WO2014174467A1 - Surexpression du neuropeptide y utilisée dans le traitement du vieillissement prématuré - Google Patents

Surexpression du neuropeptide y utilisée dans le traitement du vieillissement prématuré Download PDF

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WO2014174467A1
WO2014174467A1 PCT/IB2014/060951 IB2014060951W WO2014174467A1 WO 2014174467 A1 WO2014174467 A1 WO 2014174467A1 IB 2014060951 W IB2014060951 W IB 2014060951W WO 2014174467 A1 WO2014174467 A1 WO 2014174467A1
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overexpression
mice
npy
zmpste24
hypothalamic
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PCT/IB2014/060951
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Cláudia Margarida GONÇALVES CAVADAS
Luís Fernando MORGADO PEREIRA DE ALMEIDA
Célia Alexandra FERREIRA DE OLIVEIRA AVELEIRA
Clévio David RODRIGUES NÓBREGA
Mariana BOTELHO DA ROCHA
Sara MATIAS CARMO SILVA
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Universidade De Coimbra
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2271—Neuropeptide Y
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57545—Neuropeptide Y
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/025—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a parvovirus

Definitions

  • the present application relates to the neurosciences filed, namely gerontology.
  • Hutchinson- Gilford progeria syndrome is a rare condition with features of premature and accelerated aging in children that show short stature, low body weight, early hair loss, dermal and bone abnormalities, lipodystrophy (lack of subcutaneous fat) , bone and cardiovascular dysfunction, and atherosclerosis, all leading to a shortened lifespan (Hennekam, 2006) .
  • HGPS is primarily caused by a de novo silent mutation within exon 11 of the LMNA gene encoding lamin A (c .1824C>T;p .
  • NF-kB activation during aging has been reported in human and mouse tissues as well as in cells from HGPS patients (Tilstra et al 2012) . More recently, it was also showed that NF-kB is constitutively hyperactive in Zmpste24 ⁇ ⁇ mice tissues (Osorio et al . , 2012) .
  • cytokines and adhesion molecules such as Cxcr2, IL-6, CXCL1, and TNF-alpha are strongly up-regulated in cells and tissues from these mice, likely contributing to the initiation and maintenance of an inflammatory response (Osorio et al 2012) .
  • the hypothalamus is a key brain region crucial for body weight regulation through energy balance regulation (food intake and energy expenditure) .
  • the arcuate nucleus (ARC) neurons of the hypothalamus have a key role in sensing and integrating peripheral signals (i.e, leptin, ghrelin or insulin) (Schwartz et al 2000) .
  • the neuropeptide Y (NPY) is one of the most abundant peptides in the mammalian brain (Silva et al . 2005), especially in the ARC of hypothalamus (Allen et al .
  • ARC neurons include two distinct populations acting together to regulate feeding behavior: the orexigenic NPY/AGRP (Neuropeptide Y/Agouti-Related Protein) neurons and the anorexigenic POMC/CART ( Pro-OpioMelanocortin/Cocaine-and-Amphefamine-
  • Responsive-Transcript neurons.
  • Several conditions (dys ) regulate the function of these two neurons population leading to energy balance (dys ) regulation such as: peripheral hormones (leptin, insulin, adiponectin) , energy status, obesity, caloric restriction, autophagy, and inflammation.
  • peripheral hormones lactin, insulin, adiponectin
  • a decrease in autophagic processes in hypothalamic neurons has been shown to contribute to the metabolic and energy balance dysregulation (Coupe et al, 2012; Quan et al, 2012) .
  • POMC/CART anorexigenic neurons
  • NPY/AgRP inactivate orexigenic neurons
  • cytokine IL-lbeta promotes negative energy balance (Scarlett et al 2008) .
  • ARC may act as an inflammatory amplifier within the CNS, suggesting that neurons in the ARC are likely subject to much higher concentrations of pro-inflammatory cytokines than found in the circulation (Laye et al 1994) .
  • hypothalamic inflammation cytokine increase, microglia activation and astrogliosis induced by acute or chronic systemic inflammation (ex: infection, fever) promotes negative energy balance (decrease in food intake) (Thaler et al 2010) .
  • hypothalamus is also responsible for systemic aging and thus lifespan control.
  • hypothalamus is important for the development of whole-body aging in mice, and hypothalamic microglia acts via IKK-b and NF-kB to contribute to the role of the hypothalamus in aging development.
  • the present application describes the use of a hypothalamic neuropeptide Y overexpression in the treatment of age related pathologies progression.
