Volume 31, Issue 2 - SPECIAL ISSUE: BROWNING OF WHITE ADIPOSE TISSUE: A KEY FOR OBESITY-RELATED DISORDERS, AND EVEN MORE - ENDOCRINE ASPECTS / Editors: Gérard S. Chetrite and Bruno Fève - continued

An imbalance between energy intake and expenditure leads to obesity. Adiposity associated with obesity progressively causes inflammation, type 2 diabetes, hypertension, hyperlipidemia and cardiovascular disease. Excessive dietary intake of fat results in its accumulation and storage in the white adipose tissue (WAT), whereas energy expenditure by fat utilization and oxidation predominately occurs in the brown adipose tissue (BAT). Recently, the presence of a third type of fat, referred to as beige or brite (brown in white), has been recognized in certain kinds of WAT depots. It has been suggested that WAT can undergo the process of browning in response to stimuli that induce and enhance the expression of thermogenes characteristic of those typically associated with brown fat. The resultant beige or brite cells enhance energy expenditure by reducing lipids stored within adipose tissue. This has created significant excitement towards the development of a promising strategy to induce browning/beiging in WAT to combat the growing epidemic of obesity. This review systematically describes differential locations and functions of WAT and BAT, mechanisms of beiging of WAT and a concise analysis of drug molecules and natural products that activate the browning phenomenon in vitro and in vivo. This review also discusses potential approaches for targeting WAT with compounds for site-specific beiging induction. Overall, there are numerous mechanisms that govern browning of WAT. There are a variety of newly identified targets whereby potential molecules can promote beiging of WAT and thereby combat obesity.

The dramatically increasing world-wide prevalence of obesity is recognized as a risk factor for the development of various diseases. The growing research on the role of adipose tissue in controlling energy homeostasis and insulin sensitivity has revealed that the promotion of brown adipose tissue (BAT) activity and the browning of white adipose tissue (WAT) leads to multiple health benefits and prevents obesity and type 2 diabetes (T2D). Inducible thermogenic adipocytes do exist in adult humans and are linked with increased energy combustion and lower body fat mass. Thus brown adipocytes are currently placed at the center of attention for novel therapeutic strategies against metabolic diseases such as obesity and diabetes. Besides the classical, norepinephrine-mediated sympathetic recruitment and activation of thermogenic adipocytes, a number of novel circulating factors have been recently identified to have a positive or negative impact on thermogenic adipocyte formation and activity. In this review their mechanism of action and the plausible therapeutic applications will be summarized and discussed.

Obesity is a major risk factor for the development of diabetes, insulin resistance, dyslipidemia, cardiovascular disease and other related metabolic conditions. Obesity develops from perturbations in overall cellular bioenergetics when energy intake chronically exceeds total energy expenditure. Lifestyle interventions based on reducing total energy uptake and increasing activities including exercise have proved ineffective in the prevention and treatment of obesity because of poor adherence to such interventions for an extended period of time. Brown