Hypothalamic Regulation Of Energy Balance Research Articles

The Role of Fatty Acids in Ceramide Pathways and Their Influence on Hypothalamic Regulation of Energy Balance: A Systematic Review.

Obesity is a global health issue for which no major effective treatments have been well established. High-fat diet consumption is closely related to the development of obesity because it negatively modulates the hypothalamic control of food intake due to metaflammation and lipotoxicity. The use of animal models, such as rodents, in conjunction with in vitro models of hypothalamic cells, can enhance the understanding of hypothalamic functions related to the control of energy balance, thereby providing knowledge about the impact of diet on the hypothalamus, in addition to targets for the development of new drugs that can be used in humans to decrease body weight. Recently, sphingolipids were described as having a lipotoxic effect in peripheral tissues and the central nervous system. Specifically, lipid overload, mainly from long-chain saturated fatty acids, such as palmitate, leads to excessive ceramide levels that can be sensed by the hypothalamus, triggering the dysregulation of energy balance control. However, no systematic review has been undertaken regarding studies of sphingolipids, particularly ceramide and sphingosine-1-phosphate (S1P), the hypothalamus, and obesity. This review confirms that ceramides are associated with hypothalamic dysfunction in response to metaflammation, endoplasmic reticulum (ER) stress, and lipotoxicity, leading to insulin/leptin resistance. However, in contrast to ceramide, S1P appears to be a central satiety factor in the hypothalamus. Thus, our work describes current evidence related to sphingolipids and their role in hypothalamic energy balance control. Hypothetically, the manipulation of sphingolipid levels could be useful in enabling clinicians to treat obesity, particularly by decreasing ceramide levels and the inflammation/endoplasmic reticulum stress induced in response to overfeeding with saturated fatty acids.

Differential regulation of thyrotropin-releasing hormone mRNA expression in the paraventricular nucleus and dorsomedial hypothalamus in OLETF rats

Thyrotropin-releasing hormone (TRH) plays an important role in the regulation of energy balance. While the regulation of TRH in the paraventricular nucleus (PVN) in response to changes of energy balance has been well studied, how TRH is regulated in the dorsomedial hypothalamus (DMH) in maintaining energy homeostasis remains unclear. Here, we assessed the effects of food restriction and exercise on hypothalamic Trh expression using Otsuka Long-Evens Tokushima Fatty (OLETF) rats. Sedentary ad lib fed OLETF rats (OLETF-SED) became hyperphagic and obese. These alterations were prevented in OLETF rats with running wheel access (OLETF-RW) or food restriction in which their food was pair-fed (OLETF-PF) to the intake of lean control rats (LETO-SED). Evaluation of hypothalamic gene expression revealed that Trh mRNA expression was increased in the PVN of OLETF-SED rats and normalized in OLETF-RW and OLETF-PF rats compared to LETO-SED rats. In contrast, the expression of Trh in the DMH was decreased in OLETF-SED rats relative to LETO-SED rats. This alteration was reversed in OLETF-RW rats as seen in LETO-SED rats, but food restriction resulted in a significant increase in DMH Trh expression in OLETF-PF rats compared to LETO-SED rats. Strikingly, while Trh mRNA expression was decreased in the PVN of intact rats in response to acute food deprivation, food deprivation resulted in increased expression of Trh in the DMH. Together, these results demonstrate the differential regulation of Trh expression in the PVN and DMH in OLETF rats and suggest that DMH TRH also contributes to hypothalamic regulation of energy balance.

Hypothalamic Regulation of Liver and Muscle Nutrient Partitioning by Brain-Specific Carnitine Palmitoyltransferase 1C in Male Mice.

