Herbert Herzog

McGill University, Montréal, Quebec, Canada

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Publications (246)1031.94 Total impact

  • Kim Loh, Herbert Herzog, Yan-Chuan Shi
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    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; · 8.87 Impact Factor
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    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.
    Molecular Metabolism. 01/2015;
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    APHAR 2012; 10/2014
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    Jackie Lau, Herbert Herzog
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    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.
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    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).
    This article is viewable in ResearchGate's enriched format
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    Alzheimer's & dementia: the journal of the Alzheimer's Association; 07/2014
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    ABSTRACT: Objective Orexigenic neuropeptide Y (NPY) and dynorphin (DYN) regulate energy homeostasis. Single NPY or dynorphin deletion reduces food intake or increases fat loss. Future developments of obesity therapeutics involve targeting multiple pathways. We hypothesised that NPY and dynorphin regulate energy homeostasis independently, thus double NPY and dynorphin ablation would result in greater weight and/or fat loss than the absence of NPY or dynorphin alone. Design and Methods We generated single and double NPY and dynorphin knockout mice (NPYΔ, DYNΔ, NPYDYNΔ) and compared body weight, adiposity, feeding behaviour, glucose homeostasis and brown adipose tissue uncoupling protein-1 (UCP-1) expression to wildtype counterparts. Results Body weight and adiposity were significantly increased in NPYDYNΔ, but not in NPYΔ or DYNΔ. This was not due to increased food intake or altered UCP-1 expression, which were not significantly altered in double knockouts. NPYDYNΔ mice demonstrated increased body weight loss after a 24-hour fast, with no effect on serum glucose levels after glucose injection. Conclusions Contrary to the predicted phenotype delineated from single knockouts, double NPY and dynorphin deletion resulted in heavier mice, with increased adiposity, despite no significant changes in food intake or UCP-1 activity. This indicates that combining long-term opioid antagonism with blockade of NPY-ergic systems may not produce anti-obesity effects.
    Neuropeptides 06/2014; · 2.55 Impact Factor
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    ABSTRACT: The potent Y1 receptor antagonist, 1229U91 has an unusual cyclic dimer structure that makes syntheses of analogue series quite challenging. We have examined three new routes to the synthesis of such peptides that has given access to novel structural variants including heterodimeric compounds, ring size variants and labelled conjugates. These compounds, including a fluorescently labelled analogue VIII show potent antagonism that can be utilised in studying Y1 receptor pharmacology.
    Organic & Biomolecular Chemistry 04/2014; · 3.49 Impact Factor
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    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 02/2014; · 6.04 Impact Factor
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    ABSTRACT: Background/Aims: Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with cognitive deficits in rodents. Elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease (AD) patients, and prodynorphin (PDYN) gene polymorphisms might be linked to cognitive function in the elderly. Activation of κ-opioid receptors by dynorphins has been associated with stress-related memory impairments. Interestingly, these peptides can also modulate glutamate neurotransmission and may affect synaptic plasticity underlying memory formation. N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA) ionotropic glutamate receptor levels generally decrease with aging, and their function is impaired in AD. Methods: Here, we compared the impact of aging on ionotropic glutamate receptor levels in the hippocampal formation of wild-type (WT) and Pdyn knock-out (KO) mice. Results: We observed a significant reduction in GluR1 and GluR2 AMPA receptor subunits in the hippocampal formation of 18- to 25-month-old WT mice in comparison with 6-month-old mice. Conversely, the GluR1 protein level was maintained in old Pdyn KO mice, and the NMDA NR2B subunit level was increased by 42% when compared to old WT animals. Conclusions: These results suggest that elevated dynorphin expression occurring during aging and AD may mediate cognitive deficits by altering the glutamatergic system integrity. © 2013 S. Karger AG, Basel.
    Neurodegenerative Diseases 02/2014; 13(2-3):82-85. · 3.41 Impact Factor
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    ABSTRACT: Y-receptors control energy homeostasis, but the role of Npy6 receptors (Npy6r) is largely unknown. Young Npy6r-deficient (Npy6r(-/-)) mice have reduced body weight, lean mass, and adiposity, while older and high-fat-fed Npy6r(-/-) mice have low lean mass with increased adiposity. Npy6r(-/-) mice showed reduced hypothalamic growth hormone releasing hormone (Ghrh) expression and serum insulin-like growth factor-1 (IGF-1) levels relative to WT. This is likely due to impaired vasoactive intestinal peptide (VIP) signaling in the suprachiasmatic nucleus (SCN), where we found Npy6r coexpressed in VIP neurons. Peripheral administration of pancreatic polypeptide (PP) increased Fos expression in the SCN, increased energy expenditure, and reduced food intake in WT, but not Npy6r(-/-), mice. Moreover, intraperitoneal (i.p.) PP injection increased hypothalamic Ghrh mRNA expression and serum IGF-1 levels in WT, but not Npy6r(-/-), mice, an effect blocked by intracerebroventricular (i.c.v.) Vasoactive Intestinal Peptide (VPAC) receptors antagonism. Thus, PP-initiated signaling through Npy6r in VIP neurons regulates the growth hormone axis and body composition.
    Cell metabolism 01/2014; 19(1):58-72. · 17.35 Impact Factor
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    ABSTRACT: Hormone peptide tyrosine-tyrosine (PYY) is secreted into circulation from the gut L-endocrine cells in response to food intake, thus inducing satiation during interaction with its preferred receptor, Y2R. Clinical applications of systemically administered PYY for the purpose of reducing body weight were compromised as a result of the common side effect of visceral sickness. We describe here a novel approach of elevating PYY in saliva in mice, which, although reliably inducing strong anorexic responses, does not cause aversive reactions. The augmentation of salivary PYY activated forebrain areas known to mediate feeding, hunger, and satiation while minimally affecting brainstem chemoreceptor zones triggering nausea. By comparing neuronal pathways activated by systemic versus salivary PYY, we identified a metabolic circuit associated with Y2R-positive cells in the oral cavity and extending through brainstem nuclei into hypothalamic satiety centers. The discovery of this alternative circuit that regulates ingestive behavior without inducing taste aversion may open the possibility of a therapeutic application of PYY for the treatment of obesity via direct oral application.
    Journal of Neuroscience 11/2013; 33(47):18368-18380. · 6.75 Impact Factor
