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 2

Adiponectin improves the metabolic profile of ob/ob mice.

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Adiponectin improves the metabolic profile of ob/ob ...
(A) Circulating glucose and insulin levels measured during OGTT. (B) Plasma triglyceride (TG) levels measured during lipid challenge in adiponectin transgenic ob/ob mice and their ob/ob littermates. (C) Plasma triglyceride levels were measured during a lipid challenge in adiponectin transgenic ob/ob mice after an injection of 2 monoclonal anti-adiponectin antibodies (Mono-Ab) or control mouse IgGs (CTRL-IgG). (D) Plasma insulin (right) and FFA levels (left) monitored after i.p. CL-316,243 injection in adiponectin transgenic ob/ob mice and their ob/ob littermates. (E) Cholesterol and triglyceride levels were measured in plasma samples subfractionated by gel filtration chromatography. IDL, intermediate density lipoprotein. (F) apoE levels were measured in the same fractions by Western blot analysis (top) and quantitated (bottom). (G) Adiponectin transgenic ob/ob mice and their ob/ob littermates were fed normal chow (N chow) or high-fat diet (HF) for 6 weeks. Fasting glucose levels (top left), glucose levels during an OGTT (top right), insulin levels (bottom left), and FFA levels (bottom right) were determined in adiponectin transgenic ob/ob mice and their ob/ob littermates (A–G, n = 5 mice/group). (H) 2DG was centrally delivered to adiponectin transgenic ob/ob mice, ob/ob littermates, and WT mice, and blood glucose levels were monitored during indicated times (n = 3 mice/group). Experiments were performed with 10- to 12-week-old adiponectin transgenic ob/ob mice, ob/ob littermates, and WT male mice. *P < 0.05; **P < 0.01. Panels A and B were analyzed by ANOVA; panels D and G were analyzed by Student’s t test.