Carnitine palmitoyltransferase (CPT) 1C, a brain-specific protein localized in the endoplasmic reticulum of neurons, is expressed in almost all brain regions. Based on global knockout (KO) models, CPT1C has demonstrated relevance in hippocampus-dependent spatial learning and in hypothalamic regulation of energy balance. Specifically, it has been shown that CPT1C is protective against high-fat diet-induced obesity (DIO), and that CPT1C KO mice show reduced peripheral fatty acid oxidation (FAO) during both fasting and DIO. However, the mechanisms mediating CPT1C-dependent regulation of energy homeostasis remain unclear. Here, we focus on the mechanistic understanding of hypothalamic CPT1C on the regulation of fuel selection in liver and muscle of male mice during energy deprivation situations, such as fasting. In CPT1C-deficient mice, modulation of the main hypothalamic energy sensors (5' adenosine monophosphate-activated protein kinase, Sirtuin 1, and mammalian target of rapamycin) was impaired and plasma catecholamine levels were decreased. Consequently, CPT1C-deficient mice presented defective fasting-induced FAO in liver, leading to higher triacylglycerol accumulation and lower glycogen levels. Moreover, muscle pyruvate dehydrogenase activity was increased, which was indicative of glycolysis enhancement. The respiratory quotient did not decrease in CPT1C KO mice after 48 hours of fasting, confirming a defective switch on fuel substrate selection under hypoglycemia. Phenotype reversion studies identified the mediobasal hypothalamus (MBH) as the main area mediating CPT1C effects on fuel selection. Overall, our data demonstrate that CPT1C in the MBH is necessary for proper hypothalamic sensing of a negative energy balance and fuel partitioning in liver and muscle.

Contribution of adaptive thermogenesis to the hypothalamic regulation of energy balance.

Obesity and its related disorders are among the most pervasive diseases in contemporary societies, and there is an urgent need for new therapies and preventive approaches. Given (i) our poor social capacity to correct unhealthy habits, and (ii) our evolutionarily genetic predisposition to store excess energy as fat, the current environment of caloric surplus makes the treatment of obesity extremely difficult. During the last few decades, an increasing number of methodological approaches have increased our knowledge of the neuroanatomical basis of the control of energy balance. Compelling evidence underlines the role of the hypothalamus as a homeostatic integrator of metabolic information and its ability to adjust energy balance. A greater understanding of the neural basis of the hypothalamic regulation of energy balance might indeed pave the way for new therapeutic targets. In this regard, it has been shown that several important peripheral signals, such as leptin, thyroid hormones, oestrogens and bone morphogenetic protein 8B, converge on common energy sensors, such as AMP-activated protein kinase to modulate sympathetic tone on brown adipose tissue. This knowledge may open new ways to counteract the chronic imbalance underlying obesity. Here, we review the current state of the art on the role of hypothalamus in the regulation of energy balance with particular focus on thermogenesis.

Abstract # 1759 Age-related effects of neonatal overfeeding on leptin-mediated hypothalamic connectivity

Neonatal overfeeding leads to developmental programming of adult obesity. We and others have previously shown that neonatally overfed rats maintain an overweight phenotype and increased levels of proinflammatory adipokine leptin. Leptin’s role in a mature and healthy brain is to mediate the hypothalamic regulation of energy balance. In early life however, leptin has a distinct neurotrophic function, stimulating the establishment of hypothalamic feeding circuitry. In this study, we examined the acute and long-term effects of neonatal overfeeding on leptin-mediated development of hypothalamic connectivity. We also assessed the potential for short-term suppression of neonatal leptin’s activity with a leptin antagonist to mitigate the outcomes of neonatal overfeeding. We saw that neonatal overfeeding induces an acute resistance of the arcuate nucleus (ARC) and ventromedial hypothalamus (VMH) pStat3-positive neurons to exogenous leptin. While this leptin resistance is not maintained into adulthood, neonatal overfeeding induces long-term changes in the ARC neuropeptide Y (NPY) density, suggesting there is a long-term disruption of hypothalamic connectivity. Interestingly, short-term neonatal leptin antagonism does not reduce body weight or leptin levels in the neonatally overfed, but suppresses NPY density in control rats to levels similar to those of the overfed. Our findings demonstrate that changes in the availability of neonatal leptin are critical to the development of hypothalamic connectivity. These data also indicate a potential for developmental plasticity to ameliorate the metabolic malprogramming.

Hypothalamic inflammation and energy balance deregulations: focus on chemokines.

