Improving cardiometabolic health by controlling glucocorticoid delivery to adipose tissue

Improving cardiometabolic health by controlling glucocorticoid delivery to adipose tissue

Glucocorticoid excess, particularly in adipose tissue, drives increased cardiovascular disease risk, including visceral obesity, hyperglycemia, dyslipidemia, and hypertension. Thus, efforts to reduce glucocorticoid action in adipose tissue as a treatment for cardiometabolic disease have both scientific and clinical merit. Our research is focused on the delivery mechanism through which glucocorticoids are ‘targeted’ to metabolic tissues, with the aims of not only advancing our understanding of glucocorticoid action in cardiometabolic disease, but identifying novel pathways to limit adverse glucocorticoid exposure.

Research Methods and Objectives:

Adipose tissue modulates multiple physiological functions, including glucose and lipid metabolism, blood pressure, and immunity. In obesity, adipose dysfunction is characterised by visceral fat accumulation, immune cell infiltration, and release of pro-inflammatory, diabetogenic adipokines. Together, visceral adiposity and insulin resistance increase cardiovascular risk through dyslipidemia, hypertension, and vascular dysfunction. GCs are critical stress response hormones, yet hypercortisolemia or long-term GC therapy increase risk of cardiovascular events. In particular, increased adipose exposure to GCs results in visceral adiposity, accompanied by features of metabolic syndrome, and is associated with cardiovascular risk factors. These observations have stimulated efforts to reduce GC action in adipose tissue as a treatment for cardiometabolic disease.

Extensive research over the past 30 years has investigated the importance of intracellular GC metabolism in metabolic disease, particulary regeneration of active glucocorticoids by the enzyme 11β-HSD1. During my postdoctoral work, I began exploring the potential of additional mechanisms to control adipose GC action. We identified transmembrane export via ABCC1 as a mechanism limiting the action of corticosterone in adipocytes, published in Science Translational Medicine. More recently, I have been awarded a British Heart Foundation Intermediate Research fellowship to investigate a potential role for CBG cleavage in enhancing GC delivery to adipose tissue. CBG (SERPINA6) is synthesised in the liver. In the plasma, CBG binds 80-85% of GCs with high affinity. Traditionally, only unbound hormone is considered to be available to diffuse into tissues. However, contrary to the popular opinion that the primary role of CBG is to bind GCs, thus rendering them unavailable, accumulating evidence points to an active role for CBG in GC release and delivery to tissues (Figure 1).

Figure 1. Schematic highlighting key pathways involved in regulating intracellular glucocorticoid exposure, including regeneration of active glucocorticoids by 11βHSD1, export of glucocorticoids by ABC transporters, and diffusion/delivery of glucocorticoids by CBG-mediated mechanisms.

We are now building upon our preliminary data to address the critical questions surrounding the role of CBG in glucocorticoid delivery to metabolic tissues. Answers to these questions will fundamentally advance our understanding of tissue-specific GC action in the setting of metabolic dysregulation, and allow development of new strategies to reduce GC action and prevent cardiovascular disease.

 

Related Researchers:

Mark Nixon

Nicholas Morton