Central injection of neuropeptide Y modulates sexual behavior in male rats: interaction with GnRH and kisspeptin/neurokinin B/dynorphin.

AIMS: A number of studies have shown that neuropeptide Y (NPY) is considered to be one of the key regulators of hypothalamic-pituitary-gonadal (HPG) axis in the mammals. In addition, kisspeptin (encode by Kiss1 gene), neurokinin B (encode by Tac3 gene) and dynorphin (encode by Pdyn gene) (commonly known as KNDy secreting neurons) are a powerful upstream regulators of GnRH neuron in hypothalamus. MATERIALS AND METHODS: The present study aims to investigate the effects of the intracerebroventricular (icv) injection of NPY and BIBP3226 (NPY receptor antagonist (NPYRA)) on the male sexual behavioral. Additionally, in order to see whether NPY signals can be relayed through the pathway of kisspeptin/neurokinin B/dynorphin, the gene expression of these peptides along with Gnrh1 gene in the hypothalamus were measured. RESULTS: The icv injection of NPY decreased the latencies and increase the frequencies of sexual parameters of the male rats in a significant way. In this line, NPYRA antagonized the stimulative effects of NPY. Moreover, data from real-time quantitative PCR indicated that injection of NPY significantly increased the gene expression of Gnrh1, Kiss1 and Tac3 and decrease the Pdyn while treatment with NPYRA controlled the modulative effects of NPY on these gene expression. CONCLUSIONS: In conclusion based on the results of this study, NPY can exert its impacts on the sexual behavior of male rats via modulation of the KNDy secreting neurons as an interneural pathway to GnRH neurons.

Pleiotropic effects of proopiomelanocortin and VGF nerve growth factor inducible neuropeptides for the long-term regulation of energy balance.

Seasonal rhythms in energy balance are well documented across temperate and equatorial zones animals. The long-term regulated changes in seasonal physiology consists of a rheostatic system that is essential to successful time annual cycles in reproduction, hibernation, torpor, and migration. Most animals use the annual change in photoperiod as a reliable and robust environmental cue to entrain endogenous (i.e. circannual) rhythms. Research over the past few decades has predominantly examined the role of first order neuroendocrine peptides for the rheostatic changes in energy balance. These anorexigenic and orexigenic neuropeptides in the arcuate nucleus include neuropeptide y (Npy), agouti-related peptide (Agrp), cocaine and amphetamine related transcript (Cart) and pro-opiomelanocortin (Pomc). Recent studies also indicate that VGF nerve growth factor inducible (Vgf) in the arcuate nucleus is involved in the seasonal regulation of energy balance. In situ hybridization, qPCR and RNA-sequencing studies have identified that Pomc expression across fish, avian and mammalian species, is a neuroendocrine marker that reflects seasonal energetic states. Here we highlight that long-term changes in arcuate Pomc and Vgf expression is conserved across species and may provide rheostatic regulation of seasonal energy balance.

Double immunofluorescent evidence that oxidative stress-associated activation of JNK/AP-1 signaling participates in neuropeptide-mediated appetite control.

Amphetamine (AMPH), an appetite suppressant, alters expression levels of neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus. This study explored the potential role of cJun-N-terminal kinases (JNK) in appetite control, mediated by reactive oxygen species (ROS) and activator protein-1 (AP-1) in AMPH-treated rats. Rats were given AMPH daily for 4 days. Changes in feeding behavior and expression levels of hypothalamic NPY, CART, cFos, cJun, phosphorylated JNK (pJNK), as well as those of anti-oxidative enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GP) and glutathione S-transferase (GST), were examined and compared. Following AMPH treatment, food intake and NPY expression decreased, whereas the other proteins expression and AP-1/DNA binding activity increased. Both cerebral cJun inhibition and ROS inhibition attenuated AMPH anorexia and modified detected protein, revealing a crucial role for AP-1 and ROS in regulating AMPH-induced appetite control. Moreover, both pJNK/CART and SOD/CART activities detected by double immunofluorescent staining increased in hypothalamic arcuate nucleus in AMPH-treated rats. The results suggested that pJNK/AP-1 signaling and endogenous anti-oxidants participated in regulating NPY/CART-mediated appetite control in rats treated with AMPH. These findings advance understanding of the molecular mechanism underlying the role of pJNK/AP-1 and oxidative stress in NPY/CART-mediated appetite suppression in AMPH-treated rats.

