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Katrin Pfuhlmann, Paul T. Pfluger, Sonja C. Schriever, Timo D. Müller, Matthias H. Tschöp, Kerstin Stemmer
Dual specificity phosphatase 6 deficiency is associated with impaired systemic glucose tolerance and reversible weight retardation in mice
www.plosone.org
www.plosone.org
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10 0 0 10 200.0125 707.4141 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(studies,)Tj
3.2087 0 Td
(DUSP6)Tj
3.2032 0 Td
(deficiency)Tj
4.2689 0 Td
(had)Tj
1.7065 0 Td
(only)Tj
1.9785 0 Td
(little)Tj
2.0013 0 Td
(impact)Tj
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(on)Tj
1.2755 0 Td
(the)Tj
1.474 0 Td
(regulation)Tj
4.3087 0 Td
(of)Tj
1.0148 0 Td
(energy)Tj
2.9026 0 Td
(metabolism)Tj
4.9039 0 Td
(or)Tj
-35.223 -1.3039 Td
(lipid)Tj
2.0466 0 Td
(homeostasis.)Tj
5.312 0 Td
(Moreover,)Tj
4.3937 0 Td
(rather)Tj
2.6476 0 Td
(than)Tj
2.0296 0 Td
(improving)Tj
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(glucose)Tj
3.1748 0 Td
(tolerance,)Tj
4.1215 0 Td
(16)Tj
1.1736 0 Td
(weeks)Tj
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(of)Tj
1.0148 0 Td
(HFD)Tj
2.2507 0 Td
(feed-)Tj
-35.206 -1.2982 Td
(ing)Tj
1.5023 0 Td
(resulted)Tj
3.3959 0 Td
(in)Tj
1.0375 0 Td
(temporarily)Tj
4.9322 0 Td
(increased)Tj
3.9968 0 Td
(glucose)Tj
3.1748 0 Td
(excursions)Tj
4.4731 0 Td
(after)Tj
2.0352 0 Td
(a)Tj
0.6577 0 Td
(glucose)Tj
3.1747 0 Td
(bolus.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 652.2519 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Methods)Tj
/F0 1 Tf
0 -1.4976 Td
(Mouse)Tj
3.189 0 Td
(husbandry)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 617.2724 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Global)Tj
2.8743 0 Td
(DUSP6)Tj
3.2031 0 Td
(wild)Tj
1.9445 0 Td
(type)Tj
1.9163 0 Td
(\(WT\))Tj
2.4774 0 Td
(and)Tj
1.7291 0 Td
(knockout)Tj
4.0252 0 Td
(\(KO\))Tj
2.3187 0 Td
(mice)Tj
2.1544 0 Td
(of)Tj
1.0148 0 Td
(mixed)Tj
2.7212 0 Td
(C57Bl/6J)Tj
3.7984 0 Td
(and)Tj
1.7291 0 Td
(129)Tj
1.6498 0 Td
(back-)Tj
-33.5563 -1.2982 Td
(ground)Tj
3.1691 0 Td
(were)Tj
2.1203 0 Td
(kindly)Tj
2.7609 0 Td
(provided)Tj
3.8154 0 Td
(by)Tj
1.1792 0 Td
(Prof.)Tj
2.1713 0 Td
(Jeffery)Tj
2.8006 0 Td
(Molkentin,)Tj
4.6715 0 Td
(Children's)Tj
4.3767 0 Td
(Hospital)Tj
3.617 0 Td
(Cincinnati)Tj
4.4843 0 Td
([)Tj
0.83 0.64 0.02 0 k
(19)Tj
0 g
(].)Tj
-35.1663 -1.3039 Td
