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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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 3

ob/ob mice expressing adiponectin are heavier but healthier than ob/ob mice, displaying increased fat mass and decreased liver triglycerides.

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ob/ob mice expressing adiponectin are heavier but ...
(A) Changes in body weight were monitored (n = 15 mice/group). Representative animals are shown: an ob/ob mouse and an adiponectin transgenic ob/ob littermate at 12 weeks. (B) Body composition of 5-week-old mice was measured by MRI (n = 3 mice/group). (C) Body weight gain was tracked on normal chow or on a HF diet in 10-week-old adiponectin transgenic ob/ob mice and ob/ob littermates. (D) Sections of gonadal WAT and (E) pancreatic islets from adiponectin transgenic ob/ob mice (top) and ob/ob littermates (bottom) were H&E stained. The average adiponectin size calculated (D, right panel) and surface area of >100 islets stained for insulin was measured and average islet area is indicated (E, right panel). (F) Frozen sections of liver from adiponectin transgenic ob/ob mice and ob/ob littermates were stained with oil red O (left panel). Liver triglyceride content (middle panel) and DAG levels (right panel) were analyzed. (G) Intraabdominal visceral fat pads from WT mice, adiponectin transgenic ob/ob mice, and ob/ob littermates were weighed and presented as percentage of total body weight (F and G, n = 4–5 mice/group). (H) Pericardial fat pads from 10-week-old female mice were imaged by MRI and reconstituted into a 3D representation. A representative example is shown. (I) Mice were fasted for 6 hours and injected with 1 mU of insulin/g body weight. At indicated time points, 1 mouse was sacrificed and liver protein was extracted and analyzed for the total and phosphorylated forms of the indicated targets using 3 independent measurements for each time point. *P < 0.05; **P < 0.01. Panels A and C were analyzed by ANOVA; panels D, F, G, and I were analyzed by Student’s t test.