Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice
Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice Dana K. Sindelar 1 , Paul Mystkowski 1 , Donald J. Marsh 2 , Richard D. Palmiter 2 and Michael W. Schwartz 1 1 Department of Medicine, University of Washington, and Howard Hughes Medical Institute, University of Washington, Seattle...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2002-03, Vol.51 (3), p.778-783 |
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| creator | SINDELAR, Dana K MYSTKOWSKI, Paul MARSH, Donald J PALMITER, Richard D SCHWARTZ, Michael W |
| description | Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice
Dana K. Sindelar 1 ,
Paul Mystkowski 1 ,
Donald J. Marsh 2 ,
Richard D. Palmiter 2 and
Michael W. Schwartz 1
1 Department of Medicine, University of Washington, and Howard Hughes Medical Institute, University of Washington, Seattle,
Washington
2 Department of Biochemistry, University of Washington, Seattle, Washington
Abstract
The combined effects of increased hypothalamic signaling by neuropeptide Y (NPY) and decreased signaling by melanocortins
are hypothesized to stimulate food intake when body fat stores are depleted. To investigate NPY’s role in the hyperphagic
response to uncontrolled diabetes, streptozotocin (STZ) (200 mg/kg intraperitoneally) or saline vehicle was given to NPY-deficient
( Npy –/– ) and wild-type ( Npy +/+ ) mice. In Npy +/+ mice, STZ-induced diabetes increased mean daily food intake to plateau values 50% above baseline intake (+2.0 ± 0.6 g/day;
P ≤ 0.05), an effect that was not seen in STZ-treated Npy –/– mice (+0.8 ± 0.1 g/day; NS), despite comparably elevated levels of plasma glucose and comparably decreased levels of body
weight, fat content, and plasma leptin. Unlike the impaired feeding response to uncontrolled diabetes, Npy –/– mice exhibit intact hyperphagic responses to fasting (Erickson et al. [ 1 ], Nature 381:415–418, 1996). To investigate whether differences in hypothalamic melanocortin signaling can explain this discrepancy,
we used in situ hybridization to compare the effects of STZ-diabetes and fasting on pro-opiomelanocortin (POMC) and agouti-related
peptide (AgRP) mRNA levels in the hypothalamic arcuate nucleus (ARC) of Npy –/– and Npy +/+ mice. AgRP mRNA levels were increased by both fasting and STZ-diabetes, but the increase in STZ-diabetes was small (50–80%)
compared with the effect of fasting (∼20-fold increase of AgRP mRNA). STZ-diabetes also lowered POMC mRNA levels by 65% in
the ARC of Npy +/+ mice ( P ≤ 0.05) but by only 11% in Npy –/– mice (NS); fasting significantly lowered POMC mRNA levels in both genotypes. We conclude that NPY is required for both the
increase of food intake and the decrease of hypothalamic POMC gene expression induced by uncontrolled diabetes. In contrast,
NPY is not required for either of these responses when the stimulus is food deprivation. Moreover, fasting is a more potent
stimulus to hypothalamic AgRP gene expression than is STZ-diabetes. Therefore, central nervous system melanocortin signaling
appears to be su |
| doi_str_mv | 10.2337/diabetes.51.3.778 |
| format | Article |
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Dana K. Sindelar 1 ,
Paul Mystkowski 1 ,
Donald J. Marsh 2 ,
Richard D. Palmiter 2 and
Michael W. Schwartz 1
1 Department of Medicine, University of Washington, and Howard Hughes Medical Institute, University of Washington, Seattle,
Washington
2 Department of Biochemistry, University of Washington, Seattle, Washington
