Herbert Herzog

University of Sydney, Sydney, New South Wales, Australia

Are you Herbert Herzog?

Claim your profile

Publications (262)1081.46 Total impact

  • Source
    J Wood · D Verma · G Lach · P Bonaventure · H Herzog · G Sperk · R O Tasan
    [Show abstract] [Hide abstract]
    ABSTRACT: The amygdala is essential for generating emotional-affective behaviors. It consists of several nuclei with highly selective, elaborate functions. In particular, the central extended amygdala, consisting of the central amygdala (CEA) and the bed nucleus of the stria terminalis (BNST) is an essential component actively controlling efferent connections to downstream effectors like hypothalamus and brain stem. Both, CEA and BNST contain high amounts of different neuropeptides that significantly contribute to synaptic transmission. Among these, neuropeptide Y (NPY) has emerged as an important anxiolytic and fear-reducing neuromodulator. Here, we characterized the expression, connectivity and electrophysiological function of NPY and Y2 receptors within the CEA. We identified several NPY-expressing neuronal populations, including somatostatin- and calretinin-expressing neurons. Furthermore, in the main intercalated nucleus, NPY is expressed primarily in dopamine D1 receptor-expressing neurons but also in interspersed somatostatin-expressing neurons. Interestingly, NPY neurons did not co-localize with the Y2 receptor. Retrograde tract tracing experiments revealed that NPY neurons reciprocally connect the CEA and BNST. Functionally, the Y2 receptor agonist PYY3-36, reduced both, inhibitory as well as excitatory synaptic transmission in the centromedial amygdala (CEm). However, we also provide evidence that lack of NPY or Y2 receptors results in increased GABA release specifically at inhibitory synapses in the CEm. Taken together, our findings suggest that NPY expressed by distinct populations of neurons can modulate afferent and efferent projections of the CEA via presynaptic Y2 receptors located at inhibitory and excitatory synapses.
    Brain Structure and Function 09/2015; DOI:10.1007/s00429-015-1107-7 · 5.62 Impact Factor
  • Neuropeptides 09/2015; DOI:10.1016/j.npep.2015.09.007 · 2.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The amygdala is fundamental for associative fear and extinction learning. Recently, also the central nucleus of the amygdala (CEA) has emerged as a site of plasticity actively controlling efferent connections to downstream effectors brain areas. Although synaptic transmission is primarily mediated by glutamate and GABA, neuropeptides critically influence the overall response. While neuropeptide Y (NPY) acting via postsynaptic Y1 receptors exerts an important anxiolytic and fear-reducing action, the role of the predominantly presynaptic Y2 receptors is less defined. To investigate the role of Y2 receptors in the CEA we employed viral-vector mediated over-expression of the Y2 selective agonist NPY3-36 in fear conditioning and extinction experiments. NPY3-36 over-expression in the CEA resulted in reduced fear expression during fear acquisition and recall. Interestingly, this effect was blocked by intraperitoneal injection of a brain-penetrant Y2 receptor antagonist. Furthermore, over-expression of NPY3-36 in the CEA also reduced fear expression during fear extinction of CS-induced but not context-related fear. Again, fear extinction appeared delayed by peripheral injection of a Y2 receptor antagonist JNJ-31020028. Importantly, mice with over-expression of NPY3-36 in the CEA also displayed reduced spontaneous recovery and reinstatement, suggesting that Y2 receptor activation supports a permanent suppression of fear. Local deletion of Y2 receptors in the CEA, on the other hand, increased the expression of CS-induced freezing during fear recall and fear extinction. Thus, NPY inhibits fear learning and promotes cued extinction by reducing fear expression also via activation of presynaptic Y2 receptors on CEA neurons. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 08/2015; 99. DOI:10.1016/j.neuropharm.2015.08.038 · 5.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The TGF-b superfamily cytokine MIC-1/GDF15 circulates in the blood of healthy humans. Its levels rise substantially in cancer and other diseases and this may sometimes lead to development of an anorexia/cachexia syndrome. This is mediated by a direct action of MIC-1/GDF15 on feeding centres in the hypothalamus and brainstem. More recent studies in germline gene deleted mice also suggest that this cytokine may play a role in physiological regulation of energy homeostasis. To further characterize the role of MIC-1/GDF15 in physiological regulation of energy homeostasis in man, we have examined diurnal and food associated variation in serum levels and whether variation in circulating levels relate to BMI in human monozygotic twin pairs. We found that the within twin pair differences in serum MIC-1/GDF15 levels were significantly correlated with within twin pair differences in BMI, suggesting a role for MIC-1/GDF15 in the regulation of energy balance in man. MIC-1/GDF15 serum levels altered slightly in response to a meal, but comparison with variation its serum levels over a 24hour period suggested that these changes are likely to be due to bimodal diurnal variation which can alter serum MIC-1/GDF15 levels by about plus or minus 10% from the mesor. The lack of a rapid and substantial postprandial increase in MIC-1/GDF15 serum levels suggests that MIC1/GDF15 is unlikely to act as a satiety factor. Taken together, our findings suggest that MIC-1/GDF15 may be a physiological regulator of energy homeostasis in man, most probably due to actions on long-term regulation of energy homeostasis.
    PLoS ONE 07/2015; 10(7):e0133362. DOI:10.1371/journal.pone.0133362 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prader-Willi syndrome (PWS) is the predominant genetic cause of obesity in humans and is associated with several behavioural phenotypes such as altered motoric function, reduced activity, and learning disabilities. It can include mood instability and, in some cases, psychotic episodes. Recently, the Snord116 gene has been associated with the development of PWS, however, it's contribution to the behavioural aspects of the disease are unknown. Here we show that male and female mice lacking Snord116 on both alleles exhibit normal motor behaviours and exploration but do display task-dependent alterations to locomotion and anxiety-related behaviours. Sociability is well developed in Snord116 deficient mice as are social recognition memory, spatial working memory, and fear-associated behaviours. No sex-specific effects were found. In conclusion, the biallelic Snord116 deficiency mouse model exhibits particular endophenotypes with some relevance to PWS, suggesting partial face validity for the syndrome. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Neuropeptides 07/2015; DOI:10.1016/j.npep.2015.06.009 · 2.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Insulin secretion is tightly controlled through coordinated actions of a number of systemic and local factors. Peptide YY (PYY) is expressed in alpha cells of the islet but its role in control of islet function such as insulin release is not clear. In this study, we generated a transgenic mouse model (Pyy(tg/+)/Rip-Cre) overexpressing the Pyy gene under the control of the rat insulin 2 (Ins2) gene promoter and assessed the impact of islet-released PYY on beta cell function, insulin release and glucose homeostasis in mice. Our results show that upregulation of PYY in islet beta-cells leads to an increase in serum insulin levels as well as improved glucose tolerance. Interestingly, PYY overproducing mice show increased lean mass and reduced fat mass with no significant changes in food intake or body weight. Energy expenditure is also increased accompanied by increased RER. Mechanistically, the enhanced in insulin levels and improved in glucose tolerance are primarily due to increased beta cell mass and secretion. This is associated with alterations in the expression of genes important for beta cell proliferation and function as well as the maintenance of the beta cell phenotype. Taken together, these data demonstrate that pancreatic islet-derived PYY plays an important role in controlling glucose homeostasis through the modulation of beta cell mass and function.
    Endocrinology 06/2015; 156(9):en20151168. DOI:10.1210/en.2015-1168 · 4.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Emotions control evolutionarily conserved behavior that is central to survival in a natural environment. Imbalance within emotional circuitries, however, may result in malfunction and manifestation of anxiety disorders. Thus, a better understanding of emotional processes and in particular the interaction of the networks involved is of considerable clinical relevance. Although neurobiological substrates of emotionally controlled circuitries are increasingly evident their mutual influences are not. To investigate interactions between hunger and fear, we performed Pavlovian fear conditioning in fasted wildtype mice and in mice with genetic modification of a feeding-related gene. Furthermore we analyzed in these mice the electrophysiological microcircuits underlying fear extinction. Short-term fasting before fear acquisition specifically impaired long-term fear memory, while fasting before fear extinction facilitated extinction learning. Furthermore, genetic deletion of the Y4 receptor reduced appetite and completely impaired fear extinction, a phenomenon that was rescued by fasting. A marked increase in feed-forward inhibition between the basolateral and central amygdala has been proposed as a synaptic correlate of fear extinction and involves activation of the medial intercalated cells. This form of plasticity was lost in Y4KO mice. Fasting before extinction learning, however, resulted in specific activation of the medial intercalated neurons and re-established the enhancement of feed-forward inhibition in this amygdala microcircuit of Y4KO mice. Hence, consolidation of fear and extinction memories is differentially regulated by hunger suggesting that fasting and modification of feeding-related genes could augment the effectiveness of exposure therapy and provide novel drug-targets for treatment of anxiety disorders.Neuropsychopharmacology accepted article preview online, 11 June 2015. doi:10.1038/npp.2015.163.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.163 · 7.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Brown adipose tissue (BAT), largely controlled by the sympathetic nervous system (SNS), has the ability to dissipate energy in the form of heat through the actions of uncoupling protein-1 (UCP-1), thereby critically influencing energy expenditure. Besides BAT, the SNS also strongly influences bone, and recent studies have demonstrated a positive correlation between BAT activity and bone mass, albeit the interactions between BAT and bone remain unclear. Here we show that UCP-1 is critical for protecting bone mass in mice under conditions of permanent mild cold stress for this species (22°C). UCP-1(-/-) mice housed at 22°C showed significantly lower cancellous bone mass, with lower trabecular number and thickness, a lower bone formation rate and mineralising surface, but unaltered osteoclast number, compared to wild type mice housed at the same temperature. UCP-1(-/-) mice also displayed shorter femurs than wild types, with smaller cortical periosteal and endocortical perimeters. Importantly, these altered bone phenotypes were not observed when UCP-1(-/-) and wild type mice were housed in thermo-neutral conditions (29°C), indicating a UCP-1 dependent support of bone mass and bone formation at the lower temperature. Furthermore, at 22°C UCP-1(-/-) mice showed elevated hypothalamic expression of neuropeptide Y (NPY) relative to wild type, which is consistent with the lower bone formation and mass of UCP-1(-/-) mice at 22°C caused by the catabolic effects of hypothalamic NPY-induced SNS modulation. The results from this study suggest that during mild cold stress, when BAT-dependent thermogenesis is required, UCP-1 activity exerts a protective effect on bone mass possibly through alterations in central NPY pathways known to regulate SNS activity. Copyright © 2015. Published by Elsevier Inc.
    Bone 06/2015; DOI:10.1016/j.bone.2015.05.037 · 3.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Individuals with Prader-Willi syndrome (PWS) are commonly restricted to 60-75% of height-appropriate calorie intake because they rapidly become obese on a normal diet. This study measured changes in energy expenditure, glucose and lipid homeostasis, and metabolic flexibility in response to a meal in PWS adults. 11 adults with PWS were compared with 12 adiposity-matched and 10 lean subjects. Indirect calorimetry was conducted at baseline and 210 min after a standardized 600 kCal breakfast to assess energy expenditure and substrate utilization. Circulating glucose, insulin, C-peptide, glucagon, nonesterified fatty acids, and triglycerides were measured up to 240 min. Insulin sensitivity and insulin secretion rate were assessed by HOMA-IR and C-peptide deconvolution, respectively. Body composition was determined by dual-energy X-ray absorptiometry. The PWS group had lower lean mass than the obesity control group. Corrected for lean mass, there were no differences between the PWS and obesity groups in resting metabolic rate or metabolic flexibility. Total and abdominal fat mass, insulin sensitivity, and insulin secretion rate were also similar between these groups. This study did not detect an intrinsic metabolic defect in individuals with PWS. Rather, lower lean mass, combined with lower physical activity, may contribute to weight gain on an apparent weight-maintenance diet. © 2015 The Obesity Society.
    Obesity 05/2015; 23(6). DOI:10.1002/oby.21041 · 3.73 Impact Factor
  • Y Qi · K Inoue · M Fu · A Inui · H Herzog
    [Show abstract] [Hide abstract]
    ABSTRACT: Ghrelin is known to be a critical stimulator of feeding behavior mainly via actions in the hypothalamus. However, its functional contribution to the control of energy homeostasis under chronic elevated conditions is unknown. Here we show that overproduction of ghrelin via an AAV viral delivery system in the hypothalamus leads to an increase in food intake associated with increases in body weight. However, this increase in food intake is only temporary and is diminished and no longer significant after 3 weeks. Analysis of brain sections of mice 6 weeks after AAV-ghrelin virus injection demonstrates unaltered neuropeptide Y levels but strongly up-regulated pro-opiomelanocortin levels indicating that a compensatory mechanism has been activated to counter regulate the feeding stimulatory actions of ghrelin. This demonstrates that control mechanism exists that is activated under conditions of prolonged high ghrelin levels, which could potentially be utilized to control feeding and the development of obesity. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Neuropeptides 03/2015; 50. DOI:10.1016/j.npep.2015.02.002 · 2.64 Impact Factor
  • Kim Loh · Herbert Herzog · Yan-Chuan Shi
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity develops when energy intake exceeds energy expenditure over time. Numerous neurotransmitters, hormones, and factors have been implicated to coordinately control energy homeostasis, centrally and peripherally. However, the neuropeptide Y (NPY) system has emerged as the one with the most critical functions in this process. While NPY centrally promotes feeding and reduces energy expenditure, peptide YY (PYY) and pancreatic polypeptide (PP), the other family members, mediate satiety. Importantly, recent research has uncovered additional functions for these peptides that go beyond the simple feeding/satiety circuits and indicate a more extensive function in controlling energy homeostasis. In this review, we will discuss the actions of the NPY system in the regulation of energy balance, with a particular focus on energy expenditure. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Trends in Endocrinology and Metabolism 02/2015; 26(3). DOI:10.1016/j.tem.2015.01.003 · 9.39 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The skeleton has recently emerged as an additional player in the control of whole-body glucose metabolism; however, the mechanism behind this is not clear. Here we employ mice lacking neuropeptide Y, Y1 receptors solely in cells of the early osteoblastic lineage (Y1f3.6Cre), to examine the role of osteoblastic Y1 signalling in glycaemic control. Y1f3.6Cre mice not only have a high bone mass phenotype, but importantly also display altered glucose homeostasis; significantly decreased pancreas weight, islet number and pancreatic insulin content leading to elevated glucose levels and reduced glucose tolerance, but with no effect on insulin induced glucose clearance. The reduced glucose tolerance and elevated bone mass was corrected in Y1f3.6Cre mice by bone marrow transplant from wildtype animals, reinforcing the osteoblastic nature of this pathway. Importantly, when fed a high fat diet, Y1f3.6Cre mice, while equally gaining body weight and fat mass compared to controls, showed significantly improved glucose and insulin tolerance. Conditioned media from Y1f3.6Cre osteoblastic cultures was unable to stimulate insulin expression in MIN6 cells compared to conditioned media from wildtype osteoblast, indicating a direct signalling pathway. Importantly, osteocalcin a secreted osteoblastic factor previously identified as a modulator of insulin secretion was not altered in the Y1f3.6Cre model. This study identifies the existence of other osteoblast-derived regulators of pancreas function and insulin secretion and illustrates a mechanism by which NPY signalling in bone tissue is capable of regulating pancreatic function and glucose homeostasis.
    Molecular Metabolism 01/2015; 4(3). DOI:10.1016/j.molmet.2014.12.010
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The use of the click reaction for the introduction of conjugate groups such as affinity or fluorescent labels to a peptide for the study of peptide biochemistry and pharmacology is widespread. However, the nature and location of substituted 1,2,3-triazoles in peptide sequences may markedly impact conformation or binding as compared to native sequences. We have examined the preparation and application of propargyloxyproline (Pop) residues as a precursor to such peptide conjugates. Pop residues are available in a range of regio- and stereoisomers from hydroxyproline precursors and readily prepared in Fmoc-protected form. They can be incorporated routinely in peptide synthesis and broadly retain the conformational properties of parent proline containing peptides. This is exemplified by the preparation of biotin- and fluorophore-labelled peptides derived from linear and cyclic peptides.
    Australian Journal of Chemistry 01/2015; 'Just Accepted'. · 1.56 Impact Factor
  • Source
  • Source
  • Source
    Piyush Jain · Ahmed Hassan · Herbert Herzog · Peter Holzer
    APHAR 2012; 10/2014
  • Source
    Jackie Lau · Herbert Herzog
    [Show abstract] [Hide abstract]
    ABSTRACT: The cocaine- and amphetamine-regulated transcript (CART) has been the subject of significant interest for over a decade. Work to decipher the detailed mechanism of CART function has been hampered by the lack of specific pharmacological tools like antagonists and the absence of a specific CART receptor(s). However, extensive research has been devoted to elucidate the role of the CART peptide and it is now evident that CART is a key neurotransmitter and hormone involved in the regulation of diverse biological processes, including food intake, maintenance of body weight, reward and addiction, stress response, psychostimulant effects and endocrine functions (Rogge et al., 2008; Subhedar et al., 2014). In this review, we focus on knowledge gained on CART's role in controlling appetite and energy homeostasis, and also address certain species differences between rodents and humans.
    Frontiers in Neuroscience 10/2014; 8:313. DOI:10.3389/fnins.2014.00313 · 3.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic stress and depression have adverse consequences on many organ systems; including the skeleton, but the mechanisms underlying the stress-induced bone loss remain unclear. Here we demonstrate that neuropeptide Y (NPY), centrally and peripherally, plays a critical role in protecting against stress-induced bone loss. Mice lacking the anxiolytic factor NPY exhibit more anxious behavior and elevated corticosterone levels. Additionally, following a 6 week restraint, or cold stress-protocol, Npy null mice Exhibit 3-fold greater bone loss compared to wild type, due to suppression of osteoblast activity. This stress-protective NPY pathway acts specifically through Y2 receptors. Centrally, Y2 receptors suppress corticotropin-releasing factor expression and inhibit activation of noradrenergic neurons in the paraventricular nucleus. In the periphery, they act to control noradrenaline release from sympathetic neurons. Specific deletion of arcuate Y2 receptors recapitulates the Npy null stress response, coincident with elevated serum noradrenaline. Importantly, specific re-introduction of NPY solely in noradrenergic neurons of otherwise Npy null mice, blocks the increase in circulating noradrenaline and the stress-induced bone loss. Thus, NPY protects against excessive stress-induced bone loss, through Y2 receptor-mediated modulation of central and peripheral noradrenergic neurons. © 2014 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 10/2014; 29(10). DOI:10.1002/jbmr.2205 · 6.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuropeptide Y (NPY) and noradrenaline are commonly co-expressed in sympathetic neurons. Both are key regulators of energy homeostasis and critical for stress-coping. However, little is known about the specific function of NPY in the catechoalminergic system in these regulations. Here we show that mice with NPY expression only in the noradrenergic and adrenergic cells of the catecholaminergic system (catNPY) exhibited exacerbated diet-induced obesity, lower body and brown adipose tissue temperatures compared to WT and NPY-/- mice under a HFD. Furthermore, chronic stress increased adiposity and serum corticosterone level in WT but not NPY-/- mice. Re-introducing NPY specifically to the catecholaninergic system in catNPY mice restored stress responsiveness associated with increased respiratory exchange ratio and decreased liver pACC to tACC ratio. These results demonstrate catecholaminergic NPY signalling is critical in mediating diet- and chronic stress-induced fat gain via effects on diet-induced thermogenesis and stress-induced increases in corticosterone levels and lipogenic capacity.
    Molecular Metabolism 08/2014; 3(5). DOI:10.1016/j.molmet.2014.05.001
  • Source
    Alzheimer's & dementia: the journal of the Alzheimer's Association; 07/2014

Publication Stats

7k Citations
1,081.46 Total Impact Points

Top Journals


  • 2015
    • University of Sydney
      • Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders
      Sydney, New South Wales, Australia
  • 1993–2015
    • Garvan Institute of Medical Research
      • Cancer Research Program
      Darlinghurst, New South Wales, Australia
  • 2013–2014
    • University of New South Wales
      • Faculty of Medicine
      Kensington, New South Wales, Australia
  • 2005–2009
    • Medical University of Graz
      • Institute of Experimental and Clinical Pharmacology
      Gratz, Styria, Austria
  • 1987–1995
    • University of Innsbruck
      • Institute of Biochemistry
      Innsbruck, Tyrol, Austria