Volume 19, Issue 2 - Special Volume: Pathophysiology of Adipose Tissue: Effects of Steroid Hormones - Part D / Editors: Gérard S. Chetrite and Bruno Fève

Obesity leads to the development of type 2 diabetes mellitus, which is a strong risk factor for cardiovascular disease. A better understanding of the molecular basis of obesity will lead to the establishment of effective prevention strategies for cardiovascular diseases. Adipocytes have been shown to generate a variety of endocrine factors termed adipokines/adipocytokines. Obesity-associated changes to these adipocytokines contribute to the development of cardiovascular diseases. Adiponectin, which is one of the most well-characterized adipocytokines, is produced exclusively by adipocytes and exerts insulin-sensitizing and anti-atherogenic effects. Obese subjects have lower levels of circulating adiponectin, and this is recognized as one of the factors involved in obesity-induced insulin resistance and atherosclerosis. Another pathophysiological feature of obesity may involve the low-grade chronic inflammation in adipose tissue. This inflammatory process increases oxidative stress in adipose tissue, which may affect remote organs, leading to the development of diabetes, hypertension, and atherosclerosis. Nuclear hormone receptors (NRs) regulate the transcription of the target genes in response to binding with their ligands, which include metabolic and nutritional substrates. Among the various NRs, peroxisome proliferator-activated receptor γ promotes the transcription of adiponectin and antioxidative enzymes, whereas mineralocorticoid receptor mediates the effects of aldosterone and glucocorticoid to induce oxidative stress in adipocytes. It is hypothesized that both play crucial roles in the pathophysiology of obesity-associated insulin resistance and cardiovascular diseases. Thus, reduced adiponectin and increased oxidative stress play pathological roles in obesity-associated insulin resistance to increase the cardiovascular disease risk, and various NRs may be involved in this pathogenesis.

Crosstalk between adipose tissue and blood vessels is vital to vascular homeostasis and is disturbed in cardiovascular and metabolic diseases such as hypertension, diabetes and obesity. Cardiometabolic syndrome (CMS) refers to the clustering of obesity-related metabolic disorders such as insulin resistance, glucose and lipid profile alterations, hypertension and cardiovascular diseases. Mechanisms underlying these associations remain unclear. Adipose tissue associated with the vasculature [known as perivascular adipose tissue (PVAT)] has been shown to produce myriads of adipose tissue-derived substances called adipokines, including hormones, cytokines and reactive oxygen species (ROS), which actively participate in the regulation of vascular function and local inflammation by endocrine and/or paracrine mechanisms. As a result, the signaling from PVAT to the vasculature is emerging as a potential therapeutic target for obesity and diabetes-related vascular dysfunction. Accumulating evidence supports a shift in our understanding of the crucial role of elevated plasma levels of aldosterone in obesity, promoting insulin resistance and hypertension. In obesity, aldosterone/mineralocorticoid receptor (MR) signaling induces an abnormal secretion of adipokines, ROS production and systemic inflammation, which in turn contribute to impaired insulin signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular abnormalities. Thus, aldosterone excess exerts detrimental metabolic and vascular effects that participate to the development of the CMS and its associated cardiovascular abnormalities. In this review, we focus on the physiopathological roles of corticosteroid receptors in the interplay between PVAT and the vasculature, which underlies their potential as key regulators of vascular function.

Endogenous circadian clocks facilitate the adaptation of physiology and behavior to recurring environmental changes brought about by the Earth’s rotation around its axis. Adipose tissues harbor intrinsic circadian oscillators based on interlocked transcriptional-translational feedback loops built from a set of clock genes that regulate important aspects of lipid metabolism and adipose endocrine function. These adipocyte clocks are reset via neuronal and endocrine pathways originating from a master circadian pacemaker residing in the hypothalamic suprachiasmatic nucleus. One important mediator of circadian output is the stress hormone cortisol, which, at the same time, is one of the major regulators of adipose physiology. In this review we summarize recent findings on the interaction between circadian and stress systems in the regulation of adipose physiology and discuss the implications of this crosstalk for the development of metabolic disorders associated with circadian disruption and/or chronic stress, for example in shift workers.

Glucocorticoids (GC) and their cognate intracellular receptor, the glucocorticoid receptor (GR), have been characterised as critical checkpoints in the endocrine control of energy homeostasis in mammals. Indeed, aberrant GC action has been linked to a variety of severe metabolic diseases, including obesity, insulin resistance and type 2 diabetes. As a steroid-binding member of the nuclear receptor superfamily of transcription factors, the GR translocates into the cell nucleus upon GC binding where it serves as a transcriptional regulator of distinct GC-responsive target genes that are – in many cases – associated with glucose and lipid regulatory pathways and thereby intricately control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of GC/GR function in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism.

Nuclear receptors (NRs) belong to a superfamily of evolutionarily related DNA-binding transcription factors that can be activated by steroid and thyroid hormones, and other lipid metabolites. Ligand activated NRs can regulate target gene expression by binding to DNA response elements present in the target gene promoters. Through this regulation, NRs are broadly implicated in physiology and metabolism. In this chapter, we will focus on the xenobiotic receptors and their recently discovered functions in metabolic diseases.