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  • 1
    Online Resource
    Online Resource
    The Alzheimer's disease‐associated C99 fragment of APP regulates cellular cholesterol trafficking
    EMBO ; 2020
    In:  The EMBO Journal Vol. 39, No. 20 ( 2020-10-15)
    Details
    In: The EMBO Journal, EMBO, Vol. 39, No. 20 ( 2020-10-15)
    Type of Medium: Online Resource
    ISSN: 0261-4189 , 1460-2075
    URL: Article
    DOI: 10.15252/embj.2019103791
    RVK:
    WA 15000
    Language: English
    Publisher: EMBO
    Publication Date: 2020
    detail.hit.zdb_id: 1467419-1
    detail.hit.zdb_id: 586044-1
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Increased localization of APP ‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease
    EMBO ; 2017
    In:  The EMBO Journal Vol. 36, No. 22 ( 2017-11-15), p. 3356-3371
    Details
    In: The EMBO Journal, EMBO, Vol. 36, No. 22 ( 2017-11-15), p. 3356-3371
    Abstract: image In animal and cellular models of Alzheimer disease ( AD ) and in fibroblasts from AD patients, APP ‐C99 levels are increased in mitochondria‐associated endoplasmic reticulum membrane ( ER ‐ MAM ) regions, resulting in perturbed lipid homeostasis and mitochondrial dysfunction. Cells from AD patients and AD animal and cellular models show significant increases in C99 levels in ER ‐ MAM regions. The increased presence of C99 in MAM causes the loss of regulation of MAM functionality and greater apposition between ER and mitochondria. Among the functions located at MAM affected by the higher concentration of C99, sphingolipid homeostasis is significantly altered, resulting in the upregulation of sphingomyelin hydrolysis and the subsequent increases in ceramide. These increases in ceramide at ER ‐ MAM domains alter mitochondrial functionality. These results can help explain the cause of lipid and mitochondrial abnormalities in AD , and support a model in which increased C99 plays an early role in AD pathogenesis, via altered MAM function.
    Type of Medium: Online Resource
    ISSN: 0261-4189 , 1460-2075
    URL: Article
    DOI: 10.15252/embj.201796797
    RVK:
    WA 15000
    Language: English
    Publisher: EMBO
    Publication Date: 2017
    detail.hit.zdb_id: 1467419-1
    detail.hit.zdb_id: 586044-1
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    98-OR: Cold-Induced Hyperphagia Requires AgRP Neuron Activation
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: The adaptive response to cold exposure includes matched increases of both energy expenditure (to support thermogenesis) and energy intake, enabling core temperature to be maintained with no change of body fat stores. To investigate whether activation of agouti-related peptide (AgRP) neurons plays a role in this cold-induced hyperphagic response, we first determined whether this neuronal population is activated during cold exposure by employing AgRP-Cre/GFP marker mice and found that acute cold exposure rapidly induces cFos (a marker of neuronal activation) in these neurons. Further, relative to chow-fed controls housed at room temperature, mice subjected to chronic, mild cold exposure (14°C for 5 days) exhibited both the expected increase of food intake (28%) and a 117% increase of Agrp mRNA (p & lt;0.01 for both). Having established that AgRP neurons are activated by cold exposure, we next sought to determine whether this response is required for the associated hyperphagia. To this end, we used a DREADD-based pharmacogenetic approach using AgRP-IRES-Cre mice. Here, we found that cold-induced hyperphagia was blocked by inhibition of AgRP neurons (2h food intake upon acute housing at 14C: 0.26±0.06 g for Sal. vs. 0.10±0.04 g for CNO; p & lt;0.05). We next focused on the fidelity of this system in mice exposed to a high fat diet (HFD). We found that although HFD-fed mice exhibit intact thermogenic responses to cold and maintain normal core body temperature, they fail to increase energy intake (12.43±0.48 for 22C vs. 13.49±1.54 kcal for 14C; p=ns) and consequently experience weight loss not observed in lean, chow-fed controls (body weight change: 0.16±0.15g for chow vs. -0.49±0.23g for HFD; p=0.05). Since the absence of cold-induced hyperphagia in HFD-fed mice is accompanied by failure to increase hypothalamic Agrp mRNA (22C vs. 14C; 0.19±0.07 vs. 0.24±0.09; p=ns), these data demonstrate that 1) AgRP neuron activation is required for cold-induced hyperphagia, and 2) this response is impaired in HFD-fed mice. Disclosure J.D. Deem: None. K. Ogimoto: None. J. Nelson: None. B.N. Phan: None. K.R. Velasco: None. V. Damian: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. G.J. Morton: None. Funding University of Washington Diabetes Research Center
