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Identification of a selective glucocorticoid receptor modulator that prevents both diet-induced obesity and
José K van den Heuvel1,2, Mariëtte R Boon1,2, Ingmar van Hengel1,2
1Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
Background And Purpose:
High-fat diet consumption results in obesity and chronic low-grade inflammation in adipose tissue. Whereas glucocorticoid receptor (GR) antagonism reduces diet-induced obesity, GR agonism reduces inflammation, the combination of which would be desired in a strategy to combat the metabolic syndrome. The purpose of this study was to assess the beneficial effects of the selective GR modulator C108297 on both diet-induced weight gain and inflammation in mice and to elucidate underlying mechanisms.
Experimental Approach:
Ten-week-old C57Bl/6 J mice were fed a high-fat diet for 4 weeks while being treated with the selective GR modulator C108297, a full GR antagonist (RU486/mifepristone) or vehicle.
Key Results:
C108297 and, to a lesser extent, mifepristone reduced body weight gain and fat mass. C108297 decreased food and fructose intake and increased lipolysis in white adipose tissue (WAT) and free fatty acid levels in plasma, resulting in decreased fat cell size and increased fatty acid oxidation. Furthermore, C108297 reduced macrophage infiltration and pro-inflammatory cytokine expression in WAT, as well as in vitro LPS-stimulated TNF-α secretion in macrophage RAW 264.7 cells. However, mifepristone also increased energy expenditure, as measured by fully automatic metabolic cages, and enhanced expression of thermogenic markers in energy-combusting brown adipose tissue (BAT) but did not affect inflammation.
Conclusions And Implications:
C108297 attenuates obesity by reducing caloric intake and increasing lipolysis and fat oxidation, and in addition attenuates inflammation. These data suggest that selective GR modulation may be a viable strategy for the reduction of diet-induced obesity and inflammation.
Insights
Selective glucocorticoid receptor (GR) modulation with C108297 combats diet-induced obesity and inflammation by reducing caloric intake and increasing fat metabolism. This approach offers a promising strategy for metabolic syndrome treatment.
Area of Science:
- Metabolic disease research
- Pharmacology
- Obesity and inflammation studies
Background:
- High-fat diets induce obesity and adipose tissue inflammation, contributing to metabolic syndrome.
- Glucocorticoid receptor (GR) antagonism reduces obesity, while agonism reduces inflammation.
- A combined strategy targeting both pathways is desirable for metabolic syndrome treatment.
Purpose of the Study:
- To evaluate the effects of the selective GR modulator C108297 on diet-induced obesity and inflammation in mice.
- To elucidate the underlying mechanisms of C108297's action.
Main Methods:
- C57Bl/6J mice were fed a high-fat diet for 4 weeks.
- Mice were treated with C108297, a full GR antagonist (mifepristone), or vehicle.
- Body weight, fat mass, food intake, energy expenditure, and inflammatory markers were assessed.
Main Results:
- C108297 and mifepristone reduced body weight gain and fat mass.
- C108297 decreased food intake, increased lipolysis and fatty acid oxidation, and reduced inflammatory markers in adipose tissue.
- Mifepristone increased energy expenditure but did not impact inflammation.
Conclusions:
- C108297 attenuates obesity by reducing caloric intake and enhancing fat metabolism.
- C108297 also reduces inflammation, suggesting a dual therapeutic benefit.
- Selective GR modulation presents a viable strategy for combating diet-induced obesity and inflammation.
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