatocytes.

In addition to its renal and cardiovascular functions, angiotensin signaling is thought to be responsible for the increases in salt and water intake caused by hypovolemia. However, it remains unclear whether these behaviors require angiotensin production in the brain or liver. Here, we use in situ hybridization to identify tissue-specific expression of the genes required for producing angiotensin peptides, then use conditional genetic deletion of angiotensinogen (Agt) to test whether production in the brain or liver is necessary for sodium appetite and thirst. In the mouse brain, we identified expression of Agt (the precursor of all angiotensin peptides) in a large subset of astrocytes. We also identified Ren1 and Ace (enzymes required to produce angiotensin II) in the choroid plexus, and Ren1 in neurons within the nucleus ambiguus compact formation. In the liver, we confirmed that Agt is expressed in widespread hepatocytes. We next tested whether thirst and sodium appetite require angiotensinogen production in astrocytes or hepatocytes. Despite virtually eliminating expression in the brain, deleting astrocytic Agt did not reduce thirst or sodium appetite. Despite markedly reducing angiotensinogen in the blood, eliminating Agt from hepatocytes did not reduce thirst or sodium appetite, and in fact, these mice consumed the largest amounts of salt and water after sodium deprivation. Deleting Agt from both astrocytes and hepatocytes also did not prevent thirst or sodium appetite. Our findings suggest that angiotensin signaling is not required for sodium appetite or thirst and highlight the need to identify alternative signaling mechanisms. KEY POINTS: Angiotensin signaling is thought to be responsible for the increased thirst and sodium appetite caused by hypovolemia, producing elevated water and sodium intake. Specific cells in separate brain regions express the three genes needed to produce angiotensin peptides, but brain-specific deletion of the angiotensinogen gene (Agt), which encodes the lone precursor for all angiotensin peptides, did not reduce thirst or sodium appetite. Double-deletion of Agt from brain and liver also did not reduce thirst or sodium appetite. Liver-specific deletion of Agt reduced circulating angiotensinogen levels without reducing thirst or sodium appetite. Instead, these angiotensin-deficient mice exhibited an enhanced sodium appetite. Because the physiologic mechanisms controlling thirst and sodium appetite continued functioning without angiotensin production in the brain and liver, understanding these mechanisms requires a renewed search for the hypovolemic signals necessary for activating each behavior. Abstract figure legend Angiotensinogen is the precursor for angiotensin II, which is considered important for thirst and sodium appetite. In the brain, astrocytes express the angiotensinogen gene (Agt), but using GFAP-Cre to delete this gene from astrocytes did not reduce thirst or sodium appetite. In the liver, hepatocytes express this gene and produce circulating angiotensinogen. Using Alb-Cre to delete Agt from hepatocytes also did not reduce (and in fact enhanced) salt and water consumption. This article is protected by copyright. All rights reserved.

Inhibition of salty taste and sodium appetite by estrogens in spontaneously hypertensive rats.

Estrogen has a well-known effect of reducing salt intake in rats. This mini review focuses on recent findings regarding the interaction of estradiol with brain angiotensin II to control increased sodium palatability that occurs as a result of sodium appetite in spontaneously hypertensive rats.

The Hunger for Salt: A Tribute to Derek Denton and Jay Schulkin with an Updated Collection of Papers on Salt Appetite.

This collection of outstanding papers is a trove for all concerned with salt intake [...].

Thirst: neuroendocrine regulation in mammals.

Animals can sense their changing internal needs and then generate specific physiological and behavioural responses in order to restore homeostasis. Water-saline homeostasis derives from balances of water and sodium intake and output (drinking and diuresis, salt appetite and natriuresis), maintaining an appropriate composition and volume of extracellular fluid. Thirst is the sensation which drives to seek and consume water, regulated in the central nervous system by both neural and chemical signals. Water and electrolyte homeostasis depends on finely tuned physiological mechanisms, mainly susceptible to plasma Na+ concentration and osmotic pressure, but also to blood volume and arterial pressure. Increases of osmotic pressure as slight as 1-2% are enough to induce thirst ("homeostatic" or cellular), by activation of specialized osmoreceptors in the circumventricular organs, outside the blood-brain barrier. Presystemic anticipatory signals (by oropharyngeal or gastrointestinal receptors) inhibit thirst when fluids are ingested, or stimulate thirst associated with food intake. Hypovolemia, arterial hypotension, Angiotensin II stimulate thirst ("hypovolemic thirst", "extracellular dehydration"). Hypervolemia, hypertension, Atrial Natriuretic Peptide inhibit thirst. Circadian rhythms of thirst are also detectable, driven by suprachiasmatic nucleus in the hypothalamus. Such homeostasis and other fundamental physiological functions (cardiocircolatory, thermoregulation, food intake) are highly interdependent.

Homeostatic Reinforcement Theory Accounts for Sodium Appetitive State- and Taste-Dependent Dopamine Responding

Seeking and consuming nutrients is essential to survival and the maintenance of life. Dynamic and volatile environments require that animals learn complex behavioral strategies to obtain the necessary nutritive substances. While this has been classically viewed in terms of homeostatic regulation, recent theoretical work proposed that such strategies result from reinforcement learning processes. This theory proposed that phasic dopamine (DA) signals play a key role in signaling potentially need-fulfilling outcomes. To examine links between homeostatic and reinforcement learning processes, we focus on sodium appetite as sodium depletion triggers state- and taste-dependent changes in behavior and DA signaling evoked by sodium-related stimuli. We find that both the behavior and the dynamics of DA signaling underlying sodium appetite can be accounted for by a homeostatically regulated reinforcement learning framework (HRRL). We first optimized HRRL-based agents to sodium-seeking behavior measured in rodents. Agents successfully reproduced the state and the taste dependence of behavioral responding for sodium as well as for lithium and potassium salts. We then showed that these same agents account for the regulation of DA signals evoked by sodium tastants in a taste- and state-dependent manner. Our models quantitatively describe how DA signals evoked by sodium decrease with satiety and increase with deprivation. Lastly, our HRRL agents assigned equal preference for sodium versus the lithium containing salts, accounting for similar behavioral and neurophysiological observations in rodents. We propose that animals use orosensory signals as predictors of the internal impact of the consumed good and our results pose clear targets for future experiments. In sum, this work suggests that appetite-driven behavior may be driven by reinforcement learning mechanisms that are dynamically tuned by homeostatic need.

A gut-brain axis mediates sodium appetite via gastrointestinal peptide regulation on a medulla-hypothalamic circuit.

Salt homeostasis is orchestrated by both neural circuits and peripheral endocrine factors. The colon is one of the primary sites for electrolyte absorption, while its potential role in modulating sodium intake remains unclear. Here, we revealed that a gastrointestinal hormone, secretin, is released from colon endocrine cells under body sodium deficiency and is indispensable for inducing salt appetite. As the neural substrate, circulating secretin activates specific receptors in the nucleus of the solitary tracts, which further activates the downstream paraventricular nucleus of the hypothalamus, resulting in enhanced sodium intake. These results demonstrated a previously unrecognized gut-brain pathway for the timely regulation of sodium homeostasis.

Neurobehavioral Mechanisms of Sodium Appetite.

The objectives of this paper are to first present physiological and ecological aspects of the unique motivational state of sodium appetite, then to focus on systemic physiology and brain mechanisms. I describe how laboratory protocols have been developed to allow the study of sodium appetite under controlled conditions, and focus on two such conditions specifically. The first of these is the presentation a sodium-deficient diet (SDD) for at least one week, and the second is accelerated sodium loss using SDD for 1-2 days coupled with the diuretic furosemide. The modality of consumption is also considered, ranging from a free intake of high concentration of sodium solution, to sodium-rich food or gels, and to operant protocols. I describe the pivotal role of angiotensin and aldosterone in these appetites and discuss whether the intakes or appetite are matched to the physiological need state. Several brain systems have been identified, most recently and microscopically using molecular biological methods. These include clusters in both the hindbrain and the forebrain. Satiation of sodium appetite is often studied using concentrated sodium solutions, but these can be consumed in apparent excess, and I suggest that future studies of satiation might emulate natural conditions in which excess consumption does not occur, using either SDD only as a stimulus, offering a sodium-rich food for the assessment of appetite, or a simple operant task.