The hypothalamus is a key brain region in the regulation of energy balance. It especially controls food intake and both energy storage and expenditure through integration of humoral, neural and nutrient-related signals and cues. Hypothalamic neurons and glial cells act jointly to orchestrate, both spatially and temporally, regulated metabolic functions of the hypothalamus. Thus, the existence of a causal link between hypothalamic inflammation and deregulations of feeding behavior, such as involuntary weight-loss or obesity, has been suggested. Among the inflammatory mediators that could induce deregulations of hypothalamic control of the energy balance, chemokines represent interesting candidates. Indeed, chemokines, primarily known for their chemoattractant role of immune cells to the inflamed site, have also been suggested capable of neuromodulation. Thus, chemokines could disrupt cellular activity together with synthesis and/or secretion of multiple neurotransmitters/mediators that are involved in the maintenance of energy balance. Here, we relate, on one hand, recent results showing the primary role of the central chemokinergic signaling CCL2/CCR2 for metabolic and behavioral adaptation to high-grade inflammation, especially loss of appetite and weight, through its activity on hypothalamic neurons producing the orexigenic peptide Melanin-Concentrating Hormone (MCH) and, on the other hand, results that suggest that chemokines could also deregulate hypothalamic neuropeptidergic circuits to induce an opposite phenotype and eventually participate in the onset/development of obesity. In more details, we will emphasize a study recently showing, in a model of high-grade acute inflammation of LPS injection in mice, that central CCL2/CCR2 signaling is of primary importance for several aspects explaining weight loss associated with inflammation: after LPS injection, animals lose weight, reduce their food intake, increase their fat oxidation (thus energy consumption from fat storage)...These inflammation-induced metabolic and behavioral changes are reduced when central CCR2 signaling is disrupted either pharmacologically (by a specific inhibitor of CCR2) or genetically (in mice deficient for CCR2). This underlines the importance of this signaling in inflammation-related weight loss. We further determined that the LPS-induced and CCR2-mediated weight loss depends on the direct effect of CCR2 activation on MCH neurons activity. Indeed, the MCH neurons express CCR2, and the application of CCL2 on brain slices revealed that activation of CCR2 actually depolarizes MCH neurons and induces delays and/or failures of action potential emission. Furthermore, CCL2 is able to reduce KCl-evoked MCH secretion from hypothalamic explants. Taken together, these results demonstrate the role of the central CCL2/CCR2 signaling in metabolic and behavioral adaptation to inflammation. On the other hand, this first description of how the chemokinergic system can actually modulate the activity of the hypothalamic regulation of energy balance, but also some less advanced studies and some unpublished data, suggest that some other chemokines, such as CCL5, could participate in the development of the opposite phenotype, that is to say obesity.

Protective effect of carbenoxolone on ER stress-induced cell death in hypothalamic neurons

Hypothalamic endoplasmic reticulum (ER) stress is known to be increased in obesity. Induction of ER stress on hypothalamic neurons has been reported to cause hypothalamic neuronal apoptosis and malfunction of energy balance, leading to obesity. Carbenoxolone is an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor that converts inactive glucocorticoid into an active form. In addition to its metabolic effect via enzyme inhibitory action, carbenoxolone has shown anti-apoptotic activity in several studies. In this study, the direct effects of carbenoxolone on ER stress and cell death in hypothalamic neurons were investigated. Carbenoxolone attenuated tunicamycin induced ER stress-mediated molecules such as spliced XBP1, ATF4, ATF6, CHOP, and ROS generation. In vivo study also revealed that carbenoxolone decreased tunicamycin-induced ER stress in the hypothalamus. In conclusion, the results of this study show that carbenoxolone has protective effects against tunicamycin induced-ER stress and apoptosis in hypothalamic neurons, suggesting its direct protective effects against obesity. Further study is warranted to clarify the effects of carbenoxolone on hypothalamic regulation of energy balance in obesity.

Early leptin intervention reverses perturbed energy balance regulating hypothalamic neuropeptides in the pre- and postnatal calorie-restricted female rat offspring.

Pre- and postnatal calorie restriction is associated with postnatal growth restriction, reduced circulating leptin concentrations, and perturbed energy balance. Hypothalamic regulation of energy balance demonstrates enhanced orexigenic (NPY, AgRP) and diminished anorexigenic (POMC, CART) neuropeptide expression (PN21), setting the stage for subsequent development of obesity in female Sprague-Dawley rats. Leptin replenishment during the early postnatal period (PN2-PN8) led to reversal of the hypothalamic orexigenic:anorexigenic neuropeptide ratio at PN21 by reducing only the orexigenic (NPY, AgRP), without affecting the anorexigenic (POMC, CART) neuropeptide expression. This hypothalamic effect was mediated via enhanced leptin receptor (ObRb) signaling that involved increased pSTAT3/STAT3 but reduced PTP1B. This was further confirmed by an increase in body weight at PN21 in response to intracerebroventricular administration of antisense ObRb oligonucleotides (PN2-PN8). The change in the hypothalamic neuropeptide balance in response to leptin administration was associated with increased oxygen consumption, carbon dioxide production, and physical activity, which resulted in increased milk intake (PN14) with no change in body weight. This is in contrast to the reduction in milk intake with no effect on energy expenditure and physical activity observed in controls. We conclude that pre- and postnatal calorie restriction perturbs hypothalamic neuropeptide regulation of energy balance, setting the stage for hyperphagia and reduced energy expenditure, hallmarks of obesity. Leptin in turn reverses this phenotype by increasing hypothalamic ObRb signaling (sensitivity) and affecting only the orexigenic arm of the neuropeptide balance.