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    ABSTRACT: It has been hypothesized that the peripheral taste system may be modulated in the context of an animal's metabolic state. One purported mechanism for this phenomenon is that circulating gastrointestinal peptides modulate the functioning of the peripheral gustatory system. Recent evidence suggests endocrine signaling in the oral cavity can influence food intake (FI) and satiety. We hypothesized that these hormones may be affecting FI by influencing taste perception. We used immunohistochemistry along with genetic knockout models and the specific reconstitution of peptide YY (PYY) in saliva using gene therapy protocols to identify a role for PYY signaling in taste. We show that PYY is expressed in subsets of taste cells in murine taste buds. We also show, using brief-access testing with PYY knockouts, that PYY signaling modulates responsiveness to bitter-tasting stimuli, as well as to lipid emulsions. We show that salivary PYY augmentation, via viral vector therapy, rescues behavioral responsiveness to a lipid emulsion but not to bitter stimuli and that this response is likely mediated via activation of Y2 receptors localized apically in taste cells. Our findings suggest distinct functions for PYY produced locally in taste cells vs. that circulating systemically.-La Sala, M. S., Hurtado, M. D., Brown, A. R., Bohórquez, D. V., Liddle, R. A., Herzog, H., Zolotukhin, S., Dotson, C. D. Modulation of taste responsiveness by the satiation hormone peptide YY.
    The FASEB Journal 09/2013; · 5.48 Impact Factor
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    ABSTRACT: Immune challenge of mice with Bacille Calmette-Guérin (BCG) has been reported to cause transient weight loss and a behavioural sickness response. While BCG-induced depression involves the kynurenine pathway, weight loss occurs independently of this factor. Since neuropeptide Y (NPY) and peptide YY (PYY) are involved in the regulation of food intake, we hypothesized that they play a role in the BCG-induced weight loss. Male wild-type (WT), PYY knockout (PYY-/-), NPY knockout (NPY-/-) and NPY-/-;PYY-/- double knockout mice were injected with vehicle or BCG (approximately 10(8) CFU per mouse), and their weight, locomotion, exploration and ingestion were recorded for 2 weeks post-treatment. Deletion of PYY and NPY aggravated the BCG-induced loss of body weight, which was most pronounced in NPY-/-;PYY-/- mice (maximum loss: 15 %). The weight loss in NPY-/-;PYY-/- mice did not normalize during the 2 week observation period. BCG suppressed the circadian pattern of locomotion, exploration and food intake. However, these changes took a different time course than the prolonged weight loss caused by BCG in NPY-/-;PYY-/- mice. The effect of BCG to increase circulating interleukin-6 (measured 16 days post-treatment) remained unaltered by knockout of PYY, NPY or NPY plus PYY. These data show that NPY and PYY are both required to protect from the action of BCG-evoked immune challenge to cause prolonged weight loss and disturb energy balance. The findings attest to an important role of NPY and PYY in orchestrating homeostatic reactions to infection and immune stimulation.
    British Journal of Pharmacology 08/2013; · 5.07 Impact Factor
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    ABSTRACT: Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with memory impairments in rats. In human, prodynorphin (Pdyn) gene polymorphisms might be linked to cognitive function in the elderly. Moreover, elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease patients. However, the cellular and molecular processes affected by higher dynorphin levels during aging remain unknown. Using Pdyn(-/-) mice, we observed significant changes in the function and expression of Group 1 metabotropic glutamate receptor (mGluR). Compared with age-matched wild-type (WT) littermates, we found increased expression of mGluR1α and mGluR5 in the hippocampus and cortex of old, but not young, Pdyn(-/-) mice. Increased Group 1 mGluR expression in aged Pdyn(-/-) mice was associated with enhanced mGluR-mediated long-term depression, a form of synaptic plasticity. Notably, whereas aged WT mice developed spatial and recognition memory deficits, aged Pdyn(-/-) mice performed similarly as young mice. Pharmacological treatments with 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide, a positive modulator of mGlu5 receptors, or norbinaltorphimine, an antagonist for dynorphin-targeted κ-opioid receptor, rescued memory in old WT mice. Conversely, mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride impaired spatial memory of old Pdyn(-/-) mice. Intact cognition in aged Pdyn(-/-) mice paralleled with increased expression of Group 1 mGluR-related genes Homer 1a and Arc. Finally, aged Pdyn(-/-) mice displayed less anxiety-related behaviors than age-matched WT mice. Together, our results suggest that elevated Pdyn expression during normal aging reduces mGluR expression and signaling, which in turn impairs cognitive functions and increases anxiety.
    Journal of Neuroscience 07/2013; 33(31):12792-804. · 6.75 Impact Factor
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    ABSTRACT: Objective: PYY3-36 and PP potently inhibit food intake in rodents and humans, however, it is unclear whether they have any synergistic/additive interaction in decreasing food intake. Design and Methods: Fasted WT, Y2(-/-) , Y4(-/-) or Y2Y4(-/-) mice were i.p. administrated with saline, PYY3-36 and/or PP. Results: We demonstrate that combined injection of PYY3-36 and PP reduces food intake in an additive manner. This effect is mediated via Y2 and Y4 receptors, respectively. We demonstrate that PYY3-36 and PP activate distinct neuronal pathways in the hypothalamus, as demonstrated by immunostaining for c-fos, which shows distinct patterns in response to either hormone. After PYY3-36 injection, neurons in the dorsal aspect of the Arc, PVN and DMH are activated with minimal responses seen in the VMH and LHA of WT mice. These effects are absent in Y2(-/-) mice. PP activates preferably the lateral aspect of the Arc, the DMH, VMH and LHA in a Y4 receptor-dependent manner. Importantly, the expression pattern of c-fos immunoreactive neurons induced by combined treatment appears to be the sum of the effects of single treatments rather than a result of synergistic interaction. Conclusions: These findings demonstrate that PYY3-36 and PP activate distinct pathways in the hypothalamus to reduce food intake in an additive manner.
    Obesity 06/2013; 21(12). · 4.39 Impact Factor
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    ABSTRACT: Neuropeptide Y acting via it's Y1 receptor represents a powerful pathway in the control of bone mass. The global or osteoblast-specific Y1 receptor deletion induces pronounced bone anabolic effects in mice. However, the contribution of Y1 receptor deletion in bone repair/healing remained to be clarified. Therefore, in this study we characterized the role of Y1 receptor deletion in fracture healing. Closed tibial fractures were generated in germline (Y1 (-/-) ) and osteoblastic-specific Y1 receptor knockout mice. The progression of tibial repair monitored from 1- until 6-weeks post-fracture demonstrated that in Y1 (-/-) mice there is a delay in fracture repair, as seen by a decrease in bone callus volume and callus strength. Moreover, the histological features included elevated avascular and cartilage area and consequently delayed cartilage removal, and hence impaired union. Interestingly, this delay in bone repair was not related directly to Y1 receptors expressed by mature osteoblasts. These findings suggest that the global absence of the Y1 receptor delays fracture healing, through impairing the early phases of fracture repair to achieve bony union. The data acquired on the role of Y1 receptor signaling disruption in bone regeneration is critical for the design of future therapeutic strategies. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
    Journal of Orthopaedic Research 06/2013; 31(10). · 2.88 Impact Factor

