PDK1-Foxo1 in Agouti-Related Peptide Neurons Regulates Energy Homeostasis by Modulating Food Intake and Energy Expenditure
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{"title"=>"PDK1-Foxo1 in agouti-related peptide neurons regulates energy homeostasis by modulating food intake and energy expenditure", "type"=>"journal", "authors"=>[{"first_name"=>"Yongheng", "last_name"=>"Cao", "scopus_author_id"=>"14420924200"}, {"first_name"=>"Masanori", "last_name"=>"Nakata", "scopus_author_id"=>"7202180990"}, {"first_name"=>"Shiki", "last_name"=>"Okamoto", "scopus_author_id"=>"35393672400"}, {"first_name"=>"Eisuke", "last_name"=>"Takano", "scopus_author_id"=>"26435523800"}, {"first_name"=>"Toshihiko", "last_name"=>"Yada", "scopus_author_id"=>"7103270844"}, {"first_name"=>"Yasuhiko", "last_name"=>"Minokoshi", "scopus_author_id"=>"7004228783"}, {"first_name"=>"Yukio", "last_name"=>"Hirata", "scopus_author_id"=>"57198455239"}, {"first_name"=>"Kazunori", "last_name"=>"Nakajima", "scopus_author_id"=>"7404396467"}, {"first_name"=>"Kristy", "last_name"=>"Iskandar", "scopus_author_id"=>"23979732800"}, {"first_name"=>"Yoshitake", "last_name"=>"Hayashi", "scopus_author_id"=>"26643495200"}, {"first_name"=>"Wataru", "last_name"=>"Ogawa", "scopus_author_id"=>"35411861600"}, {"first_name"=>"Gregory S.", "last_name"=>"Barsh", "scopus_author_id"=>"35394756500"}, {"first_name"=>"Hiroshi", "last_name"=>"Hosoda", "scopus_author_id"=>"35407507700"}, {"first_name"=>"Kenji", "last_name"=>"Kangawa", "scopus_author_id"=>"35398827000"}, {"first_name"=>"Hiroshi", "last_name"=>"Itoh", "scopus_author_id"=>"55498303500"}, {"first_name"=>"Tetsuo", "last_name"=>"Noda", "scopus_author_id"=>"35396005100"}, {"first_name"=>"Masato", "last_name"=>"Kasuga", "scopus_author_id"=>"7201474187"}, {"first_name"=>"Jun", "last_name"=>"Nakae", "scopus_author_id"=>"7004088792"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-79954455756", "sgr"=>"79954455756", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0018324", "pmid"=>"21694754", "isbn"=>"1932-6203 (Electronic)\r1932-6203 (Linking)", "pui"=>"361610809"}, "id"=>"45fb8b5d-d6bb-36cd-9e7b-71066a57a4e4", "abstract"=>"Insulin and leptin intracellular signaling pathways converge and act synergistically on the hypothalamic phosphatidylinositol-3-OH kinase/3-phosphoinositide-dependent protein kinase 1 (PDK1). However, little is known about whether PDK1 in agouti-related peptide (AGRP) neurons contributes to energy homeostasis. We generated AGRP neuron-specific PDK1 knockout (AGRPPdk1(-/-)) mice and mice with selective expression of transactivation-defective Foxo1 (Δ256Foxo1(AGRP)Pdk1(-/-)). The AGRPPdk1(-/-) mice showed reductions in food intake, body length, and body weight. The Δ256Foxo1(AGRP)Pdk1(-/-) mice showed increased body weight, food intake, and reduced locomotor activity. After four weeks of calorie-restricted feeding, oxygen consumption and locomotor activity were elevated in AGRPPdk1(-/-) mice and reduced in Δ256Foxo1(AGRP)Pdk1(-/-) mice. In vitro, ghrelin-induced changes in [Ca(2+)](i) and inhibition of ghrelin by leptin were significantly attenuated in AGRPPdk1(-/-) neurons compared to control neurons. However, ghrelin-induced [Ca(2+)](i) changes and leptin inhibition were restored in Δ256Foxo1(AGRP)Pdk1(-/-) mice. These results suggested that PDK1 and Foxo1 signaling pathways play important roles in the control of energy homeostasis through AGRP-independent mechanisms.", "link"=>"http://www.mendeley.com/research/pdk1foxo1-agoutirelated-peptide-neurons-regulates-energy-homeostasis-modulating-food-intake-energy-e", "reader_count"=>23, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>4, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>1, "Student > Master"=>2, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>4, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>1, "Student > Master"=>2, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>2, "Medicine and Dentistry"=>6, "Agricultural and Biological Sciences"=>10, "Neuroscience"=>2, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Neuroscience"=>{"Neuroscience"=>2}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>10}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"United Kingdom"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/784950"], "description"=>"<p>(<b>A</b>) Subcellular localization of Foxo1 in AGRP neurons from <i>AGRPPdk1<sup>+/+</sup></i>(top panel) and <i>AGRPPdk1<sup>−/−</sup></i>(bottom panel) mice. Representative double immunofluorescence images show hypothalamic regions doubly-labeled for AGRP and Foxo1. Green, AGRP; red, Foxo1; blue, DAPI staining. White arrows indicate AGRP neurons. (<b>B</b>) Quantification of nuclear Foxo1 in AGRP neurons from <i>AGRPPdk1<sup>+/+</sup></i> and <i>AGRPPdk1<sup>−/−</sup></i> mice. The percentage of AGRP neurons with nuclear Foxo1 among all AGRP neurons was determined as described in Experimental Procedures. Values are means ± SEM of three mice in each genotype. An asterisk indicates a statistically significant difference between <i>AGRPPdk1<sup>+/+</sup></i> and <i>AGRPPdk1<sup>−/−</sup></i> mice with p<0.001 (one-factor ANOVA). (<b>C</b>) Body weights of male control (open circles), <i>Δ256Foxo1<sup>AGRP</sup></i> (open triangles), <i>AGRPPdk1<sup>−/−</sup></i> (closed circles), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1<sup>−/−</sup></i> (closed triangles) mice. Values represent the mean ± SEM of 20 mice in each genotype. Asterisks indicate statistically significant differences between <i>AGRPPdk1<sup>−/−</sup></i> and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1<sup>−/−</sup></i> with *p<0.001, **p<0.01, and ***p<0.05 (one-factor ANOVA). (<b>D</b>) The calculated weights of muscle, adipose tissue, visceral fat, and subcutaneous fat in male control (gray bar), <i>Δ256Foxo1<sup>AGRP</sup></i> (white bar), <i>AGRPPdk1<sup>−/−</sup></i>(blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup>(magenta bar) mice at 24 weeks of age. Skeletal muscle weight, adipose tissue weight (sum of visceral and subcutaneous fats), visceral fat weight, and subcutaneous fat weight were calculated as described in Experimental Procedures. The data represent the mean weight ± SEM of 10 mice per genotype. Asterisks indicate statistically significant differences as indicated with *p<0.001, **p<0.005, and ***p<0.05 (one-factor ANOVA). (<b>E</b>) Four-day food intake for male control (gray bar), <i>Δ256Foxo1<sup>AGRP</sup></i> (white bar), <i>AGRPPdk1<sup>−/−</sup></i>(blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup>(magenta bar) mice at 24 weeks of age. The data represent the mean ± SEM of 10 mice per genotype. An asterisk indicates a statistically significant difference as indicated with *p<0.005 (one-factor ANOVA). (<b>F</b>) Expression in the fed-state of hypothalamic neuropeptide genes in control (gray bar), <i>Δ256Foxo1<sup>AGRP</sup></i> (white bar), <i>AGRPPdk1<sup>−/−</sup></i>(blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup>(magenta bar) mice. Data were normalized to <i>β-actin</i> expression and represent the mean ± SEM