Appetite-associated responses to central neuropeptide Y injection in quail.

The appetite-associated effects of neuropeptide Y (NPY) have been extensively studied in mammalian models. Less knowledge exists for other vertebrate species including birds. The aim of this study was to determine the effects of central injection of NPY on feeding behavior and hypothalamic physiology in 7 day-old Japanese quail (Coturnix japonica). During the light cycle, intracerebroventricular injection of 1.9 pmol, 0.5, and 1.0 nmol doses of NPY did not affect food intake, 0.031 to 0.13 nmol increased food intake, and 2.0 nmol NPY decreased food intake, in comparison to vehicle injection. Multiple doses of NPY stimulated water intake, but when food was not available, water intake was not affected. When injected during the dark cycle, NPY did not influence food intake. NPY-injected chicks had more c-Fos immunoreactive cells in the arcuate nucleus of the hypothalamus (ARC) and greater hypothalamic agouti-related peptide and neuropeptide Y receptors 1 and 2 (NPYR1 and NPYR2, respectively) mRNA than vehicle-injected chicks. Within the ventromedial hypothalamus, NPY-treated chicks expressed less NPYR1 mRNA, within the dorsomedial hypothalamus less NPY mRNA, and in the ARC greater NPYR2 mRNA than vehicle-injected chicks. Lastly, quail injected with NPY increased feeding pecks, escape attempts, and time spent preening, while locomotion, the number of steps, and time spent perching decreased compared to chicks injected with the vehicle. Results demonstrate that NPY stimulates food intake in quail, consistent with mammals and other avian species, but with some unique responses at the molecular level that are not documented in other species.

The physiological and neuroendocrine correlates of hunger in the Red Junglefowl (Gallus gallus).

The ability to regulate food intake is critical to survival. The hypothalamus is central to this regulation, integrating peripheral signals of energy availability. Although our understanding of hunger in rodents is advanced, an equivalent understanding in birds is lacking. In particular, the relationship between peripheral energy indices and hypothalamic 'hunger' peptides, agouti-related protein (AgRP), pro-opiomelanocortin (POMC) and neuropeptide Y (NPY) is poorly understood. Here, we compare AgRP, POMC and NPY RNA levels in the hypothalamus of Red Junglefowl chicks raised under ad libitum, chronic restriction and intermittent feeding regimens. Hypothalamic gene expression differed between chronically and intermittently restricted birds, confirming that different restriction regimens elicit different patterns of hunger. By assessing the relationship between hypothalamic gene expression and carcass traits, we show for the first time in birds that AgRP and POMC are responsive to fat-related measures and therefore represent long-term energy status. Chronically restricted birds, having lower indices of fat, show elevated hunger according to AgRP and POMC. NPY was elevated in intermittently fasted birds during fasting, suggesting a role as a short-term index of hunger. The different physiological and neuroendocrine responses to quantitative versus temporal feed restriction provide novel insights into the divergent roles of avian hunger neuropeptides.

Neuronal Control of Bone Remodeling.

Although the brain is well established as a master regulator of homeostasis in peripheral tissues, central regulation of bone mass represents a novel and rapidly expanding field of study. This review examines the current understanding of central regulation of the skeleton, exploring several of the key pathways connecting brain to bone and their implications both in mice and the clinical setting. Our understanding of central bone regulation has largely progressed through examination of skeletal responses downstream of nutrient regulatory pathways in the hypothalamus. Mutations and modulation of these pathways, in cases such as leptin deficiency, induce marked bone phenotypes, which have provided vital insights into central bone regulation. These studies have identified several central neuropeptide pathways that stimulate well-defined changes in bone cell activity in response to changes in energy homeostasis. In addition, this work has highlighted the endocrine nature of the skeleton, revealing a complex cross talk that directly regulates other organ systems. Our laboratory has studied bone-active neuropeptide pathways and defined osteoblast-based actions that recapitulate central pathways linking bone, fat, and glucose homeostasis. Studies of neural control of bone have produced paradigm-shifting changes in our understanding of the skeleton and its relationship with the wider array of organ systems.

Hypothalamic effects of neonatal diet: reversible and only partially leptin dependent.

