Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance - PubMed (original) (raw)
Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance
Julie R Jones et al. Proc Natl Acad Sci U S A. 2005.
Abstract
Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a crucial role in adipocyte differentiation, glucose metabolism, and other physiological processes. To further explore the role of PPARgamma in adipose tissues, we used a Cre/loxP strategy to generate adipose-specific PPARgamma knockout mice. These animals exhibited marked abnormalities in the formation and function of both brown and white adipose tissues. When fed a high-fat diet, adipose-specific PPARgamma knockout mice displayed diminished weight gain despite hyperphagia, had diminished serum concentrations of both leptin and adiponectin, and did not develop glucose intolerance or insulin resistance. Characterization of in vivo glucose dynamics pointed to improved hepatic glucose metabolism as the basis for preventing high-fat diet-induced insulin resistance. Our findings further illustrate the essential role for PPARgamma in the development of adipose tissues and suggest that a compensatory induction of hepatic PPARgamma may stimulate an increase in glucose disposal by the liver.
Figures
Fig. 1.
Adiposity and weight gain in PPARγ adiposeKO mice. (A) Control and PPARγ adiposeKO mice at 22 weeks of age. These mice had been maintained on HFD for 18 weeks. (B) Interscapular (iWAT) and perigonadal (pgWAT) white adipose tissue weights (n = 4-7) at 20 weeks of age; *, P < 0.05; **, P < 0.01. (C) UCP1 expression in interscapular adipose tissue (n = 4). (D) Protection from diet-induced obesity in PPARγ adiposeKO male mice (n = 5-12). Asterisks, significantly greater than adiposeKOs on a HFD; *, P < 0.05; **, P < 0.01. #, Significantly less than controls on a standard diet (SD) (P < 0.05). (E) Total body fat measured by NMR. Data are expressed as a percentage of the body weight. Measurements of 3-week-old mice were made before weaning.
Fig. 3.
Plasma triglyceride levels and lipid deposition in livers from PPARγ adiposeKO mice. (A) Liver weights of mice on HFD (n = 12). ***, P < 0.001 versus controls. (B) Plasma triglyceride levels (n = 4-5). **, P < 0.01 versus controls on SD. (C) Oil Red O staining of liver sections from control and PPARγ adiposeKO mice. All panels in C are at the same magnification. (Scale bar, 50 μm.) (D) Histology of interscapular WAT in 35-week-old mice on HFD.
Fig. 4.
Real-time PCR analyses of tissues from control and PPARγ adiposeKO mice fed HFD. (A) PPARγ expression in interscapular white adipose tissue (iWAT), perigonadal white adipose tissue (pgWAT), and liver (n = 4). (B) CD36 expression was down-regulated in adipose tissues and up-regulated in liver and skeletal muscle (sk. muscle) of PPARγ adiposeKO mice compared with controls (n = 4-5). (C) Glut4 levels (n = 4-5). (D) Adiponectin expression (n = 4). (E) Resistin expression (n = 5-6). For all experiments, gene expression levels were normalized to 18S levels. *, P < 0.05; **, P < 0.01; ***, P < 0.001 versus controls.
Fig. 2.
Food intake, energy expenditure, and activity in PPARγ adiposeKO and control mice. (A) Total food intake during a 60-h period. Values are expressed as grams of food per gram of body weight (n = 3-4). (B) Energy expenditure in PPARγ adiposeKO and control mice. Energy expenditure is expressed as average VO2 per kg of body weight per h during a 22-h monitoring session (n = 4). (C) Activity during a 22-h period. Activity is expressed as the average number of times a mouse crosses both x and y axes at least twice (n = 4). *, P < 0.05; **, P < 0.01 versus controls.
Fig. 5.
Measures of glucose homeostasis in control and PPARγ adiposeKO mice. (A) Glucose tolerance tests. PPARγ adiposeKO mice on HFD show increased glucose tolerance compared to controls on HFD (n = 6). (B) Fasting plasma insulin levels (n = 4-6). (C) Fasting plasma leptin concentrations (n = 5-6). *, P < 0.05; **, P < 0.01; ***, P < 0.001 (controls on HFD versus adiposeKO mice on HFD).
Fig. 6.
Effects of hyperinsulinemia on glucose utilization during euglycemic-hyperinsulinemic clamp studies. (A) Glucose turnover rate represents the average whole body glucose disposal rate during the last 60 min of the clamp (n = 4-6). (B) Whole body glycolytic rate during clamp study (n = 3-6). (C) Insulin-stimulated glucose uptake by individual tissues: perigonadal white adipose tissue (WAT), gastrocnemius (G), and vastus lateralis (VL) in mice fed a SD or HFD (n = 4-6). #, Significantly less than adiposeKO on SD (P < 0.05). (D) Hepatic glycogen synthesis from glucose via the direct pathway (n = 4-6). (E) Hepatic glycogen content (n = 4-5). *, P < 0.05; **, P < 0.01; ***, P < 0.001 versus controls.
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