(Study)Tj
2.5058 0 Td
(cohort)Tj
2.8516 0 Td
(mice)Tj
2.1543 0 Td
(were)Tj
2.1203 0 Td
(bred)Tj
2.0523 0 Td
(true)Tj
1.8425 0 Td
(from)Tj
2.2053 0 Td
(WT)Tj
1.7972 0 Td
(and)Tj
1.7291 0 Td
(KO)Tj
1.6384 0 Td
(mice,)Tj
2.3811 0 Td
(and)Tj
1.7291 0 Td
(housed)Tj
3.0955 0 Td
(in)Tj
1.0374 0 Td
(positive)Tj
3.3109 0 Td
(individual)Tj
-32.4508 -1.2983 Td
(ventilation)Tj
4.5127 0 Td
(cages)Tj
2.3244 0 Td
(in)Tj
1.0374 0 Td
(dedicated)Tj
4.0762 0 Td
(animal)Tj
2.9651 0 Td
(housing)Tj
3.4242 0 Td
(rooms)Tj
2.7893 0 Td
(with)Tj
1.9955 0 Td
(a)Tj
0.652 0 Td
(12-h)Tj
2.0523 0 Td
(light,)Tj
2.2507 0 Td
(12-h)Tj
2.0466 0 Td
(dark)Tj
2.0522 0 Td
(cycle)Tj
2.1884 0 Td
(\(6am-)Tj
-34.367 -1.2983 Td
(6pm\))Tj
2.3697 0 Td
(at)Tj
0.9524 0 Td
(22C)Tj
2.2281 0 Td
(with)Tj
1.9955 0 Td
(free)Tj
1.7292 0 Td
(access)Tj
2.6475 0 Td
(to)Tj
1.0205 0 Td
(water)Tj
2.4321 0 Td
(and)Tj
1.7348 0 Td
(standard)Tj
3.719 0 Td
(chow)Tj
2.3641 0 Td
(diet)Tj
1.7348 0 Td
(\(Harlan)Tj
3.3618 0 Td
(Teklad)Tj
2.9594 0 Td
(LM-485\))Tj
3.77 0 Td
(or)Tj
-35.0189 -1.3039 Td
(high)Tj
2.0069 0 Td
(fat)Tj
1.2415 0 Td
(diet)Tj
1.7348 0 Td
(\(HFD;)Tj
2.8176 0 Td
(Research)Tj
3.8041 0 Td
(Diets)Tj
2.3074 0 Td
(D12331)Tj
3.3335 0 Td
(Surwit)Tj
2.846 0 Td
(Diet,)Tj
2.1713 0 Td
(58%)Tj
1.9276 0 Td
(of)Tj
1.0148 0 Td
(calories)Tj
3.2541 0 Td
(from)Tj
2.2054 0 Td
(fat,)Tj
1.4626 0 Td
(New)Tj
2.0636 0 Td
(Bruns-)Tj
-34.1912 -1.2982 Td
(wick,)Tj
2.313 0 Td
(NJ,)Tj
1.5137 0 Td
(USA\).)Tj
2.6816 0 Td
(Initially,)Tj
3.5489 0 Td
(all)Tj
1.1452 0 Td
(mice)Tj
2.1543 0 Td
(were)Tj
2.1203 0 Td
(housed)Tj
3.0954 0 Td
(in)Tj
1.0375 0 Td
(groups)Tj
2.9707 0 Td
(of)Tj
1.0148 0 Td
(2)Tj
0.6916 0 Td
(to)Tj
1.0262 0 Td
(4.)Tj
0.9241 0 Td
(By)Tj
1.2529 0 Td
(the)Tj
1.4683 0 Td
(end)Tj
1.7178 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(diet)Tj
1.7348 0 Td
(expo-)Tj
-34.8999 -1.2983 Td
(sure,)Tj
2.1259 0 Td
(6)Tj
0.6973 0 Td
(WT)Tj
1.7972 0 Td
(mice)Tj
2.1543 0 Td
(were)Tj
2.1203 0 Td
(housed)Tj
3.0954 0 Td
(2)Tj
0.6973 0 Td
(per)Tj
1.5307 0 Td
(cage,)Tj
2.194 0 Td
(2)Tj
0.6917 0 Td
(WT)Tj
1.7971 0 Td
(mice)Tj
2.1544 0 Td
(were)Tj
2.1259 0 Td
(single)Tj
2.5285 0 Td
(housed,)Tj
3.3222 0 Td
(6)Tj
0.6917 0 Td
(KO)Tj
1.644 0 Td
(mice)Tj
2.1544 0 Td
(were)Tj
-33.5223 -1.3039 Td
(housed)Tj
3.0954 0 Td
(2)Tj
0.6916 0 Td
(per)Tj
1.5364 0 Td
(cage)Tj
1.9615 0 Td
(and)Tj
1.7348 0 Td
(3)Tj
0.6917 0 Td
(KO)Tj
1.6441 0 Td
(mice)Tj
2.1543 0 Td
