Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity
Leptin is an adipocyte-derived hormone that plays a key role in energy homeostasis, yet resistance to leptin is a feature of most cases of obesity in humans and rodents. In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signali...
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| Veröffentlicht in: | Nature medicine 2004-07, Vol.10 (7), p.739-743 |
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| creator | Yoshimura, Akihiko Mori, Hiroyuki Hanada, Reiko Hanada, Toshikatsu Aki, Daisuke Mashima, Ryuichi Nishinakamura, Hitomi Torisu, Takehiro Chien, Kenneth R Yasukawa, Hideo |
| description | Leptin is an adipocyte-derived hormone that plays a key role in energy homeostasis, yet resistance to leptin is a feature of most cases of obesity in humans and rodents. In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signaling involved in leptin resistance. To determine the functional significance of Socs3 in vivo, we generated neural cell-specific SOCS3 conditional knockout mice using the Cre-loxP system. Compared to their wild-type littermates, Socs3-deficient mice showed enhanced leptin-induced hypothalamic Stat3 tyrosine phosphorylation as well as pro-opiomelanocortin (POMC) induction, and this resulted in a greater body weight loss and suppression of food intake. Moreover, the Socs3-deficient mice were resistant to high fat diet-induced weight gain and hyperleptinemia, and insulin-sensitivity was retained. These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance. Our study demonstrates the negative regulatory role of Socs3 in leptin signaling in vivo, and thus suppression of Socs3 in the brain is a potential therapy for leptin-resistance in obesity. |
| doi_str_mv | 10.1038/nm1071 |
| format | Article |
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In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signaling involved in leptin resistance. To determine the functional significance of Socs3 in vivo, we generated neural cell-specific SOCS3 conditional knockout mice using the Cre-loxP system. Compared to their wild-type littermates, Socs3-deficient mice showed enhanced leptin-induced hypothalamic Stat3 tyrosine phosphorylation as well as pro-opiomelanocortin (POMC) induction, and this resulted in a greater body weight loss and suppression of food intake. Moreover, the Socs3-deficient mice were resistant to high fat diet-induced weight gain and hyperleptinemia, and insulin-sensitivity was retained. These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance. Our study demonstrates the negative regulatory role of Socs3 in leptin signaling in vivo, and thus suppression of Socs3 in the brain is a potential therapy for leptin-resistance in obesity.</description><identifier>ISSN: 1078-8956</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/nm1071</identifier><identifier>PMID: 15208705</identifier><language>eng</language><publisher>United States: Nature Publishing Group</publisher><subject>Animals ; Body weight ; Brain Chemistry ; Diet ; Dietary Fats - administration & dosage ; DNA-Binding Proteins - metabolism ; Eating - drug effects ; Female ; Insulin Resistance ; Leptin - pharmacology ; Male ; Mice ; Obesity ; Obesity - prevention & control ; Phosphorylation ; Repressor Proteins - analysis ; Repressor Proteins - antagonists & inhibitors ; Rodents ; STAT3 Transcription Factor ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins ; Trans-Activators - metabolism ; Transcription Factors - analysis ; Transcription Factors - antagonists & inhibitors ; Transcription Factors - deficiency ; Weight Loss - drug effects</subject><ispartof>Nature medicine, 2004-07, Vol.10 (7), p.739-743</ispartof><rights>COPYRIGHT 2004 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2004</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c596t-aa962d38dc80110391c287389a0dd016809e34b3ab98a32d04fb5bb14984b7473</citedby><cites>FETCH-LOGICAL-c596t-aa962d38dc80110391c287389a0dd016809e34b3ab98a32d04fb5bb14984b7473</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,2729,27931,27932</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15208705$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yoshimura, Akihiko</creatorcontrib><creatorcontrib>Mori, Hiroyuki</creatorcontrib><creatorcontrib>Hanada, Reiko</creatorcontrib><creatorcontrib>Hanada, Toshikatsu</creatorcontrib><creatorcontrib>Aki, Daisuke</creatorcontrib><creatorcontrib>Mashima, Ryuichi</creatorcontrib><creatorcontrib>Nishinakamura, Hitomi</creatorcontrib><creatorcontrib>Torisu, Takehiro</creatorcontrib><creatorcontrib>Chien, Kenneth R</creatorcontrib><creatorcontrib>Yasukawa, Hideo</creatorcontrib><title>Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><description>Leptin