DEP domain-containing mTOR-interacting protein in the rat brain: distribution of expression and potential implication.

DEP domain-containing mTOR-interacting protein (DEPTOR) has been recently discovered as an endogenous regulator of the mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2. mTORC1 is present in the brain, and there is growing evidence that its dysregulation contributes to several brain alterations. This suggests the involvement of mTOR signaling and its modulators in neurobiological controls. Here, we characterized and mapped the expression of DEPTOR in the rat brain. We show that DEPTOR was widely expressed from the forebrain to the hindbrain, including the hippocampus, the mediobasal hypothalamus, and the circumventricular organs (CVOs). In the hippocampus, DEPTOR protein and Deptor mRNA were highly expressed in the dendate gyrus and CA3 field. In the CVOs, DEPTOR was expressed in the subfornical organ, the median eminence, and the area postrema. In the mediobasal hypothalamus, DEPTOR was expressed in neurons of the ventromedial nucleus (VMH) and colocalized with proopiomelanocortin (POMC) in the arcuate nucleus (ARC). The hypothalamic distribution suggested a role for DEPTOR in energy balance. Supporting this possibility, we observed that Deptor hypothalamic expression was modulated by the nutritional status in a context of diet-induced and genetic obesity; food deprivation increased Deptor mRNA in both the ARC and VMH of obese rats. In conclusion, the present results illustrate the presence of DEPTOR in the rat brain and suggest a role for DEPTOR in the hypothalamic regulation of energy balance, which further supports the role of mTOR in energy homeostasis. J. Comp. Neurol. 523:93-107, 2015. © 2014 Wiley Periodicals, Inc.

Hypothalamic regulation of energy balance: a key role for DICER miRNA processing in arcuate POMC neurons

Hypothalamic regulation of energy balance: a key role for DICER miRNA processing in arcuate POMC neurons

Sugaring appetite development: mechanisms of neuroendocrine programming.

Gestational diabetes is one of the most common complications of pregnancy occurring in up to 10% of women in the Western world. The short-term risks of gestational diabetes to both mother and child, including preeclampsia, preterm delivery, and increased perinatal mortality, are well established (1). However, there is now strong evidence from both human and animal models that exposure to a diabetic environment during fetal life has substantial long-term health consequences for the child, including increased risk of type 2 diabetes and obesity (2). Much research effort has therefore been directed toward understanding the mechanisms by which such metabolic programming arises. In this issue of Endocrinology, Steculorum and Bouret demonstrate that maternal diabetes leads to impaired neonatal leptin signaling and structural disorganization of hypothalamic feeding pathways in the offspring. This is associated with leptin resistance in adulthood resulting in increased food intake and increased risk of metabolic disease (3). The concept of metabolic programming has been recognized for many years (reviewed in Ref. 4). Although initial focus was directed toward the long-term detrimental effects of fetal undernutrition and low birth weight (5), in light of the global epidemic of obesity and diabetes in women of child-bearing age, recent attention has shifted toward fetal overnutrition and high birth weight (6). Both ends of the birth weight spectrum have been associated with increased risk of type 2 diabetes and other features of the metabolic syndrome that may indicate common mechanistic pathways (7). Low birth weight is often followed by accelerated postnatal growth (frequently referred to as “catch-up growth”) and this has been shown to be particularly detrimental in terms of later obesity risk, highlighting the neonatal period as a critical time window for establishment of long-term regulation of energy balance (8). It is therefore possible that accelerated early postnatal growth may represent a commonality between animal models of low birth weight followed by catch-up growth (9) and models of maternal diabetes/obesity where suckling by such dams leads to increased weight gain during the lactation period (3, 10). The hypothalamus plays a central role in regulation of energy balance and has therefore been a major focus of experiments aimed at dissecting the mechanisms underlying the programming of obesity. Early experiments that manipulated neonatal growth and nutrient intake by variation of litter size showed programmed changes in crude measures of hypothalamic function and structure, including RNA content (11) and neuronal density (12). However, as understanding of the molecular mechanisms underlying hypothalamic regulation of energy balance has increased, more detailed information on programmed changes in the hypothalamus has emerged. These include programmed changes in neuropeptide expression (13–15) that could result from altered epigenetic regulation of gene transcription (15). A common phenotypic outcome that has been reported in a number of programming models, including those of neonatal overfeeding (16, 17), intrauterine undernutrition (18), maternal high fat feeding (19), and maternal diet-induced obesity (13), is resistance to leptin in adulthood in relation to inhibition of food intake. However, there has been less focus on whether leptin resistance during the very early stages of life, at a time when leptin has no effect on food intake (20, 21), plays a mechanistic role in metabolic programming (13, 17).

