The interaction between glucocorticoids and beta-adrenergic activity in the adipose tissues and the skeleton
PhD Student: Manuel Malak Zakaria Gado
Supervisor at TUD: Holger Henneicke, Stefan Bornstein
Supervisor at KCL: Francesco Rubino
Start Date: 01.10.2016 Date of defense: 04.11.2021 Dr. rer. nat.
The potent anti-inflammatory nature of glucocorticoids (GCs) has made their clinical use for the therapy of inflammatory and immune diseases indispensable. Owing to their pleiotropic actions on almost all the body’s tissues, supra-physiological levels of GCs have been causally linked to the development of several deliberating diseases, including osteoporosis, myopathy, adiposity, and insulin resistance. To this day, these detrimental effects have limited the clinical use of therapeutic GCs. Hence, it is of utmost significance to identify the underlying mechanisms of GC-induced pathologies and develop potential therapeutic strategies to overcome these side effects and facilitate their safe clinical use. To this end, in this dissertation, we investigated the interaction between GC signaling and the sympathetic nervous system (SNS) in both the skeleton and the adipose organ.
Both, the bone and adipose tissues, differ in their anatomical locations and physiological features; however, they both respond to the activity of the SNS. While white adipose tissue (WAT) – the major energy-storing tissue in the body – responds to the increased SNS activity with the release of fatty acids, brown adipose tissue (BAT) dramatically produces heat following a sympathetic stimulus. Through the action of the mitochondrial uncoupling protein 1 (UCP1) in brown adipocytes, substrate oxidation is uncoupled from ATP synthesis leading to heat dissipation. On the molecular level, this response is driven mainly through activation of the SNS in BAT and subsequently stimulation of the beta3-adrenergic receptor (β3-AR) on brown adipocytes. In the skeleton, an increase in the SNS activity has been linked to a loss of bone mass as a result of reduced bone formation as well as increased bone resorption.
In this project, we aimed to delineate the potential interactions between GCs and sympathetic activity in skeletal and adipose tissue biology. To this end, we depended on the utilization of two methods for activating adaptive thermogenic capacity in mice: (a) long-term cold acclimatization or (b) chronic administration of a β3-AR agonist (CL316,243).
In the first part of this work, we hypothesized that the activated thermogenic capacity in BAT exerts potential positive effects on physiological bone homeostasis. To this end, we studied the skeletal phenotype of young mice after a 4-week treatment with CL316,243 while being maintained at either thermoneutral (29°C) or cold (13°C) temperatures. While each intervention alone and in combination were effective in recruiting the thermogenic capacity in BAT and inducing lipolysis in WAT, neither bone microstructure nor bone remodeling was substantially changed by these interventions. The results from the first study showed that – in our hands – the activation of thermogenic adipose tissues (through prolonged cold exposure or specific β3-AR stimulation) exerts little influence on physiological bone homeostasis.
In the second part of the thesis, we investigated the GC-induced bone loss in mice during acclimation to a cold environmental temperature (13°C) in comparison to mice maintained at thermoneutrality (29°C). Long-term exposure to exogenous corticosterone at both temperatures induced femoral cortical bone loss due to suppressed bone formation as well as increased bone resorption. Interestingly, prolonged cold exposure not only enhanced the presence of sympathetic nerve endings in BAT but also induced a trend increase in the expression of tyrosine hydroxylase (Th) – a marker of sympathetic nerve endings – in the bone. However, GC-induced bone loss was not exacerbated in the cold environment. Therefore, in our model, there is no detectable interaction between the cold-driven sympathetic activity and excess GCs in the skeleton.
In the third part of the thesis, our hypothesis was centered on exploring the potential beneficial metabolic effects of the activation of thermogenic adipose tissues during long-term exposure to exogenous GCs. Initially, we compared the outcomes of long-term treatment with corticosterone between mice maintained at different environmental temperature levels, ranging from thermoneutrality (29°C) to standard room temperature (22°C) and mild cold temperature (13°C). While GC-treated mice housed at thermoneutral and room temperatures gained more weight, accumulated more white fat, and exhibited compromised thermogenic capacity than their temperature-matched controls, cold-acclimated mice were protected from GC-driven weight gain, obesity, and excessive fat accumulation. Moreover, the thermogenic capacity in BAT was preserved in the mice maintained at 13°C compared to mice maintained at higher temperatures despite exposure to excess corticosterone. Intriguingly, cold adaptation was also effective in protecting the mice against GC-induced hyperglycemia, hyperinsulinemia, and hyperleptinemia – all of which were readily observed in corticosterone-treated mice at 29°C and 22°C. Further, prolonged cold exposure during GC treatment was associated with preserved sympathetic TH-positive innervation in adipose tissues, indicating that the enhanced SNS activity in the adipose organ may be mediating the protective effects of cold acclimation against GC-induced adipose dysfunction.
As a proof-of-principle study, we examined the use of the β3-AR specific agonist (CL316,243) in the same model of GC-induced metabolic dysfunction. Concurrent treatment with CL316,243 and corticosterone effectively averted the development of GC-induced obesity and hyperinsulinemia and preserved the thermogenic capacity in BAT as well. Taken together, our data demonstrate that both long-term cold acclimation and β3-AR activation prevent the onset of GC-induced adipose dysfunction and related metabolic comorbidities. Thus, β3-AR may be regarded as a potential therapeutic target in the prevention of GC-induced metabolic disease.
Publication:
Cutting Edge: Homeostasis of Innate Lymphoid Cells Is Imbalanced in Psoriatic Arthritis. A. Soare, S. Weber, L. Maul, S. Rauber, A.M. Gheorghiu, M. Luber, I. Houssni, A. Kleyer, G. von Pickardt, M. Gado, D. Simon, J. Rech, G. Schett, J.H.W. Distler, A. Ramming. J Immunol. 2018;200:1249-1254.