Differential regulation of AMPK activation in leptin- and creatine-deficient mice

TY - JOUR

T1 - Differential regulation of AMPK activation in leptin- and creatine-deficient mice

AU - Stockebrand, Malte

AU - Sauter, Kathrin

AU - Neu, Axel

AU - Isbrandt, Dirk

AU - Choe, Chi-un

PY - 2013/10/1

Y1 - 2013/10/1

N2 - AMP-activated protein kinase (AMPK) is a key sensor and regulator of energy homeostasis. Previously, we demonstrated that intracellular energy depletion by L-arginine:glycine amidinotransferase (AGAT) deficiency resulted in AMPK activation and protected from metabolic syndrome. In the present study, we show tissue-specific leptin dependence of AMPK activation by energy depletion. We investigated leptin-dependent AMPK regulation in AGAT- and leptin-deficient (d/d ob/ob) mice. Like ob/ob mice, but unlike d/d mice, d/d ob/ob mice were obese and glucose intolerant. Therefore, leptin is a prerequisite for resistance to metabolic syndrome in AGAT-deficient mice. Quantitative Western blots revealed a 4-fold increase in AMPK activation in skeletal muscle of d/d ob/ob mice (P<0.001). However, AMPK activation was absent in white adipose tissue (WAT) and liver. Compared with blood glucose levels in ob/ob mice, fasting levels were still reduced and therefore did not show leptin dependence (wild-type, 79.4±3.9 mg/dl; d/d, 68.4±3.2 mg/dl; P<0.05). In ob/ob mice and wild-type mice, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), in combination with leptin, augmented glucose tolerance compared with AICAR alone, whereas no improvement was found under conditions of high-fat-diet feeding. These findings reveal a previously unknown synergistic AMPK activation by leptin and intracellular energy depletion, suggesting that AMPK activation can be therapeutically effective in metabolic syndrome only if leptin sensitivity is preserved.

AB - AMP-activated protein kinase (AMPK) is a key sensor and regulator of energy homeostasis. Previously, we demonstrated that intracellular energy depletion by L-arginine:glycine amidinotransferase (AGAT) deficiency resulted in AMPK activation and protected from metabolic syndrome. In the present study, we show tissue-specific leptin dependence of AMPK activation by energy depletion. We investigated leptin-dependent AMPK regulation in AGAT- and leptin-deficient (d/d ob/ob) mice. Like ob/ob mice, but unlike d/d mice, d/d ob/ob mice were obese and glucose intolerant. Therefore, leptin is a prerequisite for resistance to metabolic syndrome in AGAT-deficient mice. Quantitative Western blots revealed a 4-fold increase in AMPK activation in skeletal muscle of d/d ob/ob mice (P<0.001). However, AMPK activation was absent in white adipose tissue (WAT) and liver. Compared with blood glucose levels in ob/ob mice, fasting levels were still reduced and therefore did not show leptin dependence (wild-type, 79.4±3.9 mg/dl; d/d, 68.4±3.2 mg/dl; P<0.05). In ob/ob mice and wild-type mice, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), in combination with leptin, augmented glucose tolerance compared with AICAR alone, whereas no improvement was found under conditions of high-fat-diet feeding. These findings reveal a previously unknown synergistic AMPK activation by leptin and intracellular energy depletion, suggesting that AMPK activation can be therapeutically effective in metabolic syndrome only if leptin sensitivity is preserved.

KW - AMP-Activated Protein Kinases

KW - Adipose Tissue, White

KW - Aminoimidazole Carboxamide

KW - Animals

KW - Blood Glucose

KW - Creatine

KW - Dietary Fats

KW - Enzyme Activation

KW - Leptin

KW - Liver

KW - Mice

KW - Mice, Knockout

KW - Muscle, Skeletal

KW - Obesity

KW - Ribonucleotides

U2 - 10.1096/fj.12-225136

DO - 10.1096/fj.12-225136

M3 - SCORING: Journal article

C2 - 23825223

VL - 27

SP - 4147

EP - 4156

JO - FASEB J

JF - FASEB J

SN - 0892-6638

IS - 10

ER -