Nociceptin/orphanin FQ suppresses the excitability of neurons in the ventromedial nucleus of the hypothalamus

Nociceptin or orphanin FQ (N/OFQ) stimulates food intake when injected into the ventromedial nucleus of the hypothalamus (VMN). The VMN negatively regulates energy balance in part by tonically activating proopiomelanocortin arcuate neurons, thereby suppressing food intake. However, it is not clear how orexigenic neurotransmission within the VMN can stimulate food intake. We tested the hypothesis that the orexigenic action of N/OFQ results from its inhibition of anorexigenic VMN neurons. We studied the effects of N/OFQ on the electrical properties of anorexigenic VMN neurons in acute brain slices. Ionic mechanisms underlying the actions of N/OFQ were studied using whole cell patch-clamp recordings from VMN neurons expressing the anorexigenic leptin receptor (LepRb). Bath application of N/OFQ to LepRb-expressing VMN neurons elicited a robust, reversible membrane hyperpolarization that suppressed neuronal excitability by raising the action potential firing threshold and cell rheobase. N/OFQ activated a postsynaptic, G-protein coupled, inwardly rectifying potassium (GIRK) current that was sensitive to G-protein inactivation, blocked by the GIRK blocker SCH23390, and occluded by the GABAB agonist and potent GIRK activator, baclofen. Application of the selective N/OFQ receptor antagonist SB-612111 blocked the inhibitory effects of N/OFQ. We concluded that N/OFQ directly inhibited VMN neurons by activating a GIRK. These results implicate the site-specific contributions of orexigenic neuropeptides at VMN neurons to suppress anorexigenic output. This study thus advances our understanding regarding the contributions of the VMN to hypothalamic regulation of energy balance.

Cloning and Characterization of the 5′-Flanking Region of the Pig Cocaine- and Amphetamine-Regulated Transcript Gene

The cocaine- and amphetamine-regulated transcript (CART) gene encodes an anorexigenic peptide. It has a key role in the hypothalamic regulation of energy balance through reducing food intake and enhancing lipid substrate utilization. To detect the CART expression pattern in pigs, reverse transcription (RT)-polymerase chain reaction (PCR) and real-time PCR were performed in various tissues. Our RT-PCR results revealed that the pig CART gene was ubiquitously expressed in all examined tissues including hypothalamus, m. longissimus, backfat, heart, liver, spleen, lung, kidney, stomach, bladder, belly fat, brain, large intestine, lymph, and skin. Real-time quantitative PCR experiments revealed that the cDNA level of CART in both the hypothalamus and backfat of adult Landrace pig (lean-type) was significantly higher than that of Chinese indigenous Lantang pig (fat-type), and it was in the hypothalamus where the highest expression of CART was observed for both adult Lantang and Landrace pigs, compared with backfat and m. longissimus muscle. To understand the regulation of the pig CART gene, the 5'-flanking region was isolated from a pig bacterial artificial chromosome library and used in a luciferase reporter assay. A positive cis-acting element for efficient CART expression was identified at nucleotides -73 to -53, using 5'-serial deletion of the promoter. Electrophoretic mobility shift assays with competing oligonucleotides revealed that the critical region contained a cis-acting element for the zinc-binding protein factor, a zinc-finger transcription factor of the Kruppel family. This element has not been reported in human or mouse CART genes. Our results indicated that zinc-binding protein factor might be an essential regulatory factor for transcription of pig CART, providing important insight into mechanisms involved in energy homeostasis regulation in the porcine and human brain.