  • a preferred embodiment of the present invention describes the use of a hypothalamic neuropeptide Y overexpression in therapies against progeroid syndromes, namely the Hutchinson-Gilford progeria syndrome.
  • the age related pathologies progression are Alzheimer's disease, Parkinson's disease or Machado Joseph disease.
  • a preferred embodiment of the present invention describes the use of a hypothalamic neuropeptide Y overexpression in the treatment of genetic or acquired lipodystrophies, such as selective loss of body fat, anorexia and cachexia.
  • the referred anorexia and cachexia are associated with other chronic conditions, for example cancer, rheumatoid arthritis, HIV infection, and chronic lung, heart, or kidney disease.
  • a preferred embodiment of the present invention describes the use of a hypothalamic neuropeptide Y overexpression in the treatment of alopecia, early hair loss, subcutaneous fat loss, bone dysfunction and recognition memory.
  • the present application describes that a sustained increase in the endogenous levels of NPY in the hypothalamus, by using techniques of gene delivery using viral vectors, can block or reverse premature aging in human progeroid syndromes or age related pathologies progression, namely when associated in HGPS .
  • hypothalamic inflammation or dysfunction that are responsible for the changes in various physiological functions regulated by the hypothalamus presented, such as, energy imbalance, low body weight and adiposity, and a premature and accelerated aging.
  • the present application describes the effect the hypothalamic neuropeptide Y (NPY) has in the aging process of Face-1 /Zmpste24 deficient mice, which exhibit multiple defects that phenocopy human accelerated aging processes such as Hutchinson-Gilford progeria syndrome.
  • non-treated-Face-l/Zmpste24 ⁇ _ mice 3 month old gained less weight (18.3 ⁇ 0.8 g) than the NPY-treated Face-1 /Zmpste24 ⁇ / ⁇ (27.7 ⁇ 0.4 g) , which reached a similar body weight to wild-type agematched mice (26.4 ⁇ 0.6 g) .
  • NPY treatment increased subcutaneous fat and decreased the degree of kyphosis and alopecia of Face-1 /Zmpste24 ⁇ / ⁇ mice. Although NPY treatment had no effect on the locomotor activity of these mice, NPY-treated Face-1 /Zmpste24 ⁇ / ⁇ mice showed a better performance in memory tasks than non-treated Face- l/Zmpste24 ⁇ / ⁇ mice.
  • NPY levels induce a beneficial effect, delaying characteristic features of the progeroid phenotype of Face-1 / ' Zmpste24 ⁇ / ⁇ mice, such as body weight loss, lipodystrophy, alopecia and memory impairment. Modulation of NPY levels act as a protective mechanism against the aging process progression and, therefore, provide a putative therapeutic strategy for the treatment of human progeroid syndromes.
  • FIG. 1 Hypothalamic NPY overexpression increases Face- 1 / Zmpste24 ⁇ / ⁇ body weight.
  • A Body weight of 2 and 3 months old Face-1 / Zm.pste24 ⁇ f ⁇ mice and age-matched wild type littermates.
  • B Body weight in male saline injected and AAV-NPY-in ected Face-1/ Zmpste24 ⁇ / ⁇ mice and female saline- injected and AAV-NPY-injected Face-1 / Zmpste24 ⁇ / ⁇ mice.
  • NPY increases adipose tissue in Face-1 / Zmpste24 ⁇ / ⁇ mice.
  • AAV-NPY- injected Face-1 / Zmpste24 ⁇ / ⁇ mice show an increase in both subcutaneous and visceral fat and gonadal fat depots.
  • Figure 4 Effect of NPY treatment in the locomotor activity and memory performance of Face-1 / Zm.pste24 ⁇ f ⁇ mice.
  • A Locomotor horizontal activity of mice was monitored for 30 min in the open field box. Data are expressed as mean ⁇ SEM of total distance travelled (centimeters) .
  • B Spatial recognition memory was tested using the Y maze test. The percentage of time spent in the novel arm during the 8 min of the second trial was determined. Data are expressed as mean ⁇ SEM. *p ⁇ 0.05; **p ⁇ 0.01 (Two-way ANOVA/Bonferroni post-test) .
  • HGPS Hutchinson-Gilford progeria syndrome
  • No therapeutic strategy is known to delay human aging and to treat progeria syndromes progression, cachexia or anorexia .
  • the technical approach used to induce a sustained increase of endogenous neuropeptide Y in the brain region hypothalamus, by using gene delivery approach (viral vectors), in aged animals delays and ameliorates age- related deteriorations, is a new strategy to rescue and ameliorates the age-related deteriorations (such as alopecia, aging-anorexia, subcutaneous fat loss, bone dysfunction, recognition memory) .
  • This methodology is a new therapeutical approach applied to ameliorates age- related deteriorations observed in progeria syndromes, in normal ageing, in aged related pathologies, such as Alzheimer's disease, Parkinson's disease, and Machado Joseph disease, in genetic or acquired lipodystrophies, such as disorders characterized by selective loss of body fat, anorexia and cachexia associated with other chronic conditions, for example cancer, rheumatoid arthritis, HIV infection, and chronic lung, heart, or kidney disease.
  • Zmpst24- null mice a mouse model of premature-aging.
  • Zmpste24 also called FACE-1
  • FACE-1 is a metalloproteinase involved in the maturation of lamin A, an essential component of the nuclear envelope.
  • Zmpste24- deficient mice exhibit multiple defects that phenocopy human accelerated aging processes such as Hutchinson- Gilford progeria syndrome.
  • Zmpste24-deficient mice exhibit retarded growth, alopecia, micrognathia, dental abnormalities, lipodystrophy, muscular dystrophy, cardiomyopathy and osteoporosis. Most Zmpste24- mice died prematurely, having an average lifespan of 5-6 months.
  • Anorexia and cachexia are common complications of aging and other chronic conditions including cancer, rheumatoid arthritis, HIV infection, and chronic lung, heart, or kidney disease.
  • An increase of endogenous hypothalamic NPY, that stimulates food intake and adiposity, is a putative relevant strategy to be applied in anorexia and cachexia.
  • the Hutchinson-Gilford progeria syndrome is characterized by clinical features mimicking physiological aging at an early age, provide insights into the mechanisms of natural aging.
  • the following experiments show that the sustained increase of hypothalamic NPY, by using gene delivery approach, in mouse model ( Zmpste24-deficient mice) of human accelerated aging ameliorates age-related deteriorations and has applicability in other disorders.
  • the increase of hypothalamic NPY is an effective therapeutic application against alopecia, early hair loss, subcutaneous fat loss, bone dysfunction and recognition memory .
  • hypothalamic NPY overexpression rescues body weight loss in a mouse model of human premature aging
  • Face-l/Zmpste24 ⁇ ⁇ mice were Face-l/Zmpste24-deficient mice were generated and genotyped as described before (Pendas et al . , 2002) and kindly provided by Carlos Lopez-Otin (University of Oviedo, Spain) . Mice were housed two per cage under a 12 h light/dark cycle in a temperature/humidity controlled room with ad libitum access to water and a standard chow diet. Face-l/Zmpste24 ⁇ ⁇ mice
  • control group saline-in ected Face-l/Zmpste24 ⁇ ⁇
  • NPY overexpressing group AAV-NPY-in ected Face-l/Zmpste24 ⁇ ⁇
  • Recombinant AAV particles were generated as described before ( Sousa-Ferreira et al . , 2011) Adeno-associated virus
  • AAV adenosarcoma -1/2 chimerical capsids, containing recombinant plasmids with NPY cDNA under a neuronal specific promoter, were injected in mice hypothalamic arcuate nucleus (ARC), in order to induce constitutive and sustained NPY overexpression .
  • Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine (100 mg/kg and 10 mg/kg, respectively) and placed on a stereotaxic frame. Injection was performed bilaterally into the ARC: 0,5 mm lateral to the middle line, 1.65 mm posterior to the bregma and -5.8 mm ventral to the brain surface.
  • the control group received sterile saline in a final volume of 1.5 l/side.
  • the NPY overexpressing group received 3.6xl09v. g. /side of AAV-hSyn-NPY, in a final volume of 1.5 ⁇ 1/ side. Injection was performed at a rate of 0.5 ⁇ /min with a 10 ml- Hamilton syringe attached to an automatic Pump Controller (WPI) .
  • WPI automatic Pump Controller
  • ARC was defined using The Paxino's Mouse Brain Atlas and AAV infection was anatomically localized by EGFP-expressing neurons in the ARC. Mice were housed in pairs and monitored after AAV injections. Since NPY is a potent orexigenic neuropeptide, to avoid major weight changes, AAV-NPY injected mice were pair-fed (given the same amount of food that AAV-GFP injected mice ate, daily - approximately 4-5 g/day) . Each mouse was weighted every other day, for weight control.
  • Fig.l shows that overexpressing NPY in the hypothalamus induces a sustained body weight gain in Face- l/Zmpste24 ⁇ ⁇ mice.
