Nuclear hormone receptors and metabolic disease

Nuclear hormone receptors (NRs) are proteins that translate endocrine, metabolic and pathophysiological signals into gene regulation. Our research utilises transgenic mouse models and focuses on understanding the molecular role of NRs (coregulators) and how they control metabolism in muscle, fat and the liver in the context of obesity and type 2 diabetes.

Epidemiological evidence points to associations between metabolic disease and cancer. Along these lines, we collaboratively examine the molecular role of NRs in breast cancer. We also use mouse models and human cohort studies to gain insights into obesity, type 2 diabetes and cancer, which we can then use to better understand human health and disease.
In our breast cancer studies, we examined normal human breast tissue, estrogen receptor-positive and negative breast cancer cohorts and tissue adjacent to breast tumors. From this work, we identified NR targets for therapeutic exploitation, classification, and prognosis, and discovered epigenetic markers that could lead to metastasis-free survival for patients.

We also investigated the role of NRs in obesity and type 2 diabetes. In these studies, we produced transgenic mouse lines with muscle-specific expression of an activated form of the nuclear receptor NOR1. We then demonstrated that NOR1 signalling controls skeletal muscle reprogramming, metabolic capacity, glucose tolerance, physical endurance, and resistance to diet-induced obesity and hepatic triglyceride accumulation. These findings were the first of their kind and were published as a cover article in the leading international journal, Molecular Endocrinology. Our future research will identify novel muscle-specific agonists targeting these NRs for therapeutic uses in obesity, type 2 diabetes and improving exercise capacity.

During the year, we demonstrated that modulators of histone methylation and epigenomic regulation, which turn the genes in DNA ‘on’ and ‘off’, in skeletal muscle cells are involved in the regulation of glycogen metabolism. Specifically, we found the modulator known as PRMT4 controls genes involved in human glycogen storage diseases, which affect a person’s ability to exercise, levels of fatigue, and sensitivity to insulin. We also identified and characterised the regulatory role of the c-ski oncogene in genetic programs that control susceptibility to diet-induced obesity, and insulin signalling in skeletal muscle.

In collaboration with IMB’s Parton Lab, we demonstrated that caveolin-1 (CAV1)—the main structural protein of caveolae—regulates liver lipid accumulation, and that this process involves regulation of bile acids and signalling by the nuclear receptor FXR. This provides new targets for the treatment of obesity and hepatic steatosis, also known as fatty liver disease. Furthermore, in collaboration with IMB’s Stow Lab, we demonstrated that an NR called ROR-alpha controls the expression of cholesterol 25-hydroxylase in macrophages, an important gene that controls responses to infection and immunity.

Finally, insights gained from studies in lean, obese and diabetic murine models are helping our team to profile the expression of NRs, NR-associated co-factors, and metabolic genes in overweight and obese children before and after introducing a nutrition and lifestyle program. This will enable the translation of this basic research into outcomes to improve childhood and human health.

Professor George Muscat is also an Honorary Guest Professor (20%) at Wallenberg Laboratory, University of Gothenburg, Sweden.