Loss of prokineticin receptor 2 signaling predisposes mice to torpor

The genes encoding prokineticin 2 polypeptide (Prok2) and its cognate receptor (Prokr2/Gpcr73l1) are widely expressed in both the suprachiasmatic nucleus and its hypothalamic targets, and this signaling pathway has been implicated in the circadian regulation of behavior and physiology. We have previously observed that the targeted null mutation of Prokr2 disrupts circadian coordination of cycles of locomotor activity and thermoregulation. We have now observed spontaneous but sporadic bouts of torpor in the majority of these transgenic mice lacking Prokr2 signaling. During these torpor bouts, which lasted for up to 8 h, body temperature and locomotor activity decreased markedly. Oxygen consumption and carbon dioxide production also decreased, and there was a decrease in respiratory quotient. These spontaneous torpor bouts generally began toward the end of the dark phase or in the early light phase when the mice were maintained on a 12:12-h light-dark cycle and persisted when mice were exposed to continuous darkness. Periods of food deprivation (16-24 h) induced a substantial decrease in body temperature in all mice, but the duration and depth of hypothermia was significantly greater in mice lacking Prokr2 signaling compared with heterozygous and wild-type littermates. Likewise, when tested in metabolic cages, food deprivation produced greater decreases in oxygen consumption and carbon dioxide production in the transgenic mice than controls. We conclude that Prokr2 signaling plays a role in hypothalamic regulation of energy balance, and loss of this pathway results in physiological and behavioral responses normally only detected when mice are in negative energy balance.

Impact of a CART promoter genetic variation on plasma lipid profile in a general population

The cocaine and amphetamine regulated transcript (CART), an anorexigenic peptide responding to leptin, is expressed in various areas of the hypothalamus. The role of CART in humans and its potential contribution to abnormalities in feeding control are mostly unknown. Since CART plays an important role in the hypothalamic regulation of energy balance by reducing food intake and increasing lipid substrate utilization, it might affect cholesterol metabolism as Neuropeptide Y or pro-opiomelanocortin do. In the present work, we studied the potential effects of three SNPs of the CART promoter in a WHO–MONICA general population from North of France ( n = 840), untreated for hypercholesterolemia, hypertension, or diabetes mellitus since any treatment is likely to interfere with lipoprotein/lipid variables. Our results show associations between these SNPs and plasma LDL-cholesterol level and the LDL/HDL ratio, a marker of atherogenicity. A haplotypic study suggests that these effects are mainly attributable to the functional SNP −3608C>T. Subjects bearing the −3608 C allele present a plasma lipid profile protective against atherogenesis: decrease of plasma LDL-cholesterol level ( p = 0.001) and of the LDL/HDL ratio ( p = 0.0003). This result offers new evidences for a potential implication of the CART gene in lipid metabolism and in atherogenesis.

Ghrelin in hypothalamic regulation of energy balance.

The novel peptide hormone ghrelin has recently been recognized as an important co-regulator of growth hormone secretion and energy homeostasis. The significance of ghrelin for obesity and cachexia as well as in the regulation of growth processes is the subject of ongoing basic research as well as clinical studies. It is our goal to emphasize the critical significance of the hypothalamic signaling modalities induced by ghrelin for a better understanding of how this novel hormone affects energy balance and metabolism.

Neuropeptide Y, the hypothalamus, and diabetes: Insights into the central control of metabolism

Neuropeptide Y (NPY), a major brain neurotransmitter, is expressed in neurons of the hypothalamic arcuate nucleus (ARC) that project mainly to the paraventricular nucleus (PVN), an important site of NPY release. NPY synthesis in the ARC is thought to be regulated by several factors, notably insulin, which may exert an inhibitory action. The effects of NPY injected into the PVN and other sites include hyperphagia, reduced energy expenditure and enhanced weight gain, insulin secretion, and stimulation of corticotropin and corticosterone release. The ARC-PVN projection appears to be overactive in insulin-deficient diabetic rats, and could contribute to the compensatory hyperphagia and reduced energy expenditure, and pituitary dysfunction found in these animals; overactivity of these NPY neurons may be due to reduction of insulin's normal inhibitory effect. The ARC-PVN projection is also stimulated in rat models of obesity +/- non-insulin diabetes, possibly because the hypothalamus is resistant to inhibition by insulin; in these animals, enhanced activity of ARC NPY neurons could cause hyperphagia, reduced energy expenditure, and obesity, and perhaps contribute to hyperinsulinemia and altered pituitary secretion. Overall, these findings suggest that NPY released in the hypothalamuss, especially from the ARC-PVN projection, plays a key role in the hypothalamic regulation of energy balance and metabolism. NPY is also found in the human hypothalamus. Its roles (if any) in human homeostasis and glucoregulation remain enigmatic, but the animal studies have identified it as a potential target for new drugs to treat obesity and perhaps NIDDM.