Abstract
The adipocyte-derived hormone adiponectin signals from the fat storage depot to regulate metabolism in peripheral tissues. Inversely correlated with body fat levels, adiponectin reduction in obese individuals may play a causal role in the symptoms of metabolic syndrome. Adiponectin lowers serum glucose through suppression of hepatic glucose production, an effect attributed to activation of AMPK. Here, we investigated the signaling pathways that mediate the effects of adiponectin by studying mice with inducible hepatic deletion of LKB1, an upstream regulator of AMPK. We found that loss of LKB1 in the liver partially impaired the ability of adiponectin to lower serum glucose, though other actions of the hormone were preserved, including reduction of gluconeogenic gene expression and hepatic glucose production as assessed by euglycemic hyperinsulinemic clamp. Furthermore, in primary mouse hepatocytes, the absence of LKB1, AMPK, or the transcriptional coactivator CRTC2 did not prevent adiponectin from inhibiting glucose output or reducing gluconeogenic gene expression. These results reveal that whereas some of the hormone's actions in vivo may be LKB1 dependent, substantial LKB1-, AMPK-, and CRTC2-independent signaling pathways also mediate effects of adiponectin.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / deficiency
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / physiology*
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Adiponectin / pharmacology
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Adiponectin / physiology
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Aminoimidazole Carboxamide / analogs & derivatives
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Aminoimidazole Carboxamide / pharmacology
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Animals
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Blood Glucose / analysis
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Fasting / blood
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Gene Deletion
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Gene Expression Regulation / drug effects
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Gluconeogenesis / drug effects*
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Gluconeogenesis / genetics
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Glucose Clamp Technique
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Hepatocytes / drug effects
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Hepatocytes / metabolism*
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Insulin / blood
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Mice
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Organ Specificity
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Recombinant Fusion Proteins / physiology
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Ribonucleotides / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Transcription Factors
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Transcription, Genetic / drug effects
Substances
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Adiponectin
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Adipoq protein, mouse
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Blood Glucose
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Crtc2 protein, mouse
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Insulin
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Recombinant Fusion Proteins
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Ribonucleotides
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Trans-Activators
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Transcription Factors
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Aminoimidazole Carboxamide
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Protein Serine-Threonine Kinases
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Stk11 protein, mouse
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AMP-Activated Protein Kinases
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AICA ribonucleotide