of six mice per genotype. An asterisk indicates a statistically significant difference between control and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> mice with p<0.05 (one-factor ANOVA). (<b>G</b>) Oxygen consumption in male control (gray bar), <i>Δ256Foxo1<sup>AGRP</sup></i> (white bar), <i>AGRPPdk1<sup>−/−</sup></i>(blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup>(magenta bar) mice at 24 weeks of age. The values represent the mean ± SEM of 10 male mice per genotype. (<b>H</b>) Respiratory quotient of male control (gray bar), <i>Δ256Foxo1<sup>AGRP</sup></i> (white bar), <i>AGRPPdk1<sup>−/−</sup></i>(blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup>(magenta bar) mice at 24 weeks of age. The values represent the mean ± SEM of 10 mice per genotype. An asterisk indicates a statistically significant difference between <i>AGRPPdk1<sup>−/−</sup></i> and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> mice with p<0.05 (one-factor ANOVA). (<b>I</b>) Basal locomotor activity for male control (gray bar), <i>Δ256Foxo1<sup>AGRP</sup></i> (white bar), <i>AGRPPdk1<sup>−/−</sup></i>(blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup>(magenta bar) mice at 24 weeks of age during the light and dark phases. The values represent the mean ± SEM of 5 mice per genotype. An asterisk indicates a statistically significant difference as indicated with p<0.001 (one-factor ANOVA).</p>", "links"=>[], "tags"=>["foxo1", "rescued", "metabolic", "phenotype"], "article_id"=>455298, "categories"=>["Chemistry"], "users"=>["Yongheng Cao", "Masanori Nakata", "Shiki Okamoto", "Eisuke Takano", "Toshihiko Yada", "Yasuhiko Minokoshi", "Yukio Hirata", "Kazunori Nakajima", "Kristy Iskandar", "Yoshitake Hayashi", "Wataru Ogawa", "Gregory S. Barsh", "Hiroshi Hosoda", "Kenji Kangawa", "Hiroshi Itoh", "Tetsuo Noda", "Masato Kasuga", "Jun Nakae"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0018324.g004", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_a_dominant_negative_FoxO1_256Foxo1_rescued_the_metabolic_phenotype_of_AGRPPdk1_8722_8722_mice_/455298", "title"=>"Expression of a dominant negative FoxO1 (Δ256Foxo1) rescued the metabolic phenotype of <i>AGRPPdk1<sup>−/−</sup></i> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-04-07 01:28:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/784615"], "description"=>"<p>(<b>A</b>) Representative immunofluorescence images of hypothalamic regions doubly labeled for AGRP and PDK1 in 24-week-old <i>AGRPPdk1<sup>+/+</sup></i> (top panel) and <i>AGRPPdk1<sup>−/−</sup></i> (bottom panel) mice fed <i>ad libitum</i>. Green, red and blue indicate AGRP, PDK1, and DAPI staining, respectively. White arrows indicate AGRP neurons. Scale bars indicate 50 µm. (<b>B</b>) Quantification of PDK1-positive AGRP neurons from <i>AGRPPdk1<sup>+/+</sup></i> (gray bar) and <i>AGRPPdk1<sup>−/−</sup></i> (blue bar) mice. The percentage of PDK1-positive AGRP neurons among AGRP neurons was determined as described in Experimental Procedures. Values are means ± SEM of three mice of each genotype. An asterisk indicates a statistically significant difference between <i>AGRPPdk1<sup>+/+</sup></i> and <i>AGRPPdk1<sup>−/−</sup></i> mice with p<0.001 (one-factor ANOVA). (<b>C</b>) Body weight of male (left panel) and female (right panel) control (open circles) and <i>AGRPPdk1<sup>−/−</sup></i> (closed circles) mice fed normal chow. Values represent mean ± SEM of 35–40 mice in each genotype. An asterisk indicates a statistically significant difference between control and <i>AGRPPdk1<sup>−/−</sup></i> mice with p<0.05 (one-factor ANOVA). (<b>D</b>) Naso-anal length (NAL) of male (left panel) and female (right panel) control mice (gray bar) and <i>AGRPPdk1<sup>−/−</sup></i> mice (blue bar) at 24 weeks of age. Values represent mean ± SEM of 30 mice in each genotype. An asterisk indicates a statistically significant difference between control and <i>AGRPPdk1<sup>−/−</sup></i> mice with p<0.05 (one-factor ANOVA). (<b>E</b>) The calculated weights of muscle, adipose tissue, visceral fat, and subcutaneous fat in male control (gray bar) and <i>AGRPPdk1<sup>−/−</sup></i>(blue bar) mice at 24 weeks of age. Skeletal muscle weight, adipose tissue weight (sum of visceral and subcutaneous fats), visceral fat weight, and subcutaneous fat weight were calculated as described in Experimental Procedures. The data represent the mean weight ± SEM of 10 mice per genotype. Asterisks indicate statistically significant differences between control and <i>AGRPPdk1<sup>−/−</sup></i> mice with *p<0.001, **p<0.005, and ***p<0.05 (one-factor ANOVA). (<b>F</b>) Four-day food intake of male and female control mice (gray bar) and <i>AGRPPdk1<sup>−/−</sup></i> mice (blue bar) at 24 weeks of age. Values represent mean ± SEM of 40 mice in each genotype. An asterisk indicates a statistically significant difference between control and <i>AGRPPdk1<sup>−/−</sup></i> mice with p<0.05 (one-factor ANOVA). (<b>G</b>) Oxygen consumption in male control (gray bar) and <i>AGRPPdk1<sup>−/−</sup></i>(blue bar) mice at 24 weeks of age. The values represent the mean ± SEM of 10 male mice per genotype. (<b>H</b>) Respiratory quotient of male control (gray bar) and <i>AGRPPdk1<sup>−/−</sup></i>(blue bar) mice at 24 weeks of age. The values represent the mean ± SEM of 10 mice per genotype. (<b>I</b>) Basal locomotor activity for male control (gray bar) and <i>AGRPPdk1<sup>−/−</sup></i>(blue bar) mice at 24 weeks of age during the light and dark phases. The values represent the mean ± SEM of 5 mice per genotype. (<b>J–K</b>) Effects of intraperitoneal leptin injections on body weight and food intake. Leptin was injected into control (open circle, n = 8) or <i>AGRPPdk1<sup>−/−</sup></i> mice (closed circle, n = 5) for three consecutive days. Body weight (J) and food intake (K) were monitored for seven days. Body weight and food intake are presented as percentages of values from saline-injected mice for each genotype. An asterisk in (J) indicates a statistically significant difference between control and <i>AGRPPdk1<sup>−/−</sup></i> mice with p<0.05 (one-factor ANOVA). An asterisk in (K) indicates a statistically significant difference between saline- and leptin-injected mice in <i>AGRPPdk1<sup>−/−</sup></i> mice with p<0.05 (one-factor ANOVA).</p>", "links"=>[], "tags"=>["metabolic", "characterization"], "article_id"=>454965, "categories"=>["Chemistry"], "users"=>["Yongheng Cao", "Masanori Nakata", "Shiki Okamoto", "Eisuke Takano", "Toshihiko Yada", "Yasuhiko Minokoshi", "Yukio Hirata", "Kazunori Nakajima", "Kristy Iskandar", "Yoshitake Hayashi", "Wataru Ogawa", "Gregory S. Barsh", "Hiroshi Hosoda", "Kenji Kangawa", "Hiroshi Itoh", "Tetsuo Noda", "Masato Kasuga", "Jun Nakae"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0018324.