Abstract
The combined effects of increased hypothalamic signaling by neuropeptide Y (NPY) and decreased signaling by melanocortins
are hypothesized to stimulate food intake when body fat stores are depleted. To investigate NPY’s role in the hyperphagic
response to uncontrolled diabetes, streptozotocin (STZ) (200 mg/kg intraperitoneally) or saline vehicle was given to NPY-deficient
( Npy –/– ) and wild-type ( Npy +/+ ) mice. In Npy +/+ mice, STZ-induced diabetes increased mean daily food intake to plateau values 50% above baseline intake (+2.0 ± 0.6 g/day;
P ≤ 0.05), an effect that was not seen in STZ-treated Npy –/– mice (+0.8 ± 0.1 g/day; NS), despite comparably elevated levels of plasma glucose and comparably decreased levels of body
weight, fat content, and plasma leptin. Unlike the impaired feeding response to uncontrolled diabetes, Npy –/– mice exhibit intact hyperphagic responses to fasting (Erickson et al. [ 1 ], Nature 381:415–418, 1996). To investigate whether differences in hypothalamic melanocortin signaling can explain this discrepancy,
we used in situ hybridization to compare the effects of STZ-diabetes and fasting on pro-opiomelanocortin (POMC) and agouti-related
peptide (AgRP) mRNA levels in the hypothalamic arcuate nucleus (ARC) of Npy –/– and Npy +/+ mice. AgRP mRNA levels were increased by both fasting and STZ-diabetes, but the increase in STZ-diabetes was small (50–80%)
compared with the effect of fasting (∼20-fold increase of AgRP mRNA). STZ-diabetes also lowered POMC mRNA levels by 65% in
the ARC of Npy +/+ mice ( P ≤ 0.05) but by only 11% in Npy –/– mice (NS); fasting significantly lowered POMC mRNA levels in both genotypes. We conclude that NPY is required for both the
increase of food intake and the decrease of hypothalamic POMC gene expression induced by uncontrolled diabetes. In contrast,
NPY is not required for either of these responses when the stimulus is food deprivation. Moreover, fasting is a more potent
stimulus to hypothalamic AgRP gene expression than is STZ-diabetes. Therefore, central nervous system melanocortin signaling
appears to be suppressed more effectively by fasting than by uncontrolled diabetes, which provides a plausible explanation
for differences in the feeding response to these two stimuli in mice lacking NPY.
Footnotes
Address correspondence and reprint requests to Michael W. Schwartz, Harborview Medical Center, Division of Endocrinology,
Box 359757, 325 9th Ave., Seattle, WA 98104. E-mail: mschwart{at}u.washington.edu .
Received for publication 20 June 2001 and accepted in revised form 3 December 2001.
M.W.S. is on the Scientific Advisory Board of Millennium Pharmaceutical and has received consulting fees for work in this
capacity. D.K.S. is currently employed as Senior Investigator at Eli Lilly, Inc., a position that he accepted after his work
on this study was completed. D.J.M. is currently employed as Senior Investigator at Merck Pharmaceuticals, Inc., a position
that he accepted after his work on this study was completed.
Current address for D.K.S.: Eli Lilly & Co., Corporate Center, Drop 0545, Indianapolis, IN 46285. Current address for D.J.M.:
Merck & Co., Inc., RY80T-126, P.O. Box 2000, Rahway, NJ 07065.
AgRP, agouti-related peptide; ARC, hypothalamic arcuate nucleus; AUC, area under the curve; CNS, central nervous system; Mcr,
melanocortin receptor; MRS, magnetic resonance spectroscopy; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; STZ, streptozotocin.
DIABETES</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/diabetes.51.3.778</identifier><identifier>PMID: 11872679</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Adipose Tissue ; Adipose tissues ; Agouti-Related Protein ; alpha-MSH - physiology ; Animals ; Arcuate Nucleus of Hypothalamus - chemistry ; Biological and medical sciences ; Blood Glucose - analysis ; Body Composition ; Body Weight ; Diabetes ; Diabetes Mellitus, Experimental - complications ; Diabetes Mellitus, Experimental - physiopathology ; Diabetes research ; Evaluation ; Fasting ; House mouse ; Hyperphagia - etiology ; Hyperphagia - prevention & control ; Hypothalamic hormones ; Hypothalamus - physiopathology ; In Situ Hybridization ; Intercellular Signaling Peptides and Proteins ; Leptin - blood ; Mice ; Mice as laboratory animals ; Mice, Inbred C57BL ; Neuropeptide Y ; Neuropeptide Y - deficiency ; Neuropeptide Y - physiology ; Physiological aspects ; Pro-Opiomelanocortin - genetics ; Proteins - genetics ; RNA, Messenger - analysis ; Signal Transduction</subject><ispartof>Diabetes (New York, N.Y.), 2002-03, Vol.51 (3), p.778-783</ispartof><rights>2002 INIST-CNRS</rights><rights>COPYRIGHT 2002 American Diabetes Association</rights><rights>COPYRIGHT 2002 American Diabetes Association</rights><rights>Copyright American Diabetes Association Mar 2002</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c643t-2e1a6648b298360a5edf811ca8b820cb10789e7bb19f7f4a4f01763596774f43</citedby><cites>FETCH-LOGICAL-c643t-2e1a6648b298360a5edf811ca8b820cb10789e7bb19f7f4a4f01763596774f43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13516969$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11872679$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SINDELAR, Dana K</creatorcontrib><creatorcontrib>MYSTKOWSKI, Paul</creatorcontrib><creatorcontrib>MARSH, Donald J</creatorcontrib><creatorcontrib>PALMITER, Richard D</creatorcontrib><creatorcontrib>SCHWARTZ, Michael W</creatorcontrib><title>Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice
Dana K. Sindelar 1 ,
Paul Mystkowski 1 ,
Donald J. Marsh 2 ,
Richard D. Palmiter 2 and
Michael W. Schwartz 1
1 Department of Medicine, University of Washington, and Howard Hughes Medical Institute, University of Washington, Seattle,
Washington
2 Department of Biochemistry, University of Washington, Seattle, Washington
Abstract
The combined effects of increased hypothalamic signaling by neuropeptide Y (NPY) and decreased signaling by melanocortins
are hypothesized to stimulate food intake when body fat stores are depleted. To investigate NPY’s role in the hyperphagic
response to uncontrolled diabetes, streptozotocin (STZ) (200 mg/kg intraperitoneally) or saline vehicle was given to NPY-deficient
( Npy –/– ) and wild-type ( Npy +/+ ) mice. In Npy +/+ mice, STZ-induced diabetes increased mean daily food intake to plateau values 50% above baseline intake (+2.0 ± 0.6 g/day;
P ≤ 0.05), an effect that was not seen in STZ-treated Npy –/– mice (+0.8 ± 0.1 g/day; NS), despite comparably elevated levels of plasma glucose and comparably decreased levels of body
weight, fat content, and plasma leptin. Unlike the impaired feeding response to uncontrolled diabetes, Npy –/– mice exhibit intact hyperphagic responses to fasting (Erickson et al. [ 1 ], Nature 381:415–418, 1996). To investigate whether differences in hypothalamic melanocortin signaling can explain this discrepancy,
we used in situ hybridization to compare the effects of STZ-diabetes and fasting on pro-opiomelanocortin (POMC) and agouti-related
peptide (AgRP) mRNA levels in the hypothalamic arcuate nucleus (ARC) of Npy –/– and Npy +/+ mice. AgRP mRNA levels were increased by both fasting and STZ-diabetes, but the increase in STZ-diabetes was small (50–80%)
compared with the effect of fasting (∼20-fold increase of AgRP mRNA). STZ-diabetes also lowered POMC mRNA levels by 65% in
the ARC of Npy +/+ mice ( P ≤ 0.05) but by only 11% in Npy –/– mice (NS); fasting significantly lowered POMC mRNA levels in both genotypes. We conclude that NPY is required for both the
increase of food intake and the decrease of hypothalamic POMC gene expression induced by uncontrolled diabetes. In contrast,
NPY is not required for either of these responses when the stimulus is food deprivation. Moreover, fasting is a more potent
stimulus to hypothalamic AgRP gene expression than is STZ-diabetes. Therefore, central nervous system melanocortin signaling
appears to be suppressed more effectively by fasting than by uncontrolled diabetes, which provides a plausible explanation
for differences in the feeding response to these two stimuli in mice lacking NPY.
Footnotes
Address correspondence and reprint requests to Michael W. Schwartz, Harborview Medical Center, Division of Endocrinology,
Box 359757, 325 9th Ave., Seattle, WA 98104. E-mail: mschwart{at}u.washington.edu .
Received for publication 20 June 2001 and accepted in revised form 3 December 2001.
M.W.S. is on the Scientific Advisory Board of Millennium Pharmaceutical and has received consulting fees for work in this
capacity. D.K.S. is currently employed as Senior Investigator at Eli Lilly, Inc., a position that he accepted after his work
on this study was completed. D.J.M. is currently employed as Senior Investigator at Merck Pharmaceuticals, Inc., a position
that he accepted after his work on this study was completed.
Current address for D.K.S.: Eli Lilly & Co., Corporate Center, Drop 0545, Indianapolis, IN 46285. Current address for D.J.M.:
Merck & Co., Inc., RY80T-126, P.O. Box 2000, Rahway, NJ 07065.
AgRP, agouti-related peptide; ARC, hypothalamic arcuate nucleus; AUC, area under the curve; CNS, central nervous system; Mcr,
melanocortin receptor; MRS, magnetic resonance spectroscopy; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; STZ, streptozotocin.
DIABETES</description><subject>Adipose Tissue</subject><subject>Adipose tissues</subject><subject>Agouti-Related Protein</subject><subject>alpha-MSH - physiology</subject><subject>Animals</subject><subject>Arcuate Nucleus of Hypothalamus - chemistry</subject><subject>Biological and medical sciences</subject><subject>Blood Glucose - analysis</subject><subject>Body Composition</subject><subject>Body Weight</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Experimental - complications</subject><subject>Diabetes Mellitus, Experimental - physiopathology</subject><subject>Diabetes research</subject><subject>Evaluation</subject><subject>Fasting</subject><subject>House mouse</subject><subject>Hyperphagia - etiology</subject><subject>Hyperphagia - prevention & control</subject><subject>Hypothalamic hormones</subject><subject>Hypothalamus - physiopathology</subject><subject>In Situ Hybridization</subject><subject>Intercellular Signaling Peptides and Proteins</subject><subject>Leptin - blood</subject><subject>Mice</subject><subject>Mice as laboratory animals</subject><subject>Mice, Inbred C57BL</subject><subject>Neuropeptide Y</subject><subject>Neuropeptide Y - deficiency</subject><subject>Neuropeptide Y - physiology</subject><subject>Physiological aspects</subject><subject>Pro-Opiomelanocortin - genetics</subject><subject>Proteins - genetics</subject><subject>RNA, Messenger - analysis</subject><subject>Signal Transduction</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpt0s1uEzEQAGALgWgaeAAuaIVEhVA3-GfXXh-jlLZIgV56gJPldcYbV5vdxfYKeuMdeEOeBJcERYFoDpasb2bs0SD0guAZZUy8WzldQ4QwK8mMzYSoHqEJkUzmjIrPj9EEY0JzIqQ4Qach3GGMeYqn6ISQSlAu5ARdzmOEbtTR9V3W2-ziT0lnsuv7Afyw1o3TmeuyTzD6foAhuhVkX379-HkB1hkHXcw-OgPP0BOr2wDPd-cU3V6-v11c58ubqw-L-TI3vGAxp0A050VVU1kxjnUJK1sRYnRVVxSbmmBRSRB1TaQVttCFxURwVkouRGELNkVn27KD77-OEKLauGCgbXUH_RiUIIWQZao9Ra_-gXf96Lv0NEUJT4gyktD5FjW6BeU620evTQMdeN32Xfpgup5XBcWyoDTx_AhPsYKNM8f8mwOfSITvsdFjCKq6Wh7Q82PU9G0LDag0wsXNASdbbnwfggerBu822t8rgtXDZqi_m6FKophKm5FyXu4mMtYbWO0zdquQwOsd0MHo1nrdGRf2jpWES_7g3m7d2jXrb87Dvtn_XX8DrFfPGQ</recordid><startdate>20020301</startdate><enddate>20020301</enddate><creator>SINDELAR, Dana K</creator><creator>MYSTKOWSKI, Paul</creator><creator>MARSH, Donald J</creator><creator>PALMITER, Richard D</creator><creator>SCHWARTZ, Michael W</creator><general>American Diabetes Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8GL</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>7X8</scope></search><sort><creationdate>20020301</creationdate><title>Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice</title><author>SINDELAR, Dana K ; MYSTKOWSKI, Paul ; MARSH, Donald J ; PALMITER, Richard D ; SCHWARTZ, Michael W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c643t-2e1a6648b298360a5edf811ca8b820cb10789e7bb19f7f4a4f01763596774f43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Adipose Tissue</topic><topic>Adipose tissues</topic><topic>Agouti-Related Protein</topic><topic>alpha-MSH - physiology</topic><topic>Animals</topic><topic>Arcuate Nucleus of Hypothalamus - chemistry</topic><topic>Biological and medical sciences</topic><topic>Blood Glucose - analysis</topic><topic>Body Composition</topic><topic>Body Weight</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Experimental - complications</topic><topic>Diabetes Mellitus, Experimental - physiopathology</topic><topic>Diabetes research</topic><topic>Evaluation</topic><topic>Fasting</topic><topic>House mouse</topic><topic>Hyperphagia - etiology</topic><topic>Hyperphagia - prevention & control</topic><topic>Hypothalamic hormones</topic><topic>Hypothalamus - physiopathology</topic><topic>In Situ Hybridization</topic><topic>Intercellular Signaling Peptides and Proteins</topic><topic>Leptin - blood</topic><topic>Mice</topic><topic>Mice as laboratory animals</topic><topic>Mice, Inbred C57BL</topic><topic>Neuropeptide Y</topic><topic>Neuropeptide Y - deficiency</topic><topic>Neuropeptide Y - physiology</topic><topic>Physiological aspects</topic><topic>Pro-Opiomelanocortin - genetics</topic><topic>Proteins - genetics</topic><topic>RNA, Messenger - analysis</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SINDELAR, Dana K</creatorcontrib><creatorcontrib>MYSTKOWSKI, Paul</creatorcontrib><creatorcontrib>MARSH, Donald J</creatorcontrib><creatorcontrib>PALMITER, Richard D</creatorcontrib><creatorcontrib>SCHWARTZ, Michael W</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: High School</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>SINDELAR, Dana K</au><au>MYSTKOWSKI, Paul</au><au>MARSH, Donald J</au><au>PALMITER, Richard D</au><au>SCHWARTZ, Michael W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2002-03-01</date><risdate>2002</risdate><volume>51</volume><issue>3</issue><spage>778</spage><epage>783</epage><pages>778-783</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice
Dana K. Sindelar 1 ,
Paul Mystkowski 1 ,
Donald J. Marsh 2 ,
Richard D. Palmiter 2 and
Michael W. Schwartz 1
1 Department of Medicine, University of Washington, and Howard Hughes Medical Institute, University of Washington, Seattle,
Washington
2 Department of Biochemistry, University of Washington, Seattle, Washington
Abstract
The combined effects of increased hypothalamic signaling by neuropeptide Y (NPY) and decreased signaling by melanocortins
are hypothesized to stimulate food intake when body fat stores are depleted. To investigate NPY’s role in the hyperphagic
response to uncontrolled diabetes, streptozotocin (STZ) (200 mg/kg intraperitoneally) or saline vehicle was given to NPY-deficient
( Npy –/– ) and wild-type ( Npy +/+ ) mice. In Npy +/+ mice, STZ-induced diabetes increased mean daily food intake to plateau values 50% above baseline intake (+2.0 ± 0.6 g/day;
P ≤ 0.05), an effect that was not seen in STZ-treated Npy –/– mice (+0.8 ± 0.1 g/day; NS), despite comparably elevated levels of plasma glucose and comparably decreased levels of body
weight, fat content, and plasma leptin. Unlike the impaired feeding response to uncontrolled diabetes, Npy –/– mice exhibit intact hyperphagic responses to fasting (Erickson et al. [ 1 ], Nature 381:415–418, 1996). To investigate whether differences in hypothalamic melanocortin signaling can explain this discrepancy,
we used in situ hybridization to compare the effects of STZ-diabetes and fasting on pro-opiomelanocortin (POMC) and agouti-related
peptide (AgRP) mRNA levels in the hypothalamic arcuate nucleus (ARC) of Npy –/– and Npy +/+ mice. AgRP mRNA levels were increased by both fasting and STZ-diabetes, but the increase in STZ-diabetes was small (50–80%)
compared with the effect of fasting (∼20-fold increase of AgRP mRNA). STZ-diabetes also lowered POMC mRNA levels by 65% in
the ARC of Npy +/+ mice ( P ≤ 0.05) but by only 11% in Npy –/– mice (NS); fasting significantly lowered POMC mRNA levels in both genotypes. We conclude that NPY is required for both the
increase of food intake and the decrease of hypothalamic POMC gene expression induced by uncontrolled diabetes. In contrast,
NPY is not required for either of these responses when the stimulus is food deprivation. Moreover, fasting is a more potent
stimulus to hypothalamic AgRP gene expression than is STZ-diabetes. Therefore, central nervous system melanocortin signaling
appears to be suppressed more effectively by fasting than by uncontrolled diabetes, which provides a plausible explanation
for differences in the feeding response to these two stimuli in mice lacking NPY.
Footnotes
Address correspondence and reprint requests to Michael W. Schwartz, Harborview Medical Center, Division of Endocrinology,
Box 359757, 325 9th Ave., Seattle, WA 98104. E-mail: mschwart{at}u.washington.edu .
Received for publication 20 June 2001 and accepted in revised form 3 December 2001.
M.W.S. is on the Scientific Advisory Board of Millennium Pharmaceutical and has received consulting fees for work in this
capacity. D.K.S. is currently employed as Senior Investigator at Eli Lilly, Inc., a position that he accepted after his work
on this study was completed. D.J.M. is currently employed as Senior Investigator at Merck Pharmaceuticals, Inc., a position
that he accepted after his work on this study was completed.
Current address for D.K.S.: Eli Lilly & Co., Corporate Center, Drop 0545, Indianapolis, IN 46285. Current address for D.J.M.:
Merck & Co., Inc., RY80T-126, P.O. Box 2000, Rahway, NJ 07065.
AgRP, agouti-related peptide; ARC, hypothalamic arcuate nucleus; AUC, area under the curve; CNS, central nervous system; Mcr,
melanocortin receptor; MRS, magnetic resonance spectroscopy; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; STZ, streptozotocin.
DIABETES</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>11872679</pmid><doi>10.2337/diabetes.51.3.778</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2002-03, Vol.51 (3), p.778-783 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_proquest_journals_216479231 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adipose Tissue Adipose tissues Agouti-Related Protein alpha-MSH - physiology Animals Arcuate Nucleus of Hypothalamus - chemistry Biological and medical sciences Blood Glucose - analysis Body Composition Body Weight Diabetes Diabetes Mellitus, Experimental - complications Diabetes Mellitus, Experimental - physiopathology Diabetes research Evaluation Fasting House mouse Hyperphagia - etiology Hyperphagia - prevention & control Hypothalamic hormones Hypothalamus - physiopathology In Situ Hybridization Intercellular Signaling Peptides and Proteins Leptin - blood Mice Mice as laboratory animals Mice, Inbred C57BL Neuropeptide Y Neuropeptide Y - deficiency Neuropeptide Y - physiology Physiological aspects Pro-Opiomelanocortin - genetics Proteins - genetics RNA, Messenger - analysis Signal Transduction |
| title | Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-13T10%3A51%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Attenuation%20of%20Diabetic%20Hyperphagia%20in%20Neuropeptide%20Y%E2%80%93Deficient%20Mice&rft.jtitle=Diabetes%20(New%20York,%20N.Y.)&rft.au=SINDELAR,%20Dana%20K&rft.date=2002-03-01&rft.volume=51&rft.issue=3&rft.spage=778&rft.epage=783&rft.pages=778-783&rft.issn=0012-1797&rft.eissn=1939-327X&rft.coden=DIAEAZ&rft_id=info:doi/10.2337/diabetes.51.3.778&rft_dat=%3Cgale_proqu%3EA84209422%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=216479231&rft_id=info:pmid/11872679&rft_galeid=A84209422&rfr_iscdi=true |