Obesity-associated improvements in metabolic profile through expansion of adipose tissue
Ja-Young Kim, … , Gary J. Schwartz, Philipp E. Scherer
Ja-Young Kim, … , Gary J. Schwartz, Philipp E. Scherer
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2621-2637. https://doi.org/10.1172/JCI31021.
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Research Article Metabolism

Obesity-associated improvements in metabolic profile through expansion of adipose tissue

Abstract

Excess caloric intake can lead to insulin resistance. The underlying reasons are complex but likely related to ectopic lipid deposition in nonadipose tissue. We hypothesized that the inability to appropriately expand subcutaneous adipose tissue may be an underlying reason for insulin resistance and β cell failure. Mice lacking leptin while overexpressing adiponectin showed normalized glucose and insulin levels and dramatically improved glucose as well as positively affected serum triglyceride levels. Therefore, modestly increasing the levels of circulating full-length adiponectin completely rescued the diabetic phenotype in ob/ob mice. They displayed increased expression of PPARγ target genes and a reduction in macrophage infiltration in adipose tissue and systemic inflammation. As a result, the transgenic mice were morbidly obese, with significantly higher levels of adipose tissue than their ob/ob littermates, leading to an interesting dichotomy of increased fat mass associated with improvement in insulin sensitivity. Based on these data, we propose that adiponectin acts as a peripheral “starvation” signal promoting the storage of triglycerides preferentially in adipose tissue. As a consequence, reduced triglyceride levels in the liver and muscle convey improved systemic insulin sensitivity. These mice therefore represent what we believe is a novel model of morbid obesity associated with an improved metabolic profile.

Authors

Ja-Young Kim, Esther van de Wall, Mathieu Laplante, Anthony Azzara, Maria E. Trujillo, Susanna M. Hofmann, Todd Schraw, Jorge L. Durand, Hua Li, Guangyu Li, Linda A. Jelicks, Mark F. Mehler, David Y. Hui, Yves Deshaies, Gerald I. Shulman, Gary J. Schwartz, Philipp E. Scherer

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Figure 1

ob/ob mice overexpressing adiponectin display physiological overexpression of adiponectin in circulation with normal adiponectin complex distribution.

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ob/ob mice overexpressing adiponectin display p...
(A) Circulating adiponectin levels were measured by RIA in 12-week-old adiponectin transgenic ob/ob mice (Ad Tg ob/ob), their ob/ob littermates, and ob/ob mice with PPARγ agonist treatment (n = 5 mice/group). (B) Tissue levels of adiponectin were measured in various fat pads, determined by Western blot analysis, and normalized with GDI in 12-week-old male adiponectin transgenic ob/ob mice, their ob/ob littermates, and ob/ob mice with PPARγ agonist treatment (n = 5 mice/group). (C) The complex distribution of adiponectin of female mice was determined using gel filtration chromatography of serum samples followed by Western blot analysis of adiponectin in different fractions. A representative sample is shown. HMW, high molecular weight form; LMW, low molecular weight form (hexamer). *P < 0.05; **P < 0.01 by Student’s t test.