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The lateral hypothalamus: A site for integration of nutrient and fluid balance
Behavioural Brain Research 221 (2011) 481–487
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Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr
Review
The lateral hypothalamus: A site for integration of nutrient and fluid balance Gertjan van Dijk a,c,∗ , Simon S. Evers a , Stefano Guidotti a,c , Simon N. Thornton d , Anton J.W. Scheurink a , Csaba Nyakas b,e a
Center for Behavior and Neurosciences, Unit of Neuroendocrinology, University of Groningen, The Netherlands Center for Behavior and Neurosciences, Unit of Molecular Neurobiology, University of Groningen, The Netherlands c Center for Isotope Research, University of Groningen, The Netherlands d INSERM, U961, Vandoeuvre les Nancy, and Université Henri Poincaré, Nancy, France e Unit of Nutrition and Physical Activity, Semmelweis University, Budapest, Hungary b
a r t i c l e
i n f o
Article history: Received 23 February 2010 Received in revised form 20 January 2011 Accepted 27 January 2011 Available online 12 February 2011 Keywords: Body water Drinking Feeding Osmotic stress Obesity Insulin
a b s t r a c t This paper reviews seemingly obligatory relations between nutrient and fluid balance. A relatively novel neuronal pathway involving interplay between acetylcholine and the melanocortins, ␣MSH and AGRP in the arcuate nucleus (Arc) of the hypothalamus projecting to the lateral hypothalamus (LH) may bridge this gap. In the fasted condition, increased expression of MCH (due to muscarinic-3 receptor stimulation and low melanocortin tone) and neuronal release of MCH (via Orexin signaling) underlies a drive towards positive energy balance, increased B cell capacity to secrete insulin, and this is associated with optimal fluid homeostasis. A hypohydrated state is hypothesized to yield downregulation of leptin signaling (potentially via inhibitory effects of osmotic stress on mTOR), but osmotic stress may prevent MCH expression via the OVLT-SFO complex. If this occurs in an obese state, impaired pancreatic B cell capacity and peripheral insulin insensitivity as a result of hypohydration may underlie cardio-metabolic diseases. © 2011 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acetylcholine in arcuate nucleus neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The lateral hypothalamus from a historical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Integrating nutrient and fluid balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and future perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Higher animals are generally capable of keeping their internal milieu relatively stable in the face of constant and rapid changes that can occur within or between environments. Claude Bernard was one of the first to realize this propensity and stated that “. . .evolutionary processes have shaped mechanisms allowing us to make our own seawater, in which we can bath our cells, provide them with oxygen and nutrients, and remove waste products. . .”
∗ Corresponding author at: Center for Behavior and Neurosciences, Unit of Neuroendocrinology, University of Groningen, The Netherlands. Tel.: +31 50 3632116, fax: +31 50 3632331. E-mail address: [email protected] (G. van Dijk). 0166-4328/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2011.01.047
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[10]. In order to perform these actions, animals have been equipped with respiratory, circulatory, excretory, and digestive systems, and they can display behaviors to track and ingest foods and fluids. In addition, most animals are capable of storing ingested nutrients in the form of glycogen and adipose tissue, which subsequently can deliver fuels to cells for prolonged periods when food is not available. A different picture emerges with respect to body fluids. Apart from a number of specialized animal species well-adapted to dessert conditions (allowing them to rely on metabolic water), most species have a rather poor capacity to maintain fluid balance without drinking frequently [56]. Although the bodies of higher animals consist of approximately 65% water or more, even the smallest reduction in body water content can have devastating consequences. For example, acute dehydration can cause hypovolemia at the systemic level, which, if not effectively met by fluid and sodium
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Fig. 1. ChAT immunopositive neurons in the hypothalamus Panel B: dorsomedial hypothalamus; Panel C: arcuate nucleus; Panel D: lateral hypothalamus (MCH area). (Note that in the arcuate nucleus especially a wide range of intensity of ChAT staining can be observed between the cholinergic neurons). Immunostaining procedure was applied to visualize choline acetyltransferase (ChAT) positive cholinergic neurons in the hypothalamus. Goat anti ChAT primary antibody (AB144P, Lot: LV1359401; Chemicon International, Temecula, CA, USA) was used in dilution 1:500. Biotinylated rabbit anti goat antibody and Vectastain ACB kit was obtained from Vector Laboratories (CA, USA). The staining was completed with nickel-enhanced diaminobenzidine (DAB) reaction in the presence of H2 O2 (for reference see [58]).
intake and retention in the kidney will compromise cardiovascular circulatory functioning [43,86]. Second, more chronic dehydration can cause cellular dysregulation and can disrupt several aspects of energy balance regulation including intake, growth and production [7,15,16,93,94]. This latter point indicates that obligatory relations may exist between nutrient and fluid balance. The current paper addresses central neural components underlying this relation. Furthermore, it emphasizes a relatively novel hypothalamic neuronal pathway involving interplay between acetylcholine (ACh) and neuropeptides potentially bridging the gap between nutrient and fluid balance. 2. Acetylcholine in arcuate nucleus neurons Cholinergic neuronal cell bodies in the brain are detected generally with immunohistochemistry by the presence of (i) choline acetyl-transferase (ChAT), which catalyses the binding of choline and acetylCoA, (ii) the vesicular ACh transporter (VAChT) necessary for synaptic release of Ach, and (iii) acetylcholine-esterase (AChE), which catalyses the breakdown of ACh. Besides being released as a transmitter from interneurons, for example in the cortex and striatum, ACh is also a transmitter in diffuse modulatory networks, in which relatively small neuronal cell groups have numerous projections and connections throughout major parts of the brain. These include the basal forebrain complex, with cholinergic neurons scattered among several related nuclei including the nucleus basalis of Meynert and the medial septal nuclei, both with widespread projections [35]. Another one, identified as the pontomesencephalo–tegmental complex in the pons and midbrain tegmentum, which together with other classical neurotransmitter systems including noradrenalin and serotonin, regulate the excitability of sensory relay nuclei [39,40]. Besides these wellknown cell groups, others can be found scattered throughout the
nervous system. Our own immunhistochemical results revealed for example ChAT-positive neuronal labeling within the dorsomedial and lateral hypothalamus, and a relatively strong labeling was observed in the arcuate nucleus (Arc) of the hypothalamus (see Fig. 1). Our observations are consistent with the work of Meister and coworkers who found extensive VAChT and ChAT labeling of neuronal cell bodies in the Arc too, but more lateral than we observed in Fig. 1 [52]. This variation might suggest that more than one peptidergic Arc neuron type may colocalize ChAT although in different concentrations. The Arc nucleus is of interest because neurons here have direct projections to neuroendocrine/ANS outflow and behavioral relay centers in the hypothalamus, as well as to hindbrain regions filtering incoming information from peripheral organs [13]. Moreover, the Arc is regarded as a key area in energy balance regulation, because (i) it contains neuronal cell bodies which express neuropeptides known to have important roles in regulation of ingestive behavior and energy fluxes in the body [72], and (ii) the expression of these neuropeptides and the neuronal activity of these cell bodies can be influenced by leptin through receptor-mediated signaling transduction cascades [59]. Leptin, through this pathway, has been suggested to regulate homeostatically the amount of body fat [97] and/or to fine-tune activity of several neuroendocrine axes to the nutritional/metabolic status [4]. Besides leptin, a host of other blood-borne signals affects signaling cascades in Arc neurons; these include fuels, and several gut/pancreas-derived peptides such as insulin, glucagon-like peptide-1 amide, peptide YY, and ghrelin [42]. Meister and co-workers also observed that ChAT and VAChT labeling co-expressed with mRNA encoding pro-opiomelanocortin (POMC). POMC is a relatively large peptide spliced posttranslationally into a number of smaller ones including adrenocorticotrophic hormone (ACTH), ␣-melanocyte stimulating hormone
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(␣-MSH), and beta-endorphin [45]. Expression of POMC is reduced during starvation, and this can be prevented by leptin infusion [72,90]. Mutation in the POMC gene, preventing its post-translation processing into smaller neuropeptide fragments, causes obesity [36], and the resultant lack of ␣-MSH synthesis seems most relevant in light of leptin’s influence on energy balance. ␣-MSH acts as an agonist on melanocortin-4 (MC4) receptors, and targeted deletion in mice or spontaneous genetic deletion in humans of this receptor leads to leptin resistance and obesity [25]. Other targets of leptin in the Arc nucleus are neurons that co-express neuropeptide Y (NPY) and agouti-related protein (AgRP). The latter acts as an inverse agonist on MC4 receptors (i.e., thus reducing the activity of MC4 receptors, instead of merely blocking the action of ␣-MSH) [57]. As opposed to POMC/ACh neurons that are activated by leptin, neurons that co-express NPY and AgRP are inhibited by leptin [8]. Thus, leptin has a dual action, increasing stimulatory influences towards the MC4 receptor, and at the same time attenuating inhibitory influences towards the MC4 receptor [3]. Second-order neurons expressing MC4 receptors are found, for example, in the paraventricular nucleus (PVN), which can produce thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH), and in the lateral hypothalamus (LH), which can produce melanin-concentrating hormone (MCH) and orexin [23]. Consistent with the idea that the MC4 receptor is down-stream from leptin actions is our previous finding that long-term pharmacological inhibition of hypothalamic MC4 receptor signaling in rats by third-intracerebroventricular (3icv) minipump infusion of the MC3/4 receptor blocker SHU9119 induced hyperphagia and obesity in rats [2]. This effect was found to occur despite increases in mRNA encoding CRH and POMC, and a reduction of mRNA encoding NPY, which are essentially responses aimed at preventing weight gain. The exception, however, was an increased expression in mRNA encoding MCH in the LH of the obese rats treated by 3icv-SHU9119, relative to animals that stayed lean due to 3icv saline treatment (in preparation). This increase in MCH expression is highly relevant in light of the fact that overexpression of MCH in mice induces obesity and hyperphagia [47], and MCH-1 receptor KO mice have the opposite phenotype [37]. Thus, these data indicate that increased activity of MCH neurons in the LH is a key step in the obesogenic effects caused by low melanocortin receptor activity. This story, however, is more complicated as other layers of regulation can be added. One of these may involve cholinergic transmission. Yamada et al. previously observed that mice lacking the muscarinic M3 receptor – which is one of five cholinergic receptor subtypes sensitive to muscarin – produced a phenotype essentially the opposite [98] to what we observed after pharmacological inhibition of the MC4 receptor by 3icv SHU9119 administration in the rat. Specifically, they found that the M3−/− mice were leaner and smaller than controls, had low levels of MCH mRNA in the LH, but this was associated with increased mRNA levels of AgRP and NPY and reduced levels of POMC mRNA in the Arc. Thus, M3−/− mice may be lean because of low activity of MCH neurons in the LH, despite Arc neuropeptide responses aimed at weight gain. This is exactly mirroring the phenomena observed with pharmacological blockade of the MC4 receptor by chronic 3icv SHU9119 administration in rats. Based on their findings, Yamada and co-workers argued that this cholinergic input in the LH via the M3 receptor is required for MCH synthesis [98]. We performed a pilot experiment to assess whether muscarinic transmission in the CNS is indeed required for the effect of low melanocortin signaling to induce weight gain because it cannot be ruled that the M3 receptor affects MCH expression via remote mechanisms (e.g., via the pancreas). Specifically, rats were treated i3cv with SHU9119 alone, or were co-infused with 4-diphenylacetoxy-Nmethyl-pipendine (4DAMP), a muscarinic receptor blocker with relative high specificity for the M3 receptor [53]. A block of
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Fig. 2. Male wistar rats of 430 ± 6.4 g (n = 6, 7 per group) equipped with cannulae placed in the third cerebral ventricle according to techniques previously described [91] received under isoflurane anaesthesia minipumps (Alzet 2001) filled to deliver either saline, SHU9119 (0.5 nmol/day), 4-diphenylacetoxy-N-methyl-pipendine (4DAMP) (0.5 nmol), or a combination of SHU9119 and 4DAMP. Treatment effects of SHU9119 were found on 3-day cummulative food intake (A), 3-day cummulative water intake (B) and weight gain over 3 days (C). An interaction effect between SHU9119 and 4DAMP treatment was observed on cummulative food intake (F(3,26) = 4.917, p = 0.037, indicated by *).
hyperphagia, and a blunting of weight gain in response to the melanocortin-receptor blocker SHU9119 were seen in rats with the i3cv minipumps co-administered 4DAMP at a dose below the threshold to induce anorexia when administered alone. These data indeed suggest strongly hypothalamic muscarinic M3 receptor involvement in weight gain induced by low brain melanocortin activity (see Fig. 2).
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While Yamada et al. argued that this cholinergic input to LH MCH neurons originates from cholinergic pontomesencephalotegmental neuronal cell bodies [98], an alternative explanation might be that this cholinergic input originates from the Arc nucleus. This seems appealing in light of the strong projection of POMC neurons in the Arc towards the LH [21], and the presence of ACh in these neurons as mentioned above. Thus, a picture emerges in which reduction of melanocortin transmission from Arc neurons (presumably due to lowering of leptin signaling in the Arc) towards LH neurons causes increased expression of MCH, and that a cholinergic tone on M3 receptors, presumably at the level of LH neurons, is required for this effect. It may even be hypothesized that, because of colocalization of ACh and POMC, transmission from the Arc neurons towards LH neurons is essentially cholinergic in nature, and that this can be modulated by melanocortinergic activity either preor post-synaptically. Although it is impossible at this stage to fully accept or disqualify any of these possibilities, modulatory roles of neuropeptides in the release of “classical” neurotransmitters have been observed before, such as in the pancreas (i.e., which belongs to the embryonic neuronal leaflet) [20]. Evidence that activation of MCH expression at least can be induced by ACh acting locally in the LH came from a study in which lateral hypothalamic tissue minces incubated with ACh exerted the expected increase in MCH mRNA [9]. A complicating factor is the finding by Van den Pol et al., who showed that ACh did not lower the activation-threshold of LH MCH neurons in isolated brain slices [89]. Instead, orexin produced by adjacent LH neurons, which is known to stimulate and maintain arousal [70], does appear to lower the activation threshold of MCH neurons. Orexin expression, however, was not altered in M3−/− mice, and may therefore not be controlled by M3 cholinergic mechanisms [98]. Thus, cholinergic and orexin input appear to stimulate respectively MCH synthesis and MCH neuronal activity, and a lowering of hypothalamic melanocortin drive, which would be the cause of reduced leptin action, might modulate this effect. Lateral hypothalamic MCH neurons are in a position to control many vegetative functions, including for example autonomic vagal output which stimulates pancreatic insulin secretion [22,47] and proliferation [64] and to cause changes in neuroendocrine outflow underlying weight gain [1,41]. In addition, LH MCH neurons have strong projections to forebrain regions involved in reward and affective functions [22]. Besides the observations that MCH can stimulate food intake and weight gain, an interesting observation was made by Clegg et al. that MCH can increase water intake independently of its stimulatory effects on food intake. This is rather unique compared to other orexigenic neuropeptides, which appear to stimulate water intake primarily by dragging it along through their stimulatory effects on food intake [14].
signals from, disrupted energy homeostasis since NMDA-treated LH rats failed to respond to a host of physiological challenges [95]. Conversely, stimulation of the LH in cats [19] promoted ingestive behavior, and could cause obesity in rats [61,80]. Mogenson and Morgan observed that rats in fact learn easily to self-stimulate lateral hypothalamic electrodes after which they drink excessive amounts of water, indicating the involvement of motivational or reward pathways [55]. This would probably be reached with solid food as well, as “drinkers” could be shaped from initial “feeders” using a modification protocol [85]. The point here is that rats with LH stimulation are motivated to drink as well as to eat, and collectively override homeostatic signals associated with a positive energy balance [61]. In an attempt to reveal the chemical nature of these responses, Grossman infused minute amounts of the cholinergic agonist carbachol or acetylcholine into the LH of rats and observed stimulation of drinking behavior [29,30]. Food intake was found not to be affected by cholinergic transmission, but only by adrenergic transmission. This was verified by Stein and Seifter using an operant conditioning paradigm in which rats that had learned to press a lever for drink rewards increased lever pressing following cholinergic stimulation [79]. Muscarin has effects similar to carbachol, while nicotine is ineffective, indicating the involvement of muscarinic receptors in this phenomenon. Others, however, found that the threshold of electrical stimulation of the LH to elicit both drinking and feeding behavior in rats could be lowered considerably by administration of physostigmine, a blocker of AChE [77,78]. Furthermore, cholinergic transmission was found to be critical for both drinking and feeding behaviors of rats when these behaviors are induced by LH infusion of a cAMP analogue known to promote synaptic transmission [73]. Finally, carbachol injection into hypothalamic nuclei of sheep induced frequently drinking and feeding, but also selective feeding or drinking responses have been observed [26,27]. Inspired by this research, Puig de Parada et al. investigated ACh release in the LH using the technique of microdialysis. They observed that waterdeprived rats had increased ACh levels in the LH when they engaged in drinking behavior [67], which indeed suggests a role for ACh in this phenomenon. In a follow-up study, they observed that cholinergic transmission in the LH increased locomotor activity in rats and increased dopamine turnover in the nucleus accumbens (NAcc), collectively underlying procurements of food and water and the reinforcement of feeding behavior [18]. This could also be mediated via increased cholinergic transmission in the ventral-tegmental area (VTA), which provides a dopaminergic input towards the NAcc as well as to the LH [68]. Alternatively, or additionally, an LH projection of MCH neurons towards the NAcc might be involved in these responses given the strong appetitive effects of local NAcc infusion of MCH or the reversal with infusion of MCH antagonists [28,31].
3. The lateral hypothalamus from a historical perspective 4. Integrating nutrient and fluid balance Specific effects of lateral hypothalamic circuits on the regulation of water intake, but with links to energy balance sound familiar now in light of the research initiated in the 1950s. Anand and Brobeck observed that electrolytic lesioning of the LH in rats and cats resulted in hypophagia and adipsia [5]. Recovery from starvation could be achieved by tube feeding [84], provided that this was maintained long enough, but adipsia was clearly more persistent than hypophagia [83]. Later on, it was suggested that part of the effects observed with LH lesioning was due to destruction of neuronal fibers passing through the LH [88]. Nevertheless, followup studies reported that bilateral infusion of ibotenic acid [48] or NMDA [96], both cytoxic compounds affecting only neuronal cell bodies and leaving passing neuronal fibres intact, produces residual body weight loss. The collective conclusion of these studies was that the lateral hypothalamus is involved in responding to, or relaying
As already mentioned in the introduction of this paper, an integration between energy and fluid balance regulation is of crucial importance, since sufficient hydration is required for growth and production [15,16,93,94]. Salter-Venzon and Watts showed recently that dehydration ameliorates 2-deoxyglucose (2DG)induced compensatory feeding in rats as well as preventing cFos labeling in the LH and PVN which was normally seen after 2DG administration [69]. This suggests that rats satisfy hunger signals by ingestion only when fluid homeostasis is optimal. While the LH and PVN are obviously involved in relaying these responses, the primary signaling of a dehydrated state probably occurs somewhere else. Dehydration increases osmolality of plasma and extracellular fluid and this triggers neuronal activity of specialized neurons [12] in the organum vasculosum of the lamina terminalis (OVLT)
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and the subfornical region (SFO) [51]. These are circumventricular brain regions with large vascular beds and fenestrated capillaries optimally suited for this function [50]. Experimental, local, dehydration (i.e., by infusing hyperosmotic salt or mannitol) in these areas is very effective in stimulating thirst and antidiuresis [62]. Lesions in these areas are reported to cause complete absence of thirst, even after injection of hypertonic saline [49]. Moreover, the SFO is the primary place where angiotensin from the periphery (as a response to hypovolemia at the level of the kidney) is able to induce drinking behavior and vasopressin release from magnocellular neurons in the PVN and the supraoptic nucleus (SON) [34]. The median preoptic nucleus is an important output center for the OVLT and SFO [38] to, among others, the PVN and LH [74]. Several excellent reviews have been written on how these networks control thirst and antidiuretic responses during hyperosmotic conditions [6,12,54,63]. However, not much attention is paid to integration of these networks with the hypothalamic neuronal circuits controlling energy balance. While MCH expression in the LH has been shown to be increased during hypovolemic stress [33], water deprivation as well as salt loading leading to hyperosmotic stress reduced clearly MCH mRNA expression in the LH [65]. Thus, although these responses might still depend on central muscarinic transmission [44,46], it is unlikely that stimulation of water intake under this condition is dependent on MCH. It is even questionable whether the LH is involved at all in compensatory drinking following intracellular or extracellular osmotic stress [24,82]. Inhibition of food consumption under situations of dehydration stress might perhaps be explained by a reduction in MCH expression, in addition to activation of well-known anorexigenic circuits including for example the brain oxytocin system [92]. These may even exist despite activation of orexigenic neuropeptide expression profiles in the Arc, which are secondary to the anorexia caused by an hyperosmotic stress [60]. In contrast, food deprivation (as opposed to water deprivation) does increase MCH mRNA expression in the LH [66]. Thus, one way to conceive a link between fluid and nutrient balance is that optimal fluid homeostasis allows the MCH system to have a positive effect on energy balance.
5. Conclusions and future perspective This paper puts forward a number of points, each with several implications, and these are listed below and depicted graphically in Fig. 3. First, it is argued that interplay between muscarinic and melanocortinergic transmission in projections arising from the Arc regulates expression of MCH in LH neuronal cell bodies. Modulatory factors for melanocortin activity have been described (i.e., such as leptin), but the mechanisms that regulate cholinergic activity in these projections are unknown. It may be speculated that melanocortinergic and cholinergic biosynthesis are intrinsically and inversely linked via opposite regulations of acetylation required for production of ACh (i.e., ChAT) and the active form of ␣MSH, which is des-acetyl MSH [87]. While the latter is known to be upregulated by leptin [32], one may predict that ChAT is inhibited by leptin. The second point relates to the function of the MCH system in the regulation of energy balance. It was argued that under conditions of increased muscarinic and low MC4 transmission, the activity of the MCH system is maximized to facilitate nutrient uptake and storage (i.e., via increased B-cell capacity to secrete insulin). These effects may be related to the arousal state of the animal because orexinergic input from adjacent neuronal cell bodies are required to stimulate the activity of MCH neuronal output [89]. A major point is that the MCH system is activated to facilitate ingestive behavior and pancreatic B cell capacity only when the individual is sufficiently hydrated. Under conditions of severe water deprivation (i.e., lead-
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Fig. 3. Relations are shown between arcuate nucleus neuropeptides and acetylcholine (ACh), and how they can alter expression of MCH in the lateral hypothalamus. In the fasted condition, increased expression of MCH (due to muscarinic-3 receptor stimulation and low melanocortin tone) and neuronal release of MCH (via Orexin signaling) underlies a drive towards positive energy balance associated with optimal fluid homeostasis. A hypohydrated state may down regulate leptin signaling (via inhibitory effects of osmotic stress on mTOR), but osmotic stress prevents MCH expression via the OVLT-SFO-MePN complex. If this occurs in an obese state, pancreatic B cell capacity and peripheral insulin sensitivity may underlie cardio-metabolic diseases.
ing to hyperosmotic stress), the MCH system becomes inhibited and fuel mobilization rather than storage predominates. Third, the OVLT-SFO system is the primary circuit to detect an increase in osmolality in the body fluid compartment, which probably puts a brake on the activity of the MCH system [65]. It is likely, however, that many other neuronal circuits have osmoreceptive properties as well [12]. Vice versa, SFO neurons have been shown to be remarkably sensitive to leptin [75]. At the moment, we do not know the function or relevance of these relations, but it suggests that the available data discussed in this review on interdependency between nutrient and fluid homeostasis is just the tip of the iceberg. One avenue of interest is that leptin acts in the hypothalamus to regulate energy balance via activation of the mammalian target of rapamycin (mTOR) [17]. Overactivation of its major effector protein SK6 protects against diet-induced weight gain and insulin resistance [11]. Ironically, mTOR may only be activated under conditions of sufficient hydration [71]. Thus, if Arc neurons are sensitive to hyperosmotic challenges, and there are indications that they can [62,76], hyperosmotic stress at the level of the Arc should inhibit leptin action and may directly underlie whole body insulin resistance. As mentioned above, hyperosmotic stress would limit MCH expression in the LH which would attenuate food intake but also fluid intake and B-cell capacity of insulin production. This may be a serious condition because many obese humans in western-industrialized societies are considered to be chronically dehydrated [81], and are expected to have relatively low activity of the MCH system. Although treatment of individuals with M3 or MCH1 receptor antagonists against obesity may cause some weight loss, because of the constituent activity of M3 and MCH1 receptors even in the case of low MCH1 receptor activity due to hypohydration, the adverse cardiometabolic risks of these treatments should not be underestimated. At least, optimizing fluid balance may be a useful approach to avoid serious side-effects associated with therapeutic targeting of the proposed melanocortin–-ACh–MCH loop. Acknowledgement This work was made possible by grants from the “Dutch Diabetes Foundation” (to G. van Dijk), the OTKA (Hungarian Scientific
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Research Found; No 68875, to C. Nyakas) and the “deWied Foundation” (to C. Nyakas). A. Salomons and M. Doornbos are thanked for technical assistance.
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Contents lists available at ScienceDirect
Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr
Review
The lateral hypothalamus: A site for integration of nutrient and fluid balance Gertjan van Dijk a,c,∗ , Simon S. Evers a , Stefano Guidotti a,c , Simon N. Thornton d , Anton J.W. Scheurink a , Csaba Nyakas b,e a
Center for Behavior and Neurosciences, Unit of Neuroendocrinology, University of Groningen, The Netherlands Center for Behavior and Neurosciences, Unit of Molecular Neurobiology, University of Groningen, The Netherlands c Center for Isotope Research, University of Groningen, The Netherlands d INSERM, U961, Vandoeuvre les Nancy, and Université Henri Poincaré, Nancy, France e Unit of Nutrition and Physical Activity, Semmelweis University, Budapest, Hungary b
a r t i c l e
i n f o
Article history: Received 23 February 2010 Received in revised form 20 January 2011 Accepted 27 January 2011 Available online 12 February 2011 Keywords: Body water Drinking Feeding Osmotic stress Obesity Insulin
a b s t r a c t This paper reviews seemingly obligatory relations between nutrient and fluid balance. A relatively novel neuronal pathway involving interplay between acetylcholine and the melanocortins, ␣MSH and AGRP in the arcuate nucleus (Arc) of the hypothalamus projecting to the lateral hypothalamus (LH) may bridge this gap. In the fasted condition, increased expression of MCH (due to muscarinic-3 receptor stimulation and low melanocortin tone) and neuronal release of MCH (via Orexin signaling) underlies a drive towards positive energy balance, increased B cell capacity to secrete insulin, and this is associated with optimal fluid homeostasis. A hypohydrated state is hypothesized to yield downregulation of leptin signaling (potentially via inhibitory effects of osmotic stress on mTOR), but osmotic stress may prevent MCH expression via the OVLT-SFO complex. If this occurs in an obese state, impaired pancreatic B cell capacity and peripheral insulin insensitivity as a result of hypohydration may underlie cardio-metabolic diseases. © 2011 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acetylcholine in arcuate nucleus neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The lateral hypothalamus from a historical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Integrating nutrient and fluid balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and future perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Higher animals are generally capable of keeping their internal milieu relatively stable in the face of constant and rapid changes that can occur within or between environments. Claude Bernard was one of the first to realize this propensity and stated that “. . .evolutionary processes have shaped mechanisms allowing us to make our own seawater, in which we can bath our cells, provide them with oxygen and nutrients, and remove waste products. . .”
∗ Corresponding author at: Center for Behavior and Neurosciences, Unit of Neuroendocrinology, University of Groningen, The Netherlands. Tel.: +31 50 3632116, fax: +31 50 3632331. E-mail address: [email protected] (G. van Dijk). 0166-4328/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2011.01.047
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[10]. In order to perform these actions, animals have been equipped with respiratory, circulatory, excretory, and digestive systems, and they can display behaviors to track and ingest foods and fluids. In addition, most animals are capable of storing ingested nutrients in the form of glycogen and adipose tissue, which subsequently can deliver fuels to cells for prolonged periods when food is not available. A different picture emerges with respect to body fluids. Apart from a number of specialized animal species well-adapted to dessert conditions (allowing them to rely on metabolic water), most species have a rather poor capacity to maintain fluid balance without drinking frequently [56]. Although the bodies of higher animals consist of approximately 65% water or more, even the smallest reduction in body water content can have devastating consequences. For example, acute dehydration can cause hypovolemia at the systemic level, which, if not effectively met by fluid and sodium
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Fig. 1. ChAT immunopositive neurons in the hypothalamus Panel B: dorsomedial hypothalamus; Panel C: arcuate nucleus; Panel D: lateral hypothalamus (MCH area). (Note that in the arcuate nucleus especially a wide range of intensity of ChAT staining can be observed between the cholinergic neurons). Immunostaining procedure was applied to visualize choline acetyltransferase (ChAT) positive cholinergic neurons in the hypothalamus. Goat anti ChAT primary antibody (AB144P, Lot: LV1359401; Chemicon International, Temecula, CA, USA) was used in dilution 1:500. Biotinylated rabbit anti goat antibody and Vectastain ACB kit was obtained from Vector Laboratories (CA, USA). The staining was completed with nickel-enhanced diaminobenzidine (DAB) reaction in the presence of H2 O2 (for reference see [58]).
intake and retention in the kidney will compromise cardiovascular circulatory functioning [43,86]. Second, more chronic dehydration can cause cellular dysregulation and can disrupt several aspects of energy balance regulation including intake, growth and production [7,15,16,93,94]. This latter point indicates that obligatory relations may exist between nutrient and fluid balance. The current paper addresses central neural components underlying this relation. Furthermore, it emphasizes a relatively novel hypothalamic neuronal pathway involving interplay between acetylcholine (ACh) and neuropeptides potentially bridging the gap between nutrient and fluid balance. 2. Acetylcholine in arcuate nucleus neurons Cholinergic neuronal cell bodies in the brain are detected generally with immunohistochemistry by the presence of (i) choline acetyl-transferase (ChAT), which catalyses the binding of choline and acetylCoA, (ii) the vesicular ACh transporter (VAChT) necessary for synaptic release of Ach, and (iii) acetylcholine-esterase (AChE), which catalyses the breakdown of ACh. Besides being released as a transmitter from interneurons, for example in the cortex and striatum, ACh is also a transmitter in diffuse modulatory networks, in which relatively small neuronal cell groups have numerous projections and connections throughout major parts of the brain. These include the basal forebrain complex, with cholinergic neurons scattered among several related nuclei including the nucleus basalis of Meynert and the medial septal nuclei, both with widespread projections [35]. Another one, identified as the pontomesencephalo–tegmental complex in the pons and midbrain tegmentum, which together with other classical neurotransmitter systems including noradrenalin and serotonin, regulate the excitability of sensory relay nuclei [39,40]. Besides these wellknown cell groups, others can be found scattered throughout the
