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FASEB J. 2013 Oct;27(10):4147-56. doi: 10.1096/fj.12-225136. Epub 2013 Jun 28.

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

Author information

1
1Experimental Neuropediatrics, Center for Molecular Neurobiology and Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany. cchoe@uke.de.

Abstract

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.

KEYWORDS:

AGAT; AICAR; ob/ob; skeletal muscle; white adipose tissue

PMID:
23825223
DOI:
10.1096/fj.12-225136
[Indexed for MEDLINE]

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