(3)Tj
0.6916 0 Td
(per)Tj
1.5364 0 Td
(cage)Tj
1.9616 0 Td
(due)Tj
1.7007 0 Td
(to)Tj
1.0262 0 Td
(fighting.)Tj
3.5716 0 Td
(Food)Tj
2.2904 0 Td
(intake)Tj
2.6872 0 Td
(was)Tj
1.7008 0 Td
(assessed)Tj
3.4696 0 Td
(in)Tj
1.0375 0 Td
(mice)Tj
-35.1834 -1.2983 Td
(exposed)Tj
3.4355 0 Td
(to)Tj
1.0205 0 Td
(HFD)Tj
2.2393 0 Td
(from)Tj
2.1997 0 Td
(week)Tj
2.2394 0 Td
(3)Tj
0.6916 0 Td
(to)Tj
1.0148 0 Td
(5,)Tj
0.9128 0 Td
(with)Tj
1.9899 0 Td
(3)Tj
0.6916 0 Td
(WT)Tj
1.7858 0 Td
(mice)Tj
2.1487 0 Td
(being)Tj
2.4208 0 Td
(temporarily)Tj
4.9209 0 Td
(single)Tj
2.5285 0 Td
(housed)Tj
3.084 0 Td
(to)Tj
1.0205 0 Td
(increase)Tj
-34.3443 -1.2983 Td
(statistical)Tj
3.9061 0 Td
(power.)Tj
2.948 0 Td
(One)Tj
1.9389 0 Td
(cage)Tj
1.9672 0 Td
(of)Tj
1.0148 0 Td
(WT)Tj
1.7971 0 Td
(mice)Tj
2.1544 0 Td
(was)Tj
1.7007 0 Td
(excluded)Tj
3.7814 0 Td
(from)Tj
2.2054 0 Td
(the)Tj
1.474 0 Td
(analysis)Tj
3.3222 0 Td
(due)Tj
1.7007 0 Td
(to)Tj
1.0262 0 Td
(spilling)Tj
3.1407 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
-35.0926 -1.2982 Td
(food.)Tj
1.1962 -1.3039 Td
(For)Tj
1.627 0 Td
(the)Tj
1.4684 0 Td
(analysis)Tj
3.3278 0 Td
(of)Tj
1.0148 0 Td
(Dusp6)Tj
2.8403 0 Td
(expression)Tj
4.4617 0 Td
(in)Tj
1.0375 0 Td
(lean)Tj
1.8709 0 Td
(vs.)Tj
1.2642 0 Td
(diet)Tj
1.7348 0 Td
(induced)Tj
3.4696 0 Td
(obese)Tj
2.4378 0 Td
(\(DIO\))Tj
2.7269 0 Td
(mice,)Tj
2.3754 0 Td
(C57Bl/6J)Tj
-32.8533 -1.2983 Td
(mice)Tj
2.1543 0 Td
(\(Jackson)Tj
3.6566 0 Td
(Laboratory,)Tj
4.8699 0 Td
(Bar)Tj
1.6044 0 Td
(Harbor,)Tj
3.4016 0 Td
(ME,)Tj
1.9105 0 Td
(USA\))Tj
2.4548 0 Td
(with)Tj
1.9956 0 Td
(an)Tj
1.2075 0 Td
(age)Tj
1.5421 0 Td
(of)Tj
1.0148 0 Td
(8)Tj
0.6916 0 Td
(to)Tj
1.0262 0 Td
(10)Tj
1.1735 0 Td
(weeks)Tj
2.6078 0 Td
(were)Tj
2.1204 0 Td
(either)Tj
-33.4316 -1.2983 Td
(maintained)Tj
4.7848 0 Td
(on)Tj
1.2756 0 Td
(chow)Tj
2.3641 0 Td
(or)Tj
1.0998 0 Td
(switched)Tj
3.7304 0 Td
(to)Tj
1.0261 0 Td
(HFD)Tj
2.2507 0 Td
(for)Tj
1.389 0 Td
(6)Tj
0.6916 0 Td
(months.)Tj
3.5093 0 Td
(The)Tj
1.7858 0 Td
(impact)Tj
2.9764 0 Td
(of)Tj
1.0148 0 Td
(leptin)Tj
2.5228 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4683 0 Td
(central)Tj
-33.1651 -1.3039 Td
(nervous)Tj
3.4128 0 Td
(system)Tj
2.9367 0 Td
(\(CNS\))Tj
/F12 1 Tf
2.778 0 Td
[()-4()-4()10()]TJ
/F7 1 Tf
2.7099 0 Td
(gene)Tj
2.0806 0 Td
(expression)Tj
4.4673 0 Td
(was)Tj
1.7008 0 Td
(assessed)Tj
3.4696 0 Td
(using)Tj
2.3924 0 Td
(adult)Tj
