Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor

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.

Constitutive Androstane Receptor: A Peripheral and a Neurovascular Stress or Environmental Sensor

“…Analysis of the hepatic transcriptome revealed a role of CAR in the catabolism of corticosterone [87]. CAR deletion resulted in down-regulation of enzymes involved in the hepatic catabolism of steroid hormones, specifically Hydroxy-Delta-5-Steroid Dehydrogenase, [87]. Altogether, these results highlight the important role of CAR in the maintenance of endocrine and metabolic equilibrium.…”

“…CAR is involved in thyroid hormone catabolism through regulation of phase II enzymes UGT1A1 and SULT1A1 [4,86]. Experimental evidence demonstrated CAR regulation of the catabolism of the stress hormone corticosterone [87]. CAR knockout mice developed hypercorticism associated with obesity, glucose intolerance, insulin insensitivity, dyslipidemia and hepatic steatosis [87].…”

“…Experimental evidence demonstrated CAR regulation of the catabolism of the stress hormone corticosterone [87]. CAR knockout mice developed hypercorticism associated with obesity, glucose intolerance, insulin insensitivity, dyslipidemia and hepatic steatosis [87]. Remarkably, the latter modifications were absent, or minor, in CAR knockout females, developing similar metabolic disorders only when ovariectomized.…”

“…Remarkably, the latter modifications were absent, or minor, in CAR knockout females, developing similar metabolic disorders only when ovariectomized. Analysis of the hepatic transcriptome revealed a role of CAR in the catabolism of corticosterone [87]. CAR deletion resulted in down-regulation of enzymes involved in the hepatic catabolism of steroid hormones, specifically Hydroxy-Delta-5-Steroid Dehydrogenase, [87].…”

Important Considerations for Sample Collection in Metabolomics Studies with a Special Focus on Applications to Liver Functions

“…Metabolomics has found numerous applications in the study of liver functions in health and disease. Among others, these include: Non-invasive biomarker investigations to discriminate between the different stages of progression of NAFLD using non-invasive biofluids (urine and plasma) [3,4]; investigation of mechanisms underlying hepatic disease progression such as acute-on-chronic liver failure using serum metabolic profiling [5] or fibrosis [6]; characterization of the gut microbiota metabotypes in urine of NAFLD patients [4,7]; nutrimetabolomics studies to unravel hepatic pathways dysregulated directly in liver samples upon various nutritional challenges [8,9]; discovery of new metabolic functions for nuclear receptors, that are important regulators of liver physiology using direct hepatic metabolomics or other informative fluids such as urine and bile [10][11][12][13]; identification of patients at risk for idiosyncratic drug-induced liver injury (IDILI) before drug administration, a concept named "pharmaco-metabolomics", that was first demonstrated in urine of animal models [14] and is now extended to human biofluids (urine and serum) [15,16]; study of mechanisms of action for pharmaceutical drugs in urine and fecal samples [17] and environmental contaminants in HepG2 cells and animal biofluids and tissues [18,19].…”