Early life diet influences metabolic programming, increasing the risk for long-lasting metabolic ill health. Neonatally overfed rats have an early increase in leptin that is maintained long term and is associated with a corresponding elevation in body weight. However, the immediate and long-term effects of neonatal overfeeding on hypothalamic anorexigenic pro-opiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP)/neuropeptide Y (NPY) circuitry, and if these are directly mediated by leptin, have not yet been examined. Here, we examined the effects of neonatal overfeeding on leptin-mediated development of hypothalamic POMC and AgRP/NPY neurons and whether these effects can be normalised by neonatal leptin antagonism in male Wistar rats. Neonatal overfeeding led to an acute (neonatal) resistance of hypothalamic neurons to exogenous leptin, but this leptin resistance was resolved by adulthood. While there were no effects of neonatal overfeeding on POMC immunoreactivity in neonates or adults, the neonatal overfeeding-induced early increase in arcuate nucleus (ARC) AgRP/NPY fibres was reversed by adulthood so that neonatally overfed adults had reduced NPY immunoreactivity in the ARC compared with controls, with no further differences in AgRP immunoreactivity. Short-term neonatal leptin antagonism did not reverse the excess body weight or hyperleptinaemia in the neonatally overfed, suggesting factors other than leptin may also contribute to the phenotype. Our findings show that changes in the availability of leptin during early life period influence the development of hypothalamic connectivity short term, but this is partly resolved by adulthood indicating an adaptation to the metabolic mal-programming effects of neonatal overfeeding.

The wake-promoting drug modafinil stimulates specific hypothalamic circuits to promote adaptive stress responses in an animal model of PTSD.

Pharmacotherapeutic intervention during traumatic memory consolidation has been suggested to alleviate or even prevent the development of posttraumatic stress disorder (PTSD). We recently reported that, in a controlled, prospective animal model, depriving rats of sleep following stress exposure prevents the development of a PTSD-like phenotype. Here, we report that administering the wake-promoting drug modafinil to rats in the aftermath of a stressogenic experience has a similar prophylactic effect, as it significantly reduces the prevalence of PTSD-like phenotype. Moreover, we show that the therapeutic value of modafinil appears to stem from its ability to stimulate a specific circuit within the hypothalamus, which ties together the neuropeptide Y, the orexin system and the HPA axis, to promote adaptive stress responses. The study not only confirms the value of sleep prevention and identifies the mechanism of action of a potential prophylactic treatment after traumatic exposure, but also contributes to understanding mechanisms underlying the shift towards adaptive behavioral response.

The effect of physical exercise on orexigenic and anorexigenic peptides and its role on long-term feeding control.

Over the past decades, life-styles changing have led to exacerbated food and caloric intake and a reduction in energy expenditure. Obesity, main outcome of these changes, increases the risk for developing type 2 diabetes, cardiovascular disease and metabolic syndrome, the leading cause of death in adult and middle age population. Body weight and energy homeostasis are maintained via complex interactions between orexigenic and anorexigenic neuropeptides that take place predominantly in the hypothalamus. Overeating may disrupt the mechanisms of feeding control, by decreasing the expression of proopiomelanocortin (POMC) and α-melanocyte stimulating hormone (α-MSH) and increasing orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP), which leads to a disturbance in appetite control and energy balance. Studies have shown that regular physical exercise might decrease body-weight, food intake and improve the metabolic profile, however until the currently there is no consensus about its effects on the expression of orexigenic/anorexigenic neuropeptides expression. Therefore, we propose that the type and length of physical exercise affect POMC/αMSH and NPY/AgRP systems differently and plays an important role in feeding behavior. Moreover, based on the present reports, we hypothesize that increased POMC/αMSH overcome NPY/AgRP expression decreasing food intake in long term physical exercise and that results in amelioration of several conditions related to overweight and obesity.

Effects of random food deprivation and refeeding on energy metabolism, behavior and hypothalamic neuropeptide expression in Apodemus chevrieri.