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-98-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
    detail.hit.zdb_id: 1501252-9
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  • 4
    Online Resource
    Online Resource
    1824-P: Leptin Receptor Neurons in the Hypothalamic Ventromedial Nucleus Play a Physiological Role in Regulating Glucose Tolerance
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: A role for leptin receptor (LepR)-expressing neurons in the hypothalamic ventromedial nucleus (VMN) in glucose homeostasis is suggested by studies in which leptin is administered into, or leptin receptors are deleted from, this brain area. However, whether LepR neurons in the VMN play a physiological role in glycemic control remains unknown. To test this hypothesis, we utilized an optogenetics approach to acutely silence VMNLepR neurons in awake, freely moving mice. We found that while photoinhibition of VMNLepR neurons had no effect on blood glucose levels under basal conditions (Control AUC: 681.6 ± 422.4 vs. Inhib AUC: 565.8 ± 350.7; p=ns, n=10), it impaired glucose tolerance significantly (Control AUC: 9251.7 ± 2032.6 vs. Inhib AUC: 13957.4 ± 4837; p & lt;0.01, n=10). Further, this effect occurred despite no change in glucose-stimulated insulin secretion (GSIS), suggesting that the effect is not secondary to reduced insulin secretion. Consistent with this conclusion, we report that insulin sensitivity was reduced by inhibition of VMNLepR neurons based on insulin tolerance testing (Control AUC: 8341 ± 531 vs. Inhib AUC: 9138 ± 658; p & lt;0.01, n=9). Together, these data suggest that VMNLepR neurons play a physiological role in the control of glucose tolerance and that activity of these neurons is required for normal insulin sensitivity. Future studies will examine both the peripheral mechanism(s) that mediate these effects and to identify the underlying neurocircuitry. Disclosure C.L. Faber: None. T.J. Harvey: None. K.R. Velasco: None. V. Damian: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. G.J. Morton: None. Funding National Institutes of Health
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-1824-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
    detail.hit.zdb_id: 1501252-9
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  • 5
    Online Resource
    Online Resource
    Distinct Neuronal Projections From the Hypothalamic Ventromedial Nucleus Mediate Glycemic and Behavioral Effects
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. 12 ( 2018-12-01), p. 2518-2529
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. 12 ( 2018-12-01), p. 2518-2529
    Abstract: The hypothalamic ventromedial nucleus (VMN) is implicated both in autonomic control of blood glucose and in behaviors including fear and aggression, but whether these divergent effects involve the same or distinct neuronal subsets and their projections is unknown. To address this question, we used an optogenetic approach to selectively activate the subset of VMN neurons that express neuronal nitric oxide synthase 1 (VMNNOS1 neurons) implicated in glucose counterregulation. We found that photoactivation of these neurons elicits 1) robust hyperglycemia achieved by activation of counterregulatory responses usually reserved for the physiological response to hypoglycemia and 2) defensive immobility behavior. Moreover, we show that the glucagon, but not corticosterone, response to insulin-induced hypoglycemia is blunted by photoinhibition of the same neurons. To investigate the neurocircuitry by which VMNNOS1 neurons mediate these effects, and to determine whether these diverse effects are dissociable from one another, we activated downstream VMNNOS1 projections in either the anterior bed nucleus of the stria terminalis (aBNST) or the periaqueductal gray (PAG). Whereas glycemic responses are fully recapitulated by activation of VMNNOS1 projections to the aBNST, freezing immobility occurred only upon activation of VMNNOS1 terminals in the PAG. These findings support previous evidence of a VMN→aBNST neurocircuit involved in glucose counterregulation and demonstrate that activation of VMNNOS1 neuronal projections supplying the PAG robustly elicits defensive behaviors.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-0380