nervous system. Our own immunhistochemical results revealed for example ChAT-positive neuronal labeling within the dorsomedial and lateral hypothalamus, and a relatively strong labeling was observed in the arcuate nucleus (Arc) of the hypothalamus (see Fig. 1). Our observations are consistent with the work of Meister and coworkers who found extensive VAChT and ChAT labeling of neuronal cell bodies in the Arc too, but more lateral than we observed in Fig. 1 [52]. This variation might suggest that more than one peptidergic Arc neuron type may colocalize ChAT although in different concentrations. The Arc nucleus is of interest because neurons here have direct projections to neuroendocrine/ANS outflow and behavioral relay centers in the hypothalamus, as well as to hindbrain regions filtering incoming information from peripheral organs [13]. Moreover, the Arc is regarded as a key area in energy balance regulation, because (i) it contains neuronal cell bodies which express neuropeptides known to have important roles in regulation of ingestive behavior and energy fluxes in the body [72], and (ii) the expression of these neuropeptides and the neuronal activity of these cell bodies can be influenced by leptin through receptor-mediated signaling transduction cascades [59]. Leptin, through this pathway, has been suggested to regulate homeostatically the amount of body fat [97] and/or to fine-tune activity of several neuroendocrine axes to the nutritional/metabolic status [4]. Besides leptin, a host of other blood-borne signals affects signaling cascades in Arc neurons; these include fuels, and several gut/pancreas-derived peptides such as insulin, glucagon-like peptide-1 amide, peptide YY, and ghrelin [42]. Meister and co-workers also observed that ChAT and VAChT labeling co-expressed with mRNA encoding pro-opiomelanocortin (POMC). POMC is a relatively large peptide spliced posttranslationally into a number of smaller ones including adrenocorticotrophic hormone (ACTH), ␣-melanocyte stimulating hormone
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(␣-MSH), and beta-endorphin [45]. Expression of POMC is reduced during starvation, and this can be prevented by leptin infusion [72,90]. Mutation in the POMC gene, preventing its post-translation processing into smaller neuropeptide fragments, causes obesity [36], and the resultant lack of ␣-MSH synthesis seems most relevant in light of leptin’s influence on energy balance. ␣-MSH acts as an agonist on melanocortin-4 (MC4) receptors, and targeted deletion in mice or spontaneous genetic deletion in humans of this receptor leads to leptin resistance and obesity [25]. Other targets of leptin in the Arc nucleus are neurons that co-express neuropeptide Y (NPY) and agouti-related protein (AgRP). The latter acts as an inverse agonist on MC4 receptors (i.e., thus reducing the activity of MC4 receptors, instead of merely blocking the action of ␣-MSH) [57]. As opposed to POMC/ACh neurons that are activated by leptin, neurons that co-express NPY and AgRP are inhibited by leptin [8]. Thus, leptin has a dual action, increasing stimulatory influences towards the MC4 receptor, and at the same time attenuating inhibitory influences towards the MC4 receptor [3]. Second-order neurons expressing MC4 receptors are found, for example, in the paraventricular nucleus (PVN), which can produce thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH), and in the lateral hypothalamus (LH), which can produce melanin-concentrating hormone (MCH) and orexin [23]. Consistent with the idea that the MC4 receptor is down-stream from leptin actions is our previous finding that long-term pharmacological inhibition of hypothalamic MC4 receptor signaling in rats by third-intracerebroventricular (3icv) minipump infusion of the MC3/4 receptor blocker SHU9119 induced hyperphagia and obesity in rats [2]. This effect was found to occur despite increases in mRNA encoding CRH and POMC, and a reduction of mRNA encoding NPY, which are essentially responses aimed at preventing weight gain. The exception, however, was an increased expression in mRNA encoding MCH in the LH of the obese rats treated by 3icv-SHU9119, relative to animals that stayed lean due to 3icv saline treatment (in preparation). This increase in MCH expression is highly relevant in light of the fact that overexpression of MCH in mice induces obesity and hyperphagia [47], and MCH-1 receptor KO mice have the opposite phenotype [37]. Thus, these data indicate that increased activity of MCH neurons in the LH is a key step in the obesogenic effects caused by low melanocortin receptor activity. This story, however, is more complicated as other layers of regulation can be added. One of these may involve cholinergic transmission. Yamada et al. previously observed that mice lacking the muscarinic M3 receptor – which is one of five cholinergic receptor subtypes sensitive to muscarin – produced a phenotype essentially the opposite [98] to what we observed after pharmacological inhibition of the MC4 receptor by 3icv SHU9119 administration in the rat. Specifically, they found that the M3−/− mice were leaner and smaller than controls, had low levels of MCH mRNA in the LH, but this was associated with increased mRNA levels of AgRP and NPY and reduced levels of POMC mRNA in the Arc. Thus, M3−/− mice may be lean because of low activity of MCH neurons in the LH, despite Arc neuropeptide responses aimed at weight gain. This is exactly mirroring the phenomena observed with pharmacological blockade of the MC4 receptor by chronic 3icv SHU9119 administration in rats. Based on their findings, Yamada and co-workers argued that this cholinergic input in the LH via the M3 receptor is required for MCH synthesis [98]. We performed a pilot experiment to assess whether muscarinic transmission in the CNS is indeed required for the effect of low melanocortin signaling to induce weight gain because it cannot be ruled that the M3 receptor affects MCH expression via remote mechanisms (e.g., via the pancreas). Specifically, rats were treated i3cv with SHU9119 alone, or were co-infused with 4-diphenylacetoxy-Nmethyl-pipendine (4DAMP), a muscarinic receptor blocker with relative high specificity for the M3 receptor [53]. A block of
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Fig. 2. Male wistar rats of 430 ± 6.4 g (n = 6, 7 per group) equipped with cannulae placed in the third cerebral ventricle according to techniques previously described [91] received under isoflurane anaesthesia minipumps (Alzet 2001) filled to deliver either saline, SHU9119 (0.5 nmol/day), 4-diphenylacetoxy-N-methyl-pipendine (4DAMP) (0.5 nmol), or a combination of SHU9119 and 4DAMP. Treatment effects of SHU9119 were found on 3-day cummulative food intake (A), 3-day cummulative water intake (B) and weight gain over 3 days (C). An interaction effect between SHU9119 and 4DAMP treatment was observed on cummulative food intake (F(3,26) = 4.917, p = 0.037, indicated by *).
hyperphagia, and a blunting of weight gain in response to the melanocortin-receptor blocker SHU9119 were seen in rats with the i3cv minipumps co-administered 4DAMP at a dose below the threshold to induce anorexia when administered alone. These data indeed suggest strongly hypothalamic muscarinic M3 receptor involvement in weight gain induced by low brain melanocortin activity (see Fig. 2).