Maintaining adaptive control of behavior and physiology is the main strategy used by animals in responding to changes of food resources. To investigate the effects of random food deprivation (FD) and refeeding on energy metabolism and behavior in Apodemus chevrieri, we acclimated adult males to FD for 4weeks, then refed them ad libitum for 4weeks (FD-Re group). During the period of FD, animals were fed ad libitum for 4 randomly assigned days each week, and deprived of food the other 3days. A control group was fed ad libitum for 8weeks. At 4 and 8weeks we measured body mass, thermogenesis, serum leptin levels, body composition, gastrointestinal tract morphology, behavior and hypothalamic neuropeptide expression. At 4weeks, food intake, gastrointestinal mass, neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expressions increased and thermogenesis, leptin levels, pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) expressions decreased in FD compared with controls. FD also showed more resting behavior and less activity than the controls on ad libitum day. There were no differences between FD-Re and controls at 8weeks, indicating significant plasticity. These results suggested that animals can compensate for unpredictable reduction in food availability by increasing food intake and reducing energy expended through thermogenesis and activity. Leptin levels, NPY, AgRP, POMC, and CART mRNA levels may also regulate energy metabolism. Significant plasticity in energy metabolism and behavior was shown by A. chevrieri over a short timescale, allowing them to adapt to food shortages in nutritionally unpredictable environments.

Role of the Paraventricular Nucleus of the Hypothalamus in the Sympathoexcitatory Effects of Leptin.

Leptin binds to receptors in multiple hypothalamic nuclei to increase sympathetic nerve activity; however, the neurocircuitry is unclear. Here, using anesthetized male Sprague-Dawley rats, we investigated the role of the paraventricular nucleus of the hypothalamus. Intracerebroventricular injection of leptin slowly increased lumbar sympathetic nerve activity (LSNA), heart rate, mean arterial pressure, and baroreflex control of LSNA and heart rate. Inhibition of the paraventricular nucleus with muscimol completely reversed leptin's effects. Blockade of paraventricular melanocortin 3/4 receptors with SHU9119 or ionotropic glutamate receptors with kynurenate, alone or together, each partially reversed the effects of leptin, implicating increased activation of glutamate and melanocortin 3/4 receptors. Conversely, although blockade of neuropeptide Y Y1 receptors in the paraventricular nucleus increased LSNA, mean arterial pressure, and heart rate, these responses were prevented by intracerebroventricular or arcuate nucleus injections of leptin, suggesting that, at least in part, leptin also increases sympathetic nerve activity by suppression of tonic neuropeptide Y inhibitory inputs from the arcuate nucleus. Injection of the melanocortin 3/4 receptor agonist melanotan-II into the paraventricular nucleus increased LSNA, mean arterial pressure, and heart rate only after blockade of neuropeptide Y Y1 receptors. Therefore, we conclude that leptin increases LSNA in part via increased glutamatergic and α-melanocyte-stimulating hormone drive of paraventricular sympathoexcitatory neurons, the latter of which requires simultaneous withdrawal of tonic neuropeptide Y inhibition.

fDWI Evaluation of Hypothalamic Appetite Regulation Pathways in Mice Genetically Deficient in Leptin or Neuropeptide Y.

We evaluate the contribution of leptin-dependent anorexigenic pathways and neuropeptide Y (NPY)-dependent orexigenic pathways to the changes in hypothalamic water diffusion parameters observed in vivo by functional diffusion weighted MRI (fDWI). Mice genetically deficient in leptin (B6.V-Lep (ob) /J) or NPY (129S-Npy (tm1Rpa) /J) and the corresponding wild-type controls, were subjected to sequential isocaloric feeding, fasting and recovery regimes. Non-invasive fDWI measurements were performed under these conditions, and complemented with parallel determinations of food and water consumption, respiratory exchange ratio (RER), locomotor activity and endocrine profiles. Control mice showed significant increases in hypothalamic water diffusion parameters upon fasting, returning to normal values in the recovery period. Leptin deficient mice depicted permanently increased water diffusion parameters under all feeding conditions as compared to wild type controls, without important changes upon fasting or recovery. These results paralleled sustained increases in food and water intake, significantly augmented body weight, and decreased RER values or locomotor activity, thus configuring an obese phenotype. NPY-deficient mice showed significantly reduced increases (or even slight decreases) in the water diffusion parameters upon fasting as compared to wild type controls, paralleled by decreased food and water intake during the recovery period. In conclusion, leptin deficiency results in sustained orexigenic stimulation, leading to increased water diffusion parameters, while NPY deficiency lead to reduced orexigenic stimulation and water diffusion parameters. Diffusion changes are proposed to reflect net astrocytic volume changes induced by the balance between the orexigenic and anorexigenic firings of AgRP/NPY and POMC/CART neurons, respectively. Together, our results suggest that fDWI provides an adequate tool to investigate hypothalamic appetite disorders.

