Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice
- Hua V. Lin1,
- Ja-Young Kim2,
- Alessandro Pocai2,
- Luciano Rossetti2,
- Lawrence Shapiro3,
- Philipp E. Scherer2 and
- Domenico Accili1
- 1Department of Medicine, Columbia University, New York, New York
- 2Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York
- 3Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York
- Address correspondence and reprint requests to Domenico Accili, MD, Columbia University Medical Center, 1150 St. Nicholas Ave., #238, New York, NY 10032. E-mail: da230{at}columbia.edu
Abstract
OBJECTIVE— Adiponectin increases insulin sensitivity and contributes to insulin's indirect effects on hepatic glucose production.
RESEARCH DESIGN AND 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)α target gene expression in liver, raising the possibility that deterioration of adiponectin/AdipoR2 signaling via PPARα 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.
- AMPK, AMP-activated protein kinase
- FoxO1, forkhead box O1
- HGP, hepatic glucose production
- IL, interleukin
- Insr, insulin receptor
- PPAR, peroxisome proliferator–activated receptor
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 2 May 2007. DOI: 10.2337/db07-0127.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted April 26, 2007.
- Received January 29, 2007.
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