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While Yamada et al. argued that this cholinergic input to LH MCH neurons originates from cholinergic pontomesencephalotegmental neuronal cell bodies [98], an alternative explanation might be that this cholinergic input originates from the Arc nucleus. This seems appealing in light of the strong projection of POMC neurons in the Arc towards the LH [21], and the presence of ACh in these neurons as mentioned above. Thus, a picture emerges in which reduction of melanocortin transmission from Arc neurons (presumably due to lowering of leptin signaling in the Arc) towards LH neurons causes increased expression of MCH, and that a cholinergic tone on M3 receptors, presumably at the level of LH neurons, is required for this effect. It may even be hypothesized that, because of colocalization of ACh and POMC, transmission from the Arc neurons towards LH neurons is essentially cholinergic in nature, and that this can be modulated by melanocortinergic activity either preor post-synaptically. Although it is impossible at this stage to fully accept or disqualify any of these possibilities, modulatory roles of neuropeptides in the release of “classical” neurotransmitters have been observed before, such as in the pancreas (i.e., which belongs to the embryonic neuronal leaflet) [20]. Evidence that activation of MCH expression at least can be induced by ACh acting locally in the LH came from a study in which lateral hypothalamic tissue minces incubated with ACh exerted the expected increase in MCH mRNA [9]. A complicating factor is the finding by Van den Pol et al., who showed that ACh did not lower the activation-threshold of LH MCH neurons in isolated brain slices [89]. Instead, orexin produced by adjacent LH neurons, which is known to stimulate and maintain arousal [70], does appear to lower the activation threshold of MCH neurons. Orexin expression, however, was not altered in M3−/− mice, and may therefore not be controlled by M3 cholinergic mechanisms [98]. Thus, cholinergic and orexin input appear to stimulate respectively MCH synthesis and MCH neuronal activity, and a lowering of hypothalamic melanocortin drive, which would be the cause of reduced leptin action, might modulate this effect. Lateral hypothalamic MCH neurons are in a position to control many vegetative functions, including for example autonomic vagal output which stimulates pancreatic insulin secretion [22,47] and proliferation [64] and to cause changes in neuroendocrine outflow underlying weight gain [1,41]. In addition, LH MCH neurons have strong projections to forebrain regions involved in reward and affective functions [22]. Besides the observations that MCH can stimulate food intake and weight gain, an interesting observation was made by Clegg et al. that MCH can increase water intake independently of its stimulatory effects on food intake. This is rather unique compared to other orexigenic neuropeptides, which appear to stimulate water intake primarily by dragging it along through their stimulatory effects on food intake [14].
signals from, disrupted energy homeostasis since NMDA-treated LH rats failed to respond to a host of physiological challenges [95]. Conversely, stimulation of the LH in cats [19] promoted ingestive behavior, and could cause obesity in rats [61,80]. Mogenson and Morgan observed that rats in fact learn easily to self-stimulate lateral hypothalamic electrodes after which they drink excessive amounts of water, indicating the involvement of motivational or reward pathways [55]. This would probably be reached with solid food as well, as “drinkers” could be shaped from initial “feeders” using a modification protocol [85]. The point here is that rats with LH stimulation are motivated to drink as well as to eat, and collectively override homeostatic signals associated with a positive energy balance [61]. In an attempt to reveal the chemical nature of these responses, Grossman infused minute amounts of the cholinergic agonist carbachol or acetylcholine into the LH of rats and observed stimulation of drinking behavior [29,30]. Food intake was found not to be affected by cholinergic transmission, but only by adrenergic transmission. This was verified by Stein and Seifter using an operant conditioning paradigm in which rats that had learned to press a lever for drink rewards increased lever pressing following cholinergic stimulation [79]. Muscarin has effects similar to carbachol, while nicotine is ineffective, indicating the involvement of muscarinic receptors in this phenomenon. Others, however, found that the threshold of electrical stimulation of the LH to elicit both drinking and feeding behavior in rats could be lowered considerably by administration of physostigmine, a blocker of AChE [77,78]. Furthermore, cholinergic transmission was found to be critical for both drinking and feeding behaviors of rats when these behaviors are induced by LH infusion of a cAMP analogue known to promote synaptic transmission [73]. Finally, carbachol injection into hypothalamic nuclei of sheep induced frequently drinking and feeding, but also selective feeding or drinking responses have been observed [26,27]. Inspired by this research, Puig de Parada et al. investigated ACh release in the LH using the technique of microdialysis. They observed that waterdeprived rats had increased ACh levels in the LH when they engaged in drinking behavior [67], which indeed suggests a role for ACh in this phenomenon. In a follow-up study, they observed that cholinergic transmission in the LH increased locomotor activity in rats and increased dopamine turnover in the nucleus accumbens (NAcc), collectively underlying procurements of food and water and the reinforcement of feeding behavior [18]. This could also be mediated via increased cholinergic transmission in the ventral-tegmental area (VTA), which provides a dopaminergic input towards the NAcc as well as to the LH [68]. Alternatively, or additionally, an LH projection of MCH neurons towards the NAcc might be involved in these responses given the strong appetitive effects of local NAcc infusion of MCH or the reversal with infusion of MCH antagonists [28,31].
3. The lateral hypothalamus from a historical perspective 4. Integrating nutrient and fluid balance Specific effects of lateral hypothalamic circuits on the regulation of water intake, but with links to energy balance sound familiar now in light of the research initiated in the 1950s. Anand and Brobeck observed that electrolytic lesioning of the LH in rats and cats resulted in hypophagia and adipsia [5]. Recovery from starvation could be achieved by tube feeding [84], provided that this was maintained long enough, but adipsia was clearly more persistent than hypophagia [83]. Later on, it was suggested that part of the effects observed with LH lesioning was due to destruction of neuronal fibers passing through the LH [88]. Nevertheless, followup studies reported that bilateral infusion of ibotenic acid [48] or NMDA [96], both cytoxic compounds affecting only neuronal cell bodies and leaving passing neuronal fibres intact, produces residual body weight loss. The collective conclusion of these studies was that the lateral hypothalamus is involved in responding to, or relaying
As already mentioned in the introduction of this paper, an integration between energy and fluid balance regulation is of crucial importance, since sufficient hydration is required for growth and production [15,16,93,94]. Salter-Venzon and Watts showed recently that dehydration ameliorates 2-deoxyglucose (2DG)induced compensatory feeding in rats as well as preventing cFos labeling in the LH and PVN which was normally seen after 2DG administration [69]. This suggests that rats satisfy hunger signals by ingestion only when fluid homeostasis is optimal. While the LH and PVN are obviously involved in relaying these responses, the primary signaling of a dehydrated state probably occurs somewhere else. Dehydration increases osmolality of plasma and extracellular fluid and this triggers neuronal activity of specialized neurons [12] in the organum vasculosum of the lamina terminalis (OVLT)
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and the subfornical region (SFO) [51]. These are circumventricular brain regions with large vascular beds and fenestrated capillaries optimally suited for this function [50]. Experimental, local, dehydration (i.e., by infusing hyperosmotic salt or mannitol) in these areas is very effective in stimulating thirst and antidiuresis [62]. Lesions in these areas are reported to cause complete absence of thirst, even after injection of hypertonic saline [49]. Moreover, the SFO is the primary place where angiotensin from the periphery (as a response to hypovolemia at the level of the kidney) is able to induce drinking behavior and vasopressin release from magnocellular neurons in the PVN and the supraoptic nucleus (SON) [34]. The median preoptic nucleus is an important output center for the OVLT and SFO [38] to, among others, the PVN and LH [74]. Several excellent reviews have been written on how these networks control thirst and antidiuretic responses during hyperosmotic conditions [6,12,54,63]. However, not much attention is paid to integration of these networks with the hypothalamic neuronal circuits controlling energy balance. While MCH expression in the LH has been shown to be increased during hypovolemic stress [33], water deprivation as well as salt loading leading to hyperosmotic stress reduced clearly MCH mRNA expression in the LH [65]. Thus, although these responses might still depend on central muscarinic transmission [44,46], it is unlikely that stimulation of water intake under this condition is dependent on MCH. It is even questionable whether the LH is involved at all in compensatory drinking following intracellular or extracellular osmotic stress [24,82]. Inhibition of food consumption under situations of dehydration stress might perhaps be explained by a reduction in MCH expression, in addition to activation of well-known anorexigenic circuits including for example the brain oxytocin system [92]. These may even exist despite activation of orexigenic neuropeptide expression profiles in the Arc, which are secondary to the anorexia caused by an hyperosmotic stress [60]. In contrast, food deprivation (as opposed to water deprivation) does increase MCH mRNA expression in the LH [66]. Thus, one way to conceive a link between fluid and nutrient balance is that optimal fluid homeostasis allows the MCH system to have a positive effect on energy balance.
5. Conclusions and future perspective This paper puts forward a number of points, each with several implications, and these are listed below and depicted graphically in Fig. 3. First, it is argued that interplay between muscarinic and melanocortinergic transmission in projections arising from the Arc regulates expression of MCH in LH neuronal cell bodies. Modulatory factors for melanocortin activity have been described (i.e., such as leptin), but the mechanisms that regulate cholinergic activity in these projections are unknown. It may be speculated that melanocortinergic and cholinergic biosynthesis are intrinsically and inversely linked via opposite regulations of acetylation required for production of ACh (i.e., ChAT) and the active form of ␣MSH, which is des-acetyl MSH [87]. While the latter is known to be upregulated by leptin [32], one may predict that ChAT is inhibited by leptin. The second point relates to the function of the MCH system in the regulation of energy balance. It was argued that under conditions of increased muscarinic and low MC4 transmission, the activity of the MCH system is maximized to facilitate nutrient uptake and storage (i.e., via increased B-cell capacity to secrete insulin). These effects may be related to the arousal state of the animal because orexinergic input from adjacent neuronal cell bodies are required to stimulate the activity of MCH neuronal output [89]. A major point is that the MCH system is activated to facilitate ingestive behavior and pancreatic B cell capacity only when the individual is sufficiently hydrated. Under conditions of severe water deprivation (i.e., lead-
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Fig. 3. Relations are shown between arcuate nucleus neuropeptides and acetylcholine (ACh), and how they can alter expression of MCH in the lateral hypothalamus. In the fasted condition, increased expression of MCH (due to muscarinic-3 receptor stimulation and low melanocortin tone) and neuronal release of MCH (via Orexin signaling) underlies a drive towards positive energy balance associated with optimal fluid homeostasis. A hypohydrated state may down regulate leptin signaling (via inhibitory effects of osmotic stress on mTOR), but osmotic stress prevents MCH expression via the OVLT-SFO-MePN complex. If this occurs in an obese state, pancreatic B cell capacity and peripheral insulin sensitivity may underlie cardio-metabolic diseases.
ing to hyperosmotic stress), the MCH system becomes inhibited and fuel mobilization rather than storage predominates. Third, the OVLT-SFO system is the primary circuit to detect an increase in osmolality in the body fluid compartment, which probably puts a brake on the activity of the MCH system [65]. It is likely, however, that many other neuronal circuits have osmoreceptive properties as well [12]. Vice versa, SFO neurons have been shown to be remarkably sensitive to leptin [75]. At the moment, we do not know the function or relevance of these relations, but it suggests that the available data discussed in this review on interdependency between nutrient and fluid homeostasis is just the tip of the iceberg. One avenue of interest is that leptin acts in the hypothalamus to regulate energy balance via activation of the mammalian target of rapamycin (mTOR) [17]. Overactivation of its major effector protein SK6 protects against diet-induced weight gain and insulin resistance [11]. Ironically, mTOR may only be activated under conditions of sufficient hydration [71]. Thus, if Arc neurons are sensitive to hyperosmotic challenges, and there are indications that they can [62,76], hyperosmotic stress at the level of the Arc should inhibit leptin action and may directly underlie whole body insulin resistance. As mentioned above, hyperosmotic stress would limit MCH expression in the LH which would attenuate food intake but also fluid intake and B-cell capacity of insulin production. This may be a serious condition because many obese humans in western-industrialized societies are considered to be chronically dehydrated [81], and are expected to have relatively low activity of the MCH system. Although treatment of individuals with M3 or MCH1 receptor antagonists against obesity may cause some weight loss, because of the constituent activity of M3 and MCH1 receptors even in the case of low MCH1 receptor activity due to hypohydration, the adverse cardiometabolic risks of these treatments should not be underestimated. At least, optimizing fluid balance may be a useful approach to avoid serious side-effects associated with therapeutic targeting of the proposed melanocortin–-ACh–MCH loop. Acknowledgement This work was made possible by grants from the “Dutch Diabetes Foundation” (to G. van Dijk), the OTKA (Hungarian Scientific
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Research Found; No 68875, to C. Nyakas) and the “deWied Foundation” (to C. Nyakas). A. Salomons and M. Doornbos are thanked for technical assistance.
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