is an adipocyte-derived hormone that plays a key role in energy homeostasis, yet resistance to leptin is a feature of most cases of obesity in humans and rodents. In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signaling involved in leptin resistance. To determine the functional significance of Socs3 in vivo, we generated neural cell-specific SOCS3 conditional knockout mice using the Cre-loxP system. Compared to their wild-type littermates, Socs3-deficient mice showed enhanced leptin-induced hypothalamic Stat3 tyrosine phosphorylation as well as pro-opiomelanocortin (POMC) induction, and this resulted in a greater body weight loss and suppression of food intake. Moreover, the Socs3-deficient mice were resistant to high fat diet-induced weight gain and hyperleptinemia, and insulin-sensitivity was retained. These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance. Our study demonstrates the negative regulatory role of Socs3 in leptin signaling in vivo, and thus suppression of Socs3 in the brain is a potential therapy for leptin-resistance in obesity.</description><subject>Animals</subject><subject>Body weight</subject><subject>Brain Chemistry</subject><subject>Diet</subject><subject>Dietary Fats - administration & dosage</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Eating - drug effects</subject><subject>Female</subject><subject>Insulin Resistance</subject><subject>Leptin - pharmacology</subject><subject>Male</subject><subject>Mice</subject><subject>Obesity</subject><subject>Obesity - prevention & control</subject><subject>Phosphorylation</subject><subject>Repressor Proteins - analysis</subject><subject>Repressor Proteins - antagonists & inhibitors</subject><subject>Rodents</subject><subject>STAT3 Transcription Factor</subject><subject>Suppressor of Cytokine Signaling 3 Protein</subject><subject>Suppressor of Cytokine Signaling Proteins</subject><subject>Trans-Activators - 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Academic</collection><jtitle>Nature medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yoshimura, Akihiko</au><au>Mori, Hiroyuki</au><au>Hanada, Reiko</au><au>Hanada, Toshikatsu</au><au>Aki, Daisuke</au><au>Mashima, Ryuichi</au><au>Nishinakamura, Hitomi</au><au>Torisu, Takehiro</au><au>Chien, Kenneth R</au><au>Yasukawa, Hideo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity</atitle><jtitle>Nature medicine</jtitle><addtitle>Nat Med</addtitle><date>2004-07-01</date><risdate>2004</risdate><volume>10</volume><issue>7</issue><spage>739</spage><epage>743</epage><pages>739-743</pages><issn>1078-8956</issn><eissn>1546-170X</eissn><abstract>Leptin is an adipocyte-derived hormone that plays a key role in energy homeostasis, yet resistance to leptin is a feature of most cases of obesity in humans and rodents. In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signaling involved in leptin resistance. To determine the functional significance of Socs3 in vivo, we generated neural cell-specific SOCS3 conditional knockout mice using the Cre-loxP system. Compared to their wild-type littermates, Socs3-deficient mice showed enhanced leptin-induced hypothalamic Stat3 tyrosine phosphorylation as well as pro-opiomelanocortin (POMC) induction, and this resulted in a greater body weight loss and suppression of food intake. Moreover, the Socs3-deficient mice were resistant to high fat diet-induced weight gain and hyperleptinemia, and insulin-sensitivity was retained. These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance. Our study demonstrates the negative regulatory role of Socs3 in leptin signaling in vivo, and thus suppression of Socs3 in the brain is a potential therapy for leptin-resistance in obesity.</abstract><cop>United States</cop><pub>Nature Publishing Group</pub><pmid>15208705</pmid><doi>10.1038/nm1071</doi><tpages>5</tpages></addata></record> |
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| subjects | Animals Body weight Brain Chemistry Diet Dietary Fats - administration & dosage DNA-Binding Proteins - metabolism Eating - drug effects Female Insulin Resistance Leptin - pharmacology Male Mice Obesity Obesity - prevention & control Phosphorylation Repressor Proteins - analysis Repressor Proteins - antagonists & inhibitors Rodents STAT3 Transcription Factor Suppressor of Cytokine Signaling 3 Protein Suppressor of Cytokine Signaling Proteins Trans-Activators - metabolism Transcription Factors - analysis Transcription Factors - antagonists & inhibitors Transcription Factors - deficiency Weight Loss - drug effects |
| title | Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity |
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