Publication Stats

6k Citations
1,031.94 Total Impact Points

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  • 1995–2014
    • McGill University
      • • Department of Psychiatry
      • • Department of Neurology and Neurosurgery
      Montréal, Quebec, Canada
  • 1992–2014
    • Garvan Institute of Medical Research
      • Cancer Research Program
      Darlinghurst, New South Wales, Australia
  • 2013
    • University of Porto
      • Instituto de Engenharia Biomédica (INEB)
      Oporto, Porto, Portugal
    • Udmurt State University
      Ishewsk, Udmurtiya, Russia
  • 2006–2013
    • Medical University of Graz
      • Institute of Experimental and Clinical Pharmacology
      Graz, Styria, Austria
    • Weill Cornell Medical College
      New York, New York, United States
  • 2011–2012
    • University of Florida
      Gainesville, Florida, United States
  • 2010
    • King's College London
      Londinium, England, United Kingdom
  • 1987–2010
    • University of Innsbruck
      • • Institut für Pharmazie
      • • Institut für Biochemie
      Innsbruck, Tyrol, Austria
  • 2008
    • The Florey Institute of Neuroscience and Mental Health
      Melbourne, Victoria, Australia
  • 2003–2007
    • University of Southampton
      • Clinical Neurosciences
      Southampton, ENG, United Kingdom
  • 2005–2006
    • Karolinska Institutet
      • Institutionen för neurovetenskap
      Solna, Stockholm, Sweden