Adiponectin resistance exacerbates insulin resistance in insulin receptor transgenic/knockout mice.
OBJECTIVE
Adiponectin increases insulin sensitivity and contributes to insulin's indirect effects on hepatic glucose production.


METHODS
To examine adiponectin's contribution to insulin action, we analyzed adiponectin levels and activation of AMP-activated protein kinase (AMPK) in insulin receptor transgenic/knockout mice (L1), a genetic model of resistance to insulin's indirect effects on hepatic glucose production.


RESULTS
In euglycemic, insulin-resistant L1 mice, we detected hyperadiponectinemia with normal levels of adiponectin receptor-1 and -2. Moreover, adiponectin administration is unable to lower glucose levels or induce activation of AMPK, consistent with a state of adiponectin resistance. In a subset of hyperglycemic L1 mice, we observed decreased mRNA expression of AdipoR2 in liver and muscle, as well as decreased peroxisome proliferator-activated receptor (PPAR)alpha target gene expression in liver, raising the possibility that deterioration of adiponectin/AdipoR2 signaling via PPARalpha activation contributes to the progression from compensated insulin resistance to diabetes. In contrast, we failed to detect changes in other markers of the systemic or local inflammatory response.


CONCLUSIONS
These data provide evidence for a mechanism of adiponectin resistance and corroborate the notion that adiponectin potentiates hepatic insulin sensitivity.
Lin
Hua V
HV
Department of Medicine, Columbia University, New York, NY 10032, USA.
Kim
Ja-Young
JY
Pocai
Alessandro
A
Rossetti
Luciano
L
Shapiro
Lawrence
L
Scherer
Philipp E
PE
Accili
Domenico
D
D055372:AMP-Activated Protein Kinases; D052242:Adiponectin / Q000097:blood* / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers; D001786:Blood Glucose / Q000378:metabolism; D004198:Disease Susceptibility; D005786:Gene Expression Regulation; D044882:Glucose Metabolism Disorders / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface / Q000235:genetics; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood; D013997:Time Factors
D052242:Adiponectin; D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D009097:Multienzyme Complexes; D047493:PPAR alpha; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface; C475421:adiponectin receptor 2, mouse; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases