Mice Lacking Adiponectin Show Decreased Hepatic Insulin Sensitivity and Reduced Responsiveness to Peroxisome Proliferator-activated Receptor γ Agonists*

By A. Nawrocki, Michael W. Rajala, E. Tomás, U. Pajvani, A. Saha, M. Trumbauer, Z. Pang, Airu S. Chen, N. Ruderman, Howard Y. Chen and 2 more. Journal of Biological Chemistry, 2006

663 citations recorded by the source corpus.

The adipose tissue-derived hormone adiponectin improves insulin sensitivity and its circulating levels are decreased in obesity-induced insulin resistance. Here, we report the generation of a mouse line with a genomic disruption of the adiponectin locus. We aimed to identify whether these mice develop insulin resistance and which are the primary target tissues affected in this model. Using euglycemic/insulin clamp studies, we demonstrate that these mice display severe hepatic but not peripheral insulin resistance. Furthermore, we wanted to test whether the lack of adiponectin magnifies the impairments of glucose homeostasis in the context of a dietary challenge. When exposed to high fat diet, adiponectin null mice rapidly develop glucose intolerance. Specific PPARγ agonists such as thiazolidinediones (TZDs) improve insulin sensitivity by mechanisms largely unknown. Circulating adiponectin levels are significantly up-regulated in vivo upon activation of PPARγ. Both TZDs and adiponectin have been shown to activate AMP-activated protein kinase (AMPK) in the same target tissues. We wanted to address whether the ability of TZDs to improve glucose tolerance is dependent on adiponectin and whether this improvement involved AMPK activation. We demonstrate that the ability of PPARγ agonists to improve glucose tolerance in ob/ob mice lacking adiponectin is diminished. Adiponectin is required for the activation of AMPK upon TZD administration in both liver and muscle. In summary, adiponectin is an important contributor to PPARγ-mediated improvements in glucose tolerance through mechanisms that involve the activation of the AMPK pathway.

Subfields: Epidemiology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/727cd640468f57e2873de89bd3444d27cd49f6b1

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In Epidemiology

1. P. Scherer
2. Haiming Cao
3. Herbert Tilg
4. B. Spiegelman
5. E. Rosen
6. A. Moschen
7. Gerald I. Shulman
8. Takashi Kadowaki

In Molecular Biology

1. B. Spiegelman
2. E. Rosen
3. Gerald I. Shulman
4. V. Samuel
5. Herbert Tilg
6. M. Trujillo
7. Toshimasa Yamauchi
8. Takashi Kadowaki

In Physiology

1. B. Spiegelman
2. P. Scherer
3. Haiming Cao
4. E. Rosen
5. Herbert Tilg
6. V. Samuel
7. Gerald I. Shulman
8. Sushil Kumar Jain

Citations in the corpus

• Adipokines in inflammation and metabolic disease (2011, result): “In line with these observations, adiponectin-deficient mice develop exacerbated diet-induced insulin resistanc”
• The Hormonal Control of Food Intake (2007, neutral): “Data from knockout mouse models suggest that adiponectin is protective against the development of insulin resistance, glucose intolerance, and dyslipidemia (Nawrocki et al., 2006).”
• Regulation of energy metabolism by long-chain fatty acids. (2014, background): “Indeed, improvement of insulin sensitivity by a PPARc agonist was blunted in Adiponectin KO mice [195].”
• Adipose tissue-derived factors: impact on health and disease. (2006, background): “these findings, mice lacking adiponectin have reduced insulin sensitivity primarily at the level of the liver (95).”
• Adipocytokines in Obesity and Metabolic Disease (2014, neutral): “…mice develop insulin resistance associated with high level of TNFa in adipose tissue and reduced responsiveness to PPARl (Maeda et al. 2002, Nawrocki et al. 2006), although an independently gener- ated adiponectin knockout mouse line has no change in insulin sensitivity (Ma et al. 2002).”
• Adiponectin, a Therapeutic Target for Obesity, Diabetes, and Endothelial Dysfunction (2017, background): “Thiazolidinedione drugs restore the glycemic status by increasing the circulating levels of adiponectin in type 2 diabetic patients, adiponectin transgenic models, and knockout mouse models [91,95,96].”
• The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. (2016, background): “Mice lacking adiponectin are prone to hepatic steatosis and hepatic insulin resistance (91, 92).”
• Adipose Tissue (2006, neutral): “We have recently shown that ob/ob mice that lack adiponectin display a reduced response to PPAR- agonist treatment, as judged by the lack of improvements of glucose clearance after TZD treatment compared with ob/ob mice that have adiponectin available (34).”