  • Face-l/Zmpste24 ⁇ ⁇ mice are smaller and have a lower body weight (15.4 ⁇ 0.3 g) compared to age-matched wild type ( Zmpste24+/+ ) littermates (22.8 ⁇ 0.4 g) .
  • hypothalamic NPY overexpression rescues body weight loss in this mouse model of human premature aging.
  • hypothalamic NPY overexpression increases fat depots, ameliorating lipodystrophy, in a mouse model of human premature aging
  • Adipose tissue is reduced in Face-l/Zmpste24 ⁇ ⁇ mice.
  • Fig.2 shows that hypothalamic NPY overexpression (as described in example 1) increases adipose tissue mass in Face-l/Zmpste24 ⁇ ⁇ mice.
  • AAV-NPY-inj ected Face-l/Zmpste24 ⁇ ⁇ mice have an increase in both subcutaneous and visceral fat and also gonadal fat depots increase.
  • hypothalamic NPY overexpression decreases lipodistrophy in a mouse model of human premature aging.
  • hypothalamic NPY overexpression delays alopecia/fur loss in a mouse model of human premature aging
  • the Fig.3 shows that hypothalamic NPY overexpression decreases/delays fur loss in Face-1/Zmpste24-/ mice.
  • Fur loss was assessed twice a week and quantified by a semi ⁇ quantitative ranking score system on a scale of 0 to 3: 0 for absent fur loss, 1 for mild fur loss, 2 for moderate fur loss, and 3 for marked fur loss.
  • the results were summed up for each animal group after 30, 60, 90 and 120 days upon hypothalamic injections and the frequency of each ranking score was calculated and plotted on a bar chart.
  • Both salinein ected Face-l/Zmpste24 ⁇ ⁇ and AAV-NPY-in ected Face-l/Zmpste24 ⁇ ⁇ mice loose fur, however alopecia is more evident in control mice at all time points evaluated.
  • hypothalamic NPY overexpression delays alopecia in a mouse model of human premature aging.
  • hypothalamic NPY overexpression reduces bone fractures risk, the degree of kyphosis of the spine and muscular dystrophy in the mouse model of human premature aging
  • Face-l/Zmpste24 ⁇ ⁇ mice phenotype is characterized by osteoporosis, muscular dystrophy, kyphosis of the spine, a hunched position and scoliosis, reduction of cortical and trabecular bone volumes and develop multiple spontaneous bone fractures particularly ribs fractures.
  • Face-l/Zmpste24 ⁇ ⁇ mice with hypothalamic NPY overexpression showed less muscular dystrophy with an increased lower limb muscle mass, compared to saline-injected mice.
  • Face- 1/Zmpste24 mice with hypothalamic NPY overexpression have lower degree of kyphosis of the spine in (resulting in a normal posture) , a reduced number of rib fractures (demonstrated by the reduced number of hypertrophic calluses at the costovertebral junctions) when compared with saline-in ected Face-l/Zmpste24 ⁇ ⁇ mice.
  • hypothalamic NPY overexpression reduces bone fractures risk, the degree of kyphosis of the spine, and muscular dystrophy in the mouse model of human premature aging .
  • hypothalamic NPY overexpression improves spatial recognition memory in a mouse model of human premature aging
  • mice locomotor horizontal activity For the assessment of mice locomotor horizontal activity, open field tests were performed. Mice were acclimated into test room for 60 min. Mice were placed in a 50x50 cm arena with 50 cm high walls and their movement activity was recorded for 30 min using the Acti-Track System (Panlab, Barcelona, Spain) . Mean values for total distance travelled were calculated. To assess the memory/cognitive performance in mice, a two-trial Y-maze test designed to measure spatial recognition memory was performed (Dellu et al . 1997) . The three arms of the Y-maze were randomly designated: start arm, in which rats started to explore (always open) , novel arm, which was blocked during the first trial, but open during the second trial, and other arm (always open) .
  • the Y-maze task consisted of two trials separated by an inter-trial interval (ITI) of 2 h.
  • ITI inter-trial interval
  • mice were allowed to explore only two arms (start and other arm), with the third arm (novel arm) closed.
  • the mice were placed back in the same starting arm, with free access to all three arms for 8 min.
  • the number of entries and time spent in each arm was determined. Data was expressed as percentage of total entries during the 8 min. Data was also expressed as percentage of time spent in each time for the total 8 min.
  • Fig. 4 shows that hypothalamic NPY overexpression increases memory performance of Face- l/Zmpste24 ⁇ ⁇ mice but does not alter the locomotor activity of these mice.