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Generation_and_metabolic_characterization_of_AGRPPdk1_8722_8722_mice_/454965", "title"=>"Generation and metabolic characterization of <i>AGRPPdk1<sup>−/−</sup></i> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-04-07 01:22:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/785094"], "description"=>"<p>(<b>A</b>) Effects of 4 weeks of calorie restriction on body weight of 20-week-old male control (gray bar), <i>AGRPPdk1<sup>−/−</sup></i>(blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup>(magenta bar) mice. Values represent means ± SEM of the percentages of reduction of body weight at the end (4 week) of pair feeding compared to at the beginning of pair feeding. An asterisk indicates a statistically significant difference between bodyweight at the beginning and at the end of calorie restriction with p<0.05 (one-factor ANOVA; n = 10 male mice per genotype). (<b>B</b>) Oxygen consumption of male calorie-restricted control (gray bar), <i>AGRPPdk1<sup>−/−</sup></i> (blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup>(magenta bar) during the light and dark phases. Values represent the mean ± SEM of 10 mice per genotype. An asterisk indicates a statistically significant difference between <i>AGRPPdk1<sup>−/−</sup></i> and control or <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> mice with p<0.05 (one-factor ANOVA). (<b>C</b>) Respiratory quotients of male pair-fed control (gray bar), <i>AGRPPdk1<sup>−/−</sup></i> (blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> (magenta bar) mice during the light and dark phases. Values represent the mean ± SEM of 10 mice per genotype. An asterisk indicates a statistically significant difference between <i>AGRPPdk1<sup>−/−</sup></i> and control or <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> mice with p<0.001 (one-factor ANOVA). (<b>D</b>) Basal locomotor activity of male pair-fed control (gray bar), <i>AGRPPdk1<sup>−/−</sup></i> (blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> (magenta bar) during the light and dark phases. Values represent the mean ± SEM of 10 mice per genotype. An asterisk indicates a statistically significant difference between <i>AGRPPdk1<sup>−/−</sup></i> and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> mice with p<0.05 (one-factor ANOVA). (<b>E–F</b>) Effects of intraperitoneal leptin injections on body weight and food intake of pair-fed control (open squares, n = 10), <i>AGRPPdk1<sup>−/−</sup></i> mice (blue closed circles, n = 10), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup>(red squares, n = 10) mice. Leptin was injected on 3 consecutive days. Body weight (E) and food intake (F) were monitored for eight days. Body weight and food intake data are presented as the percentage of that for saline-injected mice for each genotype. An asterisk in (F) indicates statistically significant differences between control and <i>AGRPPdk1<sup>−/−</sup></i> mice with *p<0.001, **p<0.01, and ***p<0.05 by one-factor ANOVA. (<b>G</b>) Cumulative food intake for male pair-fed control (gray bar), <i>AGRPPdk1<sup>−/−</sup></i> (blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> (magenta bar) mice injected with saline or ghrelin after a 24-h fast. Cumulative food intake was monitored for 6 h. Values represent the ratio of the mean cumulative food intakes of ghrelin:vehicle injected mice for each genotype. An asterisk indicates statistically significant differences between control and <i>AGRPPdk1<sup>−/−</sup></i> mice with *p<0.02 (one-factor ANOVA; n = 10 per genotype for each condition). (<b>H</b>) Cumulative food intake of male pair-fed control (gray bar), <i>AGRPPdk1<sup>−/−</sup></i> (blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> (magenta bar) mice injected with saline or MTII after a 24-h fast. Cumulative food intake was monitored for 24 h. Values represent the ratio of the mean cumulative food intakes of MTII:vehicle injected mice for each genotype. Asterisks indicate statistically significant differences between control and <i>AGRPPdk1<sup>−/−</sup></i> mice with p<0.05 (one-factor ANOVA; n = 10 per genotype).