2.2507 0 Td
(chow-fed)Tj
3.9515 0 Td
(leptin-defi-)Tj
-32.1503 -1.2982 Td
(cient)Tj
2.1769 0 Td
(\(Lep)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 239.9811 413.6881 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(ob)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 247.5779 409.2661 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(\))Tj
0.5612 0 Td
(mice)Tj
2.1543 0 Td
(\(71.12)Tj
/F13 1 Tf
2.6873 0 Td
[()]TJ
/F7 1 Tf
0.788 0 Td
(0.71)Tj
1.8708 0 Td
(g\))Tj
1.0262 0 Td
(that)Tj
1.7801 0 Td
(once)Tj
2.1203 0 Td
(daily)Tj
2.1543 0 Td
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3.532 0 Td
(subcutaneous)Tj
5.6692 0 Td
(injections)Tj
4.1216 0 Td
(of)Tj
1.0148 0 Td
(either)Tj
-34.2366 -1.2982 Td
(human)Tj
3.0785 0 Td
(recombinant)Tj
5.3686 0 Td
(leptin)Tj
2.5172 0 Td
(\(1)Tj
1.0375 0 Td
(mg/kg;)Tj
3.0217 0 Td
(R&D)Tj
2.2847 0 Td
(Systems\))Tj
3.753 0 Td
(or)Tj
1.0942 0 Td
(vehicle)Tj
2.9877 0 Td
(\(PBS\).)Tj
2.7439 0 Td
(An)Tj
1.4513 0 Td
(additional)Tj
4.2747 0 Td
(group)Tj
2.6078 0 Td
(of)Tj
-36.2208 -1.3039 Td
(vehicle-treated)Tj
6.1114 0 Td
(Lep)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 275.9244 387.7228 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(ob)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 285.7322 383.244 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(mice)Tj
2.1486 0 Td
(was)Tj
1.7008 0 Td
(food)Tj
2.0522 0 Td
(restricted)Tj
3.9855 0 Td
(to)Tj
1.0262 0 Td
(receive)Tj
3.0047 0 Td
(daily)Tj
2.1486 0 Td
(only)Tj
1.9786 0 Td
(the)Tj
1.4683 0 Td
(amount)Tj
3.3562 0 Td
(of)Tj
1.0148 0 Td
(food)Tj
2.0466 0 Td
(eaten)Tj
-34.503 -1.2982 Td
(by)Tj
1.1792 0 Td
(the)Tj
1.4684 0 Td
(leptin-treated)Tj
5.6522 0 Td
(mice)Tj
2.1542 0 Td
(\(pair-fed)Tj
3.7361 0 Td
(to)Tj
1.0261 0 Td
(leptin\).)Tj
3.0898 0 Td
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1.3379 0 Td
(assess)Tj
2.5172 0 Td
(the)Tj
1.4683 0 Td
(impact)Tj
2.982 0 Td
(of)Tj
1.0148 0 Td
(fasting)Tj
2.88 0 Td
(and)Tj
1.7348 0 Td
(re-feeding)Tj
-32.241 -1.2983 Td
(on)Tj
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1.2756 0 Td
[()-4()-4()10()]TJ
/F7 1 Tf
2.7099 0 Td
(gene)Tj
2.0806 0 Td
(expression,)Tj
4.6941 0 Td
(male)Tj
2.143 0 Td
(chow-fed)Tj
3.9514 0 Td
(C57BL/6J)Tj
4.0876 0 Td
(mice)Tj
2.1543 0 Td
(were)Tj
2.1203 0 Td
(subjected)Tj
3.9685 0 Td
(to)Tj
1.0261 0 Td
(12,)Tj
1.3946 0 Td
(24)Tj
1.1736 0 Td
(or)Tj
1.0998 0 Td
(36)Tj
1.1679 0 Td