Neuropeptide Y stimulates autophagy in hypothalamic neurons.

Aging is characterized by autophagy impairment that contributes to age-related disease aggravation. Moreover, it was described that the hypothalamus is a critical brain area for whole-body aging development and has impact on lifespan. Neuropeptide Y (NPY) is one of the major neuropeptides present in the hypothalamus, and it has been shown that, in aged animals, the hypothalamic NPY levels decrease. Because caloric restriction (CR) delays aging, at least in part, by stimulating autophagy, and also increases hypothalamic NPY levels, we hypothesized that NPY could have a relevant role on autophagy modulation in the hypothalamus. Therefore, the aim of this study was to investigate the role of NPY on autophagy in the hypothalamus. Using both hypothalamic neuronal in vitro models and mice overexpressing NPY in the hypothalamus, we observed that NPY stimulates autophagy in the hypothalamus. Mechanistically, in rodent hypothalamic neurons, NPY increases autophagy through the activation of NPY Y1 and Y5 receptors, and this effect is tightly associated with the concerted activation of PI3K, MEK/ERK, and PKA signaling pathways. Modulation of hypothalamic NPY levels may be considered a potential strategy to produce protective effects against hypothalamic impairments associated with age and to delay aging.

Actions of NPY, and its Y1 and Y2 receptors on pulsatile growth hormone secretion during the fed and fasted state.

The hypothalamic NPY system plays an important role in regulating food intake and energy expenditure. Different biological actions of NPY are assigned to NPY receptor subtypes. Recent studies demonstrated a close relationship between food intake and growth hormone (GH) secretion; however, the mechanism through which endogenous NPY modulates GH release remains unknown. Moreover, conclusive evidence demonstrating a role for NPY and Y-receptors in regulating the endogenous pulsatile release of GH does not exist. We used genetically modified mice (germline Npy, Y1, and Y2 receptor knock-out mice) to assess pulsatile GH secretion under both fed and fasting conditions. Deletion of NPY did not impact fed GH release; however, it reversed the fasting-induced suppression of pulsatile GH secretion. The recovery of GH secretion was associated with a reduction in hypothalamic somatotropin release inhibiting factor (Srif; somatostatin) mRNA expression. Moreover, observations revealed a differential role for Y1 and Y2 receptors, wherein the postsynaptic Y1 receptor suppresses GH secretion in fasting. In contrast, the presynaptic Y2 receptor maintains normal GH output under long-term ad libitum-fed conditions. These data demonstrate an integrated neural circuit that modulates GH release relative to food intake, and provide essential information to address the differential roles of Y1 and Y2 receptors in regulating the release of GH under fed and fasting states.

Transgenic mice overexpressing amyloid precursor protein exhibit early metabolic deficits and a pathologically low leptin state associated with hypothalamic dysfunction in arcuate neuropeptide Y neurons.

Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-ß (Aß) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aß. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aß can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aß accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aß.

Molecular and cellular regulation of hypothalamic melanocortin neurons controlling food intake and energy metabolism.

The brain receives and integrates environmental and metabolic information, transforms these signals into adequate neuronal circuit activities, and generates physiological behaviors to promote energy homeostasis. The responsible neuronal circuitries show lifetime plasticity and guaranty metabolic health and survival. However, this highly evolved organization has become challenged nowadays by chronic overload with nutrients and reduced physical activity, which results in an ever-increasing number of obese individuals worldwide. Research within the last two decades has aimed to decipher the responsible molecular and cellular mechanisms for regulation of the hypothalamic melanocortin neurons, which have a key role in the control of food intake and energy metabolism. This review maps the central connections of the melanocortin system and highlights its global position and divergent character in physiological and pathological metabolic events. Moreover, recently uncovered molecular and cellular processes in hypothalamic neurons and glial cells that drive plastic morphological and physiological changes in these cells, and account for regulation of food intake and energy metabolism, are brought into focus. Finally, potential functional interactions between metabolic disorders and psychiatric diseases are discussed.

Neuropeptide Y regulates the leptin receptors in rat hypothalamic and pituitary explant cultures.

