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Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor
Céline Lukowicz1, Sandrine Ellero-Simatos1, Marion Régnier1
1Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, 31300, Toulouse, France.
Abstract:
Metabolic diseases such as obesity, type II diabetes and hepatic steatosis are a public health concern in developed countries. The metabolic risk is gender-dependent. The constitutive androstane receptor (CAR), which is at the crossroads between energy metabolism and endocrinology, has recently emerged as a promising therapeutic agent for the treatment of obesity and type 2 diabetes. In this study we sought to determine its role in the dimorphic regulation of energy homeostasis. We tracked male and female WT and CAR deficient (CAR-/-) mice for over a year. During aging, CAR-/- male mice developed hypercortisism, obesity, glucose intolerance, insulin insensitivity, dyslipidemia and hepatic steatosis. Remarkably, the latter modifications were absent, or minor, in female CAR-/- mice. When ovariectomized, CAR-/- female mice developed identical patterns of metabolic disorders as observed in male mice. These results highlight the importance of steroid hormones in the regulation of energy metabolism by CAR. They unveil a sexually dimorphic role of CAR in the maintenance of endocrine and metabolic homeostasis underscoring the importance of considering sex in treatment of metabolic diseases.
Insights
Constitutive androstane receptor (CAR) plays a key role in regulating energy balance. CAR deficiency causes metabolic disorders in male mice, but not females, highlighting sex-specific effects in metabolic diseases.
Area of Science:
- Endocrinology
- Metabolic Diseases
- Molecular Biology
Background:
- Metabolic diseases like obesity, type II diabetes, and hepatic steatosis are significant public health issues.
- The metabolic risk associated with these conditions exhibits gender-dependent variations.
- The constitutive androstane receptor (CAR) is a nuclear receptor involved in energy metabolism and endocrinology, showing potential for treating obesity and type 2 diabetes.
Purpose of the Study:
- To investigate the role of CAR in the sexually dimorphic regulation of energy homeostasis.
- To understand how CAR deficiency impacts metabolic health in male and female mice.
- To explore the influence of sex hormones on CAR's function in metabolic regulation.
Main Methods:
- Longitudinal tracking of male and female wild-type (WT) and CAR-deficient (CAR-/-) mice for over one year.
- Monitoring of metabolic parameters including body weight, glucose tolerance, insulin sensitivity, lipid profiles, and liver steatosis.
- Ovariectomy was performed on female CAR-/- mice to assess the role of ovarian hormones.
Main Results:
- CAR-/- male mice developed hypercortisolism, obesity, glucose intolerance, insulin resistance, dyslipidemia, and hepatic steatosis with aging.
- Female CAR-/- mice exhibited minimal or no such metabolic alterations.
- Ovariectomized CAR-/- female mice displayed metabolic disorder patterns similar to those in male mice.
Conclusions:
- CAR plays a sexually dimorphic role in maintaining endocrine and metabolic homeostasis.
- Steroid hormones are crucial for CAR's regulation of energy metabolism.
- These findings underscore the importance of considering sex as a biological variable in the treatment strategies for metabolic diseases.