</p>", "links"=>[], "tags"=>["phenotypes", "calorie-restricted"], "article_id"=>455446, "categories"=>["Chemistry"], "users"=>["Yongheng Cao", "Masanori Nakata", "Shiki Okamoto", "Eisuke Takano", "Toshihiko Yada", "Yasuhiko Minokoshi", "Yukio Hirata", "Kazunori Nakajima", "Kristy Iskandar", "Yoshitake Hayashi", "Wataru Ogawa", "Gregory S. Barsh", "Hiroshi Hosoda", "Kenji Kangawa", "Hiroshi Itoh", "Tetsuo Noda", "Masato Kasuga", "Jun Nakae"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0018324.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Metabolic_phenotypes_of_calorie_restricted_AGRPPdk1_8722_8722_and_256Foxo1_AGRP_Pdk1_8722_8722_mice_/455446", "title"=>"Metabolic phenotypes of calorie-restricted <i>AGRPPdk1<sup>−/−</sup></i> and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-04-07 01:30:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/785263"], "description"=>"<p>(<b>A</b>)–(<b>C</b>) Administration of 10<sup>−10</sup> M of ghrelin increased cytosolic calcium ([Ca<sup>2+</sup>]<sub>i</sub>) in AGRP neurons from <i>AGRPPdk1<sup>+/+</sup></i> (A), <i>AGRPPdk1<sup>−/−</sup></i> (B), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> (C) mice. Administration of 10<sup>−12</sup> M of leptin inhibited increases in [Ca<sup>2+</sup>]<sub>i</sub> induced by ghrelin in <i>AGRPPdk1<sup>+/+</sup></i> (A) and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> (B) neurons, but not in <i>AGRPPdk1<sup>−/−</sup></i> neurons (C). (<b>D</b>) Amplitude of [Ca<sup>2+</sup>]<sub>i</sub> responses to ghrelin in the absence or presence of leptin (10<sup>−12</sup> M) in AGRP neurons of <i>AGRPPdk1<sup>+/+</sup></i>(gray bar), <i>AGRPPdk1<sup>−/−</sup></i>(blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup>(magenta bar) mice. Values are means ± SEM of the ratio of [Ca<sup>2+</sup>]<sub>i</sub> in the presence and absence of leptin. An asterisk indicates a statistically significant difference between the absence and the presence of leptin with p<0.05 (one-factor ANOVA: n = 10 AGRP neurons per genotype). (<b>E</b>) Fura-2 detection of [Ca<sup>2+</sup>]<sub>i</sub> in response to ghrelin. Values are means ± SEM of ghrelin-stimulated fura-2 ratios in AGRP neurons from <i>AGRPPdk1<sup>+/+</sup></i>(gray bar), <i>AGRPPdk1<sup>−/−</sup></i>(blue bar), and <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup>(magenta bar). An asterisk indicates a statistically significant difference between <i>AGRPPdk1<sup>−/−</sup></i> and control or <i>Δ256Foxo1<sup>AGRP</sup>Pdk1</i><sup>−/−</sup> mice with p<0.05 (one-factor ANOVA: n = 10 AGRP neurons per genotype).</p>", "links"=>[], "tags"=>["defects", "agrp", "neurons"], "article_id"=>455610, "categories"=>["Chemistry"], "users"=>["Yongheng Cao", "Masanori Nakata", "Shiki Okamoto", "Eisuke Takano", "Toshihiko Yada", "Yasuhiko Minokoshi", "Yukio Hirata", "Kazunori Nakajima", "Kristy Iskandar", "Yoshitake Hayashi", "Wataru Ogawa", "Gregory S. Barsh", "Hiroshi Hosoda", "Kenji Kangawa", "Hiroshi Itoh", "Tetsuo Noda", "Masato Kasuga", "Jun Nakae"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0018324.