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1501252-9
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  • 6
    Online Resource
    Online Resource
    101-OR: Identification of Warm Sensitive Neurons in the Hypothalamic Preoptic Area as Powerful Regulators of Glucose Homeostasis
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Inhibition of warm sensitive neurons (WSNs) in the hypothalamic preoptic area (POA) has been suggested to play a key role in the thermogenic response to cold exposure. As this response is enabled by a marked increase of insulin sensitivity in thermogenic tissues, we hypothesized that 1) WSN inhibition mediates metabolic as well as thermogenic responses to cold, and therefore, 2) WSN activation has the opposite effects. To test this hypothesis, we utilized DREADD technology to activate or inhibit a recently identified subpopulation of POA WSNs defined by their expression of the neuropeptide, Pacap, using the drug clozapine-N-oxide (CNO). We report that, pharmacogenetic activation of this POA WSN population found significant reductions in energy expenditure (Sal vs. CNO: 0.32±0.10 vs. 0.21±0.02 kcal/hr; p & lt;0.05) and, as previously reported, core temperature (Tc) (Sal vs. CNO: 35.4±0.1 vs. 30.4±0.1C; p=0.0001). Further, the response to pharmacogenetic activation was quite long-lived (∼2-3 days) and was accompanied by severe glucose intolerance both 1h and 24h following a single injection of CNO relative to vehicle (glucose AUC: 3610±1216 for Sal vs. 23985±2742 for 1h CNO; 28459±2411 for 24h CNO au; p & lt;0.05 vs. saline), an effect that occurred despite a compensatory increase of glucose-induced insulin secretion at the 24h (but not the 1h) time point (p & lt;0.05 vs. Sal). Thus, activation of POA Pacap+ WSNs is sufficient to reduce thermogenesis and impair glucose tolerance. Conversely, we found that inhibition of POA Pacap+ neurons in chow-fed mice led to a modest but significant increase in Tc (Sal vs. CNO: 35.4±0.1 vs. 35.9±0.1C; p=0.01) and whereas glucose tolerance was not improved in these animals, it was improved by POA Pacap+ neuron inhibition in mice with diet-induced obesity (glucose AUC: 9630±571 for Sal vs. 7517±628 for CNO au; p & lt;0.05). We conclude that POA Pacap+ neurons constitute a subset of WSNs with profound and previously unrecognized effects on glucose homeostasis. Disclosure J.D. Deem: None. K. Ogimoto: None. J. Nelson: None. B.N. Phan: None. K.R. Velasco: None. V. Damian: None. Z. Knight: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. G.J. Morton: None. Funding University of Washington Diabetes Research Center
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-101-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
    detail.hit.zdb_id: 1501252-9
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  • 7
    Online Resource
    Online Resource
    Leptin regulation of core body temperature involves mechanisms independent of the thyroid axis
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 315, No. 4 ( 2018-10-01), p. E552-E564
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 315, No. 4 ( 2018-10-01), p. E552-E564
    Abstract: The ability to maintain core temperature within a narrow range despite rapid and dramatic changes in environmental temperature is essential for the survival of free-living mammals, and growing evidence implicates an important role for the hormone leptin. Given that thyroid hormone plays a major role in thermogenesis and that circulating thyroid hormone levels are reduced in leptin-deficient states (an effect partially restored by leptin replacement), we sought to determine the extent to which leptin’s role in thermogenesis is mediated by raising thyroid hormone levels. To this end, we 1) quantified the effect of physiological leptin replacement on circulating levels of thyroid hormone in leptin-deficient ob/ob mice, and 2) determined if the effect of leptin to prevent the fall in core temperature in these animals during cold exposure is mimicked by administration of a physiological replacement dose of triiodothyronine (T 3 ). We report that, as with leptin, normalization of circulating T 3 levels is sufficient both to increase energy expenditure, respiratory quotient, and ambulatory activity and to reduce torpor in ob/ob mice. Yet, unlike leptin, infusing T 3 at a dose that normalizes plasma T 3 levels fails to prevent the fall of core temperature during mild cold exposure. Because thermal conductance (e.g., heat loss to the environment) was reduced by administration of leptin but not T 3 , leptin regulation of heat dissipation is implicated as playing a uniquely important role in thermoregulation. Together, these findings identify a key role in thermoregulation for leptin-mediated suppression of thermal conduction via a mechanism that is independent of the thyroid axis.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00462.2017
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
    detail.hit.zdb_id: 1477331-4
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    MFN2 mutations in Charcot–Marie–Tooth disease alter mitochondria-associated ER membrane function but do not impair bioenergetics
    Oxford University Press (OUP) ; 2019
    In:  Human Molecular Genetics Vol. 28, No. 11 ( 2019-06-01), p. 1782-1800
    Details
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 28, No. 11 ( 2019-06-01), p. 1782-1800
    Type of Medium: Online Resource
    ISSN: 0964-6906 , 1460-2083
    URL: Article
    DOI: 10.1093/hmg/ddz008
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 1474816-2
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    Identification of Warm-Sensitive Neurons in the Hypothalamic Preoptic Area as Powerful Regulators of Glucose Homeostasis
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Inhibition of warm sensitive neurons (WSN) in the hypothalamic preoptic area (POA) has been suggested to play a key role in the thermogenic response to cold exposure. As this response is enabled by a marked increase of insulin sensitivity in thermogenic tissues, we hypothesized that WSN inhibition mediates the metabolic as well as the thermogenic response, and therefore that WSN activation would have the opposite effects. To test this hypothesis, we utilized pharmacogenetic technology to activate or inhibit a recently identified subpopulation of POA WSN defined by their expression of the neuropeptide, Pacap, using the drug clozapine-N-oxide (CNO). We report that, as predicted, pharmacogenetic activation of this POA WSN population reduces energy expenditure (EE) (Sal vs. CNO: 0.32±0.10 vs. 0.21±0.02 kcal/hour; p & lt;0.05) and core temperature (Tc) (Sal vs. CNO: 35.4±0.1 vs. 30.4±0.1°C; p=0.0001), while inhibition had the opposite effect (EE: Sal vs. CNO: 0.25±0.03 vs. 0.26±0.03 kcal/hour; Tc: Sal vs. CNO: 35.8±0.1 vs. 36.4±0.2°C; p & lt;0.05). The response to pharmacogenetic activation of POA Pacap+ neurons was quite long-lived (∼2-3 days) and was accompanied by severe glucose intolerance both 1 hour and 24 hour following CNO relative to vehicle treatment (glucose AUC: 3610±1216 for saline vs. 23985±2742 for 1 hour CNO vs. 28459±2411 vs. 24 hour CNO au; p & lt;0.05 vs. saline). Moreover, this marked impairment of glucose tolerance occurred even after a compensatory increase of glucose-induced insulin secretion at the 24 hour time point (Plasma insulin (t=30): 0.42±0.10 for saline vs. 0.45±0.10 ng/mL for 1 hour CNO vs. 1.05±0.20 ng/mL for 24 hour CNO; p=ns). However, despite significant increases in Tc, acute inhibition of POA Pacap+ neurons did not improve glucose tolerance, possibly due to compensation by other WSN populations activated by the thermogenic response. We conclude that POA Pacap+ neurons constitute a subset of WSN that exert profound, previously unrecognized effects on glucose homeostasis. Disclosure J.D. Deem: None. K. Ogimoto: None. K.R. Velasco: None. V. Damian: None. Z. Knight: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. G.J. Morton: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-246-LB
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1501252-9
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  • 10
    Online Resource
    Online Resource
    A second update on mapping the human genetic architecture of COVID-19
    Springer Science and Business Media LLC ; 2023
    In:  Nature Vol. 621, No. 7977 ( 2023-09-07), p. E7-E26
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 621, No. 7977 ( 2023-09-07), p. E7-E26
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-023-06355-3
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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