(h)Tj
0.7483 0 Td
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-35.7956 -1.3039 Td
(fasting)Tj
2.88 0 Td
(as)Tj
1.0148 0 Td
(well)Tj
1.8198 0 Td
(as)Tj
1.0148 0 Td
(refeeding)Tj
3.9571 0 Td
(for)Tj
1.3889 0 Td
(6)Tj
0.6974 0 Td
(h)Tj
0.7483 0 Td
(with)Tj
1.9956 0 Td
(fat-free)Tj
3.0954 0 Td
(diet)Tj
1.7348 0 Td
(\(FFD;)Tj
2.5795 0 Td
(0%)Tj
1.4513 0 Td
(kcal)Tj
1.8199 0 Td
(from)Tj
2.2053 0 Td
(fat,)Tj
1.4683 0 Td
(D04112303)Tj
-29.8712 -1.2983 Td
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3.8041 0 Td
(Diets\))Tj
2.6475 0 Td
(or)Tj
1.0999 0 Td
(HFD)Tj
2.2506 0 Td
([)Tj
0.83 0.64 0.02 0 k
(26)Tj
0 g
(].)Tj
2.0749 0 Td
(Mice)Tj
2.228 0 Td
(were)Tj
2.1203 0 Td
(sacrificed)Tj
4.0082 0 Td
(by)Tj
1.1792 0 Td
(asphyxiation)Tj
5.3064 0 Td
(with)Tj
1.9956 0 Td
(CO)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 501.2787 329.6125 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(2)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 504.7937 331.2566 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(.)Tj
0.4478 0 Td
(All)Tj
1.3947 0 Td
(studies)Tj
2.9877 0 Td
(were)Tj
-35.3081 -1.2982 Td
(approved)Tj
3.9742 0 Td
(by)Tj
1.1792 0 Td
(and)Tj
1.7291 0 Td
(performed)Tj
4.4731 0 Td
(according)Tj
4.1839 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4683 0 Td
(guidelines)Tj
4.2803 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
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5.1646 0 Td
(Animal)Tj
3.2201 0 Td
(Care)Tj
2.1089 0 Td
(and)Tj
-35.291 -1.2983 Td
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1.7405 0 Td
(Committee)Tj
4.7395 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(University)Tj
4.405 0 Td
(of)Tj
1.0148 0 Td
(Cincinnati,)Tj
4.7112 0 Td
(USA.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 276.1511 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Glucose)Tj
3.8504 0 Td
(tolerance)Tj
4.2803 0 Td
(tests)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 259.1433 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Following)Tj
4.2179 0 Td
(16)Tj
1.1735 0 Td
(weeks)Tj
2.6079 0 Td
(of)Tj
1.0148 0 Td
(HFD)Tj
2.2507 0 Td
(feeding,)Tj
3.3902 0 Td
(DUSP6)Tj
3.2031 0 Td
(WT)Tj
1.7972 0 Td
(and)Tj
1.7291 0 Td
(KO)Tj
1.6384 0 Td
(mice)Tj
2.1543 0 Td
(were)Tj
2.1203 0 Td
(fasted)Tj
2.5569 0 Td
(for)Tj
1.3832 0 Td
(6)Tj
0.6974 0 Td
(h,)Tj
0.9694 0 Td
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