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_defects_of_AGRP_neurons_in_AGRPPdk1_8722_8722_mice_/455610", "title"=>"Functional defects of AGRP neurons in <i>AGRPPdk1<sup>−/−</sup></i> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-04-07 01:33:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/784813"], "description"=>"<p>(<b>A</b>) Cumulative food intake of male control (gray bar) and <i>AGRPPdk1<sup>−/−</sup></i> (blue bar) mice injected with saline or MTII after a 24-h fast. Cumulative food intake was monitored for 24 h. Values represent the ratio of the mean cumulative food intakes of MTII: vehicle injected mice for each genotype. Asterisks indicate statistically significant differences between control and <i>AGRPPdk1<sup>−/−</sup></i> mice with p<0.05 (one-factor ANOVA; n = 6 per genotype). (<b>B</b>) Cumulative food intake of male control (gray bar) and <i>AGRPPdk1<sup>−/−</sup></i> (blue bar) mice injected with saline or ghrelin after a 24-h fast. Cumulative food intake was monitored for six hours. Values represent the ratio of the mean cumulative food intakes of ghrelin: vehicle injected mice for each genotype. A asterisk indicates statistically significant differences between control and <i>AGRPPdk1<sup>−/−</sup></i> mice with *p<0.01 (one-factor ANOVA; n = 6 per genotype for each condition).</p>", "links"=>[], "tags"=>["ghrelin", "responses", "fed"], "article_id"=>455165, "categories"=>["Chemistry"], "users"=>["Yongheng Cao", "Masanori Nakata", "Shiki Okamoto", "Eisuke Takano", "Toshihiko Yada", "Yasuhiko Minokoshi", "Yukio Hirata", "Kazunori Nakajima", "Kristy Iskandar", "Yoshitake Hayashi", "Wataru Ogawa", "Gregory S. Barsh", "Hiroshi Hosoda", "Kenji Kangawa", "Hiroshi Itoh", "Tetsuo Noda", "Masato Kasuga", "Jun Nakae"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0018324.g003", "stats"=>{"downloads"=>3, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MTII_and_ghrelin_responses_in_ad_libitum_fed_AGRPPdk1_8722_8722_/455165", "title"=>"MTII and ghrelin responses in <i>ad libitum</i> fed <i>AGRPPdk1<sup>−/−</sup></i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-04-07 01:26:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/784722"], "description"=>"<p>(<b>A</b>) Numbers of AGRP positive cells in the arcuate nuclei of <i>AGRPPdk1<sup>+/+</sup></i> (gray bar) and <i>AGRPPdk1<sup>−/−</sup></i> (blue bar) mice. AGRP cell counts indifferent regions of the arcuate nucleus showed different numbers of AGRP neurons in <i>AGRPPdk1<sup>+/+</sup></i> (n = 3) and <i>AGRPPdk1<sup>−/−</sup></i> mice (n = 3). (<b>B</b>) Representative Immunofluorescence images of AGRP in the hypothalamic regions of <i>AGRPPdk1<sup>+/+</sup></i> (left panel) and <i>AGRPPdk1<sup>−/−</sup></i> mice (right panel). Green, AGRP; blue, DAPI. Scale bars indicate 100 µm. (<b>C</b>) Expression in the fed-state of hypothalamic neuropeptide genes in control (gray bar) and <i>AGRPPdk1<sup>−/−</sup></i>(blue bar) mice. Data were normalized to <i>β-actin</i> expression and represent the mean ± SEM of six mice per genotype.</p>", "links"=>[], "tags"=>["defects", "agrp", "neurons"], "article_id"=>455069, "categories"=>["Chemistry"], "users"=>["Yongheng Cao", "Masanori Nakata", "Shiki Okamoto", "Eisuke Takano", "Toshihiko Yada", "Yasuhiko Minokoshi", "Yukio Hirata", "Kazunori Nakajima", "Kristy Iskandar", "Yoshitake Hayashi", "Wataru Ogawa", "Gregory S. Barsh", "Hiroshi Hosoda", "Kenji Kangawa", "Hiroshi Itoh", "Tetsuo Noda", "Masato Kasuga", "Jun Nakae"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0018324.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_defects_of_AGRP_neurons_in_AGRPPdk1_8722_8722_mice_/455069", "title"=>"Functional defects of AGRP neurons in <i>AGRPPdk1<sup>−/−</sup></i> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-04-07 01:24:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/393394", "https://ndownloader.figshare.com/files/393413", "https://ndownloader.figshare.com/files/393433", "https://ndownloader.figshare.com/files/393452", "https://ndownloader.figshare.com/files/393473", "https://ndownloader.figshare.com/files/393499", "https://ndownloader.figshare.com/files/393518", "https://ndownloader.figshare.com/files/393540"], "description"=>"<div><p>Insulin and leptin intracellular signaling pathways converge and act synergistically on the hypothalamic phosphatidylinositol-3-OH kinase/3-phosphoinositide-dependent protein kinase 1 (PDK1). However, little is known about whether PDK1 in agouti-related peptide (AGRP) neurons contributes to energy homeostasis. We generated AGRP neuron-specific PDK1 knockout (<em>AGRPPdk1<sup>−/−</sup></em>) mice and mice with selective expression of transactivation-defective Foxo1 (<em>Δ256Foxo1<sup>AGRP</sup>Pdk1<sup>−/−</sup></em>). The <em>AGRPPdk1<sup>−/−</sup></em> mice showed reductions in food intake, body length, and body weight. The <em>Δ256Foxo1<sup>AGRP</sup>Pdk1<sup>−/−</sup></em> mice showed increased body weight, food intake, and reduced locomotor activity. After four weeks of calorie-restricted feeding, oxygen consumption and locomotor activity were elevated in <em>AGRPPdk1<sup>−/−</sup></em> mice and reduced in <em>Δ256Foxo1<sup>AGRP</sup>Pdk1<sup>−/−</sup></em> mice. <em>In vitro</em>, ghrelin-induced changes in [Ca<sup>2+</sup>]<sub>i</sub> and inhibition of ghrelin by leptin were significantly attenuated in <em>AGRPPdk1<sup>−/−</sup></em> neurons compared to control neurons. However, ghrelin-induced [Ca<sup>2+</sup>]<sub>i</sub> changes and leptin inhibition were restored in <em>Δ256Foxo1<sup>AGRP</sup>Pdk1<sup>−/−</sup></em> mice. These results suggested that PDK1 and Foxo1 signaling pathways play important roles in the control of energy homeostasis through AGRP-independent mechanisms.</p> </div>", "links"=>[], "tags"=>["pdk1-foxo1", "agouti-related", "peptide", "neurons", "regulates", "homeostasis", "modulating", "intake", "expenditure"], "article_id"=>137679, "categories"=>["Chemistry"], "users"=>["Yongheng Cao", "Masanori Nakata", "Shiki Okamoto", "Eisuke Takano", "Toshihiko Yada", "Yasuhiko Minokoshi", "Yukio Hirata", "Kazunori Nakajima", "Kristy Iskandar", "Yoshitake Hayashi", "Wataru Ogawa", "Gregory S. Barsh", "Hiroshi Hosoda", "Kenji Kangawa", "Hiroshi Itoh", "Tetsuo Noda", "Masato Kasuga", "Jun Nakae"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0018324.s001", "https://dx.doi.org/10.1371/journal.pone.0018324.s002", "https://dx.doi.org/10.1371/journal.pone.0018324.s003", "https://dx.doi.org/10.1371/journal.pone.0018324.s004", "https://dx.doi.org/10.1371/journal.pone.0018324.s005", "https://dx.doi.org/10.1371/journal.pone.0018324.s006", "https://dx.doi.org/10.1371/journal.pone.0018324.s007", "https://dx.doi.org/10.1371/journal.pone.0018324.s008"], "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/PDK1_Foxo1_in_Agouti_Related_Peptide_Neurons_Regulates_Energy_Homeostasis_by_Modulating_Food_Intake_and_Energy_Expenditure/137679", "title"=>"PDK1-Foxo1 in Agouti-Related Peptide Neurons Regulates Energy Homeostasis by Modulating Food Intake and Energy Expenditure", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-04-07 02:07:59"}

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Relative Metric

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