  • salinein ected Face-l/Zmpste24 ⁇ ⁇ mice show an abnormal posture characterized by a hunched position and scoliosis and mice began to splay their hind paws while walking.
  • AAV-NPY- in ected Face-1/Zmpste24 ⁇ 7 ⁇ mice that have increased levels of hypothalamic NPY, showed a normal posture, no alterations were found in the locomotor activity of these mice compared to saline-in ected Face- 1/Zmpste24 ⁇ 7 ⁇ mice.
  • AAV-NPY Face-1/Zmpste24 ⁇ 7 ⁇ mice have a better performance in the Y maze test.
  • This methodology of increasing the endogenous hypothalamic NPY, by using viral vectors, is a new technological approach applied to progeria syndromes (Hutchinson-Gilford syndrome; Werner Syndrome) , to deteriorations associated to normal ageing, to aged related pathologies (such as Alzheimer's disease; Parkinson's disease; Machado Joseph disease) , to genetic or acquired lipodystrophies (disorders characterized by the loss of body fat) , and cancer
  • an increase of endogenous hypothalamic NPY by the methodology described here, by stimulating food intake and adiposity is a therapeutics strategy to be applied in anorexia and cachexia associated with aging and with other chronic conditions (i.e: cancer, rheumatoid arthritis, HIV infection, and chronic lung, heart, or kidney disease) .
  • the present embodiments are not in any way limited to the embodiments described in this document and a person with average knowledge in the field will be able to predict many possible changes to it without deviating from

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Abstract

La présente invention concerne l'effet thérapeutique de la surexpression du neuropeptide Y hypothalamique contre la progression de pathologies liées au vieillissement et les syndromes progéroïdes, à savoir le syndrome progéroïde de Hutchinson-Gilford. L'invention concerne également l'utilisation de la surexpression du neuropeptide Y hypothalamique dans le traitement de lipodystrophies génétiques ou acquises, telles que la perte sélective de graisse corporelle, l'anorexie et la cachexie, ou dans le traitement de l'alopécie, de la perte de cheveux précoce, de la perte de graisse sous-cutanée, des troubles osseux et de la mémoire de reconnaissance.
PCT/IB2014/060951 2013-04-23 2014-04-23 Surexpression du neuropeptide y utilisée dans le traitement du vieillissement prématuré WO2014174467A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2005037211A2 (fr) * 2003-10-14 2005-04-28 Neurologix Research, Inc. Methodes et compositions pour le traitement de maladies neurologiques
WO2010071454A1 (fr) * 2008-12-17 2010-06-24 Auckland Uniservices Limited Vecteurs viraux adéno-associés et leurs utilisations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4891357A (en) * 1985-02-11 1990-01-02 University Of Florida Methods and compositions for stimulation of appetite
WO2005037211A2 (fr) * 2003-10-14 2005-04-28 Neurologix Research, Inc. Methodes et compositions pour le traitement de maladies neurologiques
WO2010071454A1 (fr) * 2008-12-17 2010-06-24 Auckland Uniservices Limited Vecteurs viraux adéno-associés et leurs utilisations

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Title
F. G. OSORIO ET AL: "Nuclear lamina defects cause ATM-dependent NF- B activation and link accelerated aging to a systemic inflammatory response", GENES & DEVELOPMENT, vol. 26, no. 20, 26 September 2012 (2012-09-26), pages 2311 - 2324, XP055133194, ISSN: 0890-9369, DOI: 10.1101/gad.197954.112 *
FENPING ZHENG ET AL: "Overexpression of Neuropeptide Y in the Dorsomedial Hypothalamus Causes Hyperphagia and Obesity in Rats", OBESITY, vol. 21, no. 6, 21 March 2013 (2013-03-21), pages 1086 - 1092, XP055132936, ISSN: 1930-7381, DOI: 10.1002/oby.20467 *
JEREMY S. TILSTRA ET AL: "NF-[kappa]B inhibition delays DNA damage-induced senescence and aging in mice", JOURNAL OF CLINICAL INVESTIGATION, vol. 122, no. 7, 2 July 2012 (2012-07-02), pages 2601 - 2612, XP055133186, ISSN: 0021-9738, DOI: 10.1172/JCI45785 *
L. YANG ET AL: "Role of Dorsomedial Hypothalamic Neuropeptide Y in Modulating Food Intake and Energy Balance", JOURNAL OF NEUROSCIENCE, vol. 29, no. 1, 7 January 2009 (2009-01-07), pages 179 - 190, XP055133008, ISSN: 0270-6474, DOI: 10.1523/JNEUROSCI.4379-08.2009 *

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