The aim of this work was to investigate whether the expression of leptin receptors (OBR) in the hypothalamic-pituitary (HP) axis is regulated by the orexigenic neuropeptide Y (NPY) during ovulation. To this end, we performed in vitro assays, using cultures of both hypothalamic and anterior pituitary explants from immature rats primed with gonadotropins to induce ovulation. In hypothalamic explants, protein expression of both the long and short OBR isoforms was increased by the presence of NPY at 100-500 ng/ml and at 300-500 ng/ml, respectively. Similarly, in pituitary explants, protein expression of the long isoform was increased between 30 and 300 ng/ml while that of the short isoform was increased only at 300 ng/ml. When both tissues were incubated with NPY and BIBP3226, a specific antagonist of the NPY Y1 receptor subtype, the NPY-induced protein expression was totally reversed by the antagonist at almost every concentration assayed. However, this antagonist was not always capable of blocking the increase caused by the presence of NPY at transcript level. In conclusion, our results indicate that NPY is able to regulate the expression of both the long and the short isoforms of OBR in the HP axis, at least in part, through the NPY Y1 receptor. These results reinforce the fact that NPY and its NPY Y1 receptor play a critical role in reproduction by modulating leptin sensitivity.

Posttraumatic stress disorder and cardiometabolic disease.

The need for addressing posttraumatic stress disorder (PTSD) among combat veterans returning from Afghanistan and Iraq is a growing public health concern. Current PTSD management addresses psychiatric parameters of this condition. However, PTSD is not simply a psychiatric disorder. Traumatic stress increases the risk for inflammation-related somatic diseases and early mortality. The metabolic syndrome reflects the increased health risk associated with combat stress and PTSD. Obesity, dyslipidemia, hypertension, diabetes mellitus, and cardiovascular disease are prevalent among PTSD patients. However, there has been little appreciation for the need to address these somatic PTSD comorbidities. Medical professionals treating this vulnerable population should screen patients for cardiometabolic risk factors and avail themselves of existing preventive diet, exercise, and pharmacologic modalities that will reduce such risk factors and improve overall long-term health outcomes and quality of life. There is the promise that cardiometabolic preventive therapy complementing psychiatric intervention may, in turn, help improve the posttraumatic stress system dysregulation and favorably impact psychiatric and neurologic function. © 2013 S. Karger AG, Basel.

Browning of white adipose tissue: role of hypothalamic signaling.

Two types of fat, white adipose tissue (WAT) and brown adipose tissue (BAT), exist in mammals including adult humans. While WAT stores excess calories and an excessive accumulation of fat causes obesity, BAT dissipates energy to produce heat through nonshivering thermogenesis for protection against cold environments and provides the potential for the development of novel anti-obesity treatments. The hypothalamus plays a central role in the control of energy balance. Specifically, recent observations indicate the importance of the dorsomedial hypothalamus (DMH) in thermoregulation. We have found that the orexigenic neuropeptide Y (NPY) in the DMH has distinct actions in modulating adiposity and BAT thermogenesis. Knockdown of NPY in the DMH elevates the thermogenic activity of classic BAT and promotes the development of brown adipocytes in WAT, leading to increased thermogenesis. These findings identify a novel potential target for combating obesity.

Role of homeobox genes in the hypothalamic development and energy balance.

Homeobox genes contribute to the regionalization, patterning and cell differentiation during embryogenesis and organ development. During mammalian embryonic development, homeobox genes, including orthopedia (Otp), a brain-specific homeobox transcription factor (Bsx) and a thyroid transcription factor-1 (TTF-1), are expressed in the hypothalamus. The genetic ablation of these genes indicated that Otp and TTF-1 are essential for the normal morphological development of the hypothalamus, including the arcuate nucleus (ARC), whereas Bsx is not required. In the adult stage, Bsx and TTF-1 continue to be expressed in the hypothalamus, including the ARC, and serve as transcription factors of neuropeptide Y and agouti-related protein. The expression of hypothalamic Bsx and TTF-1 can be altered by the feeding state and appetite regulatory hormones such as ghrelin and leptin. Although Bsx and TTF-1 are essential for normal feeding behavior in adult mice, they exert different effects on the expression of hypothalamic pro-opiomelanocortin (POMC) and body weight homeostasis. Thus, the hypothalamic homeobox genes may contribute to the dissociation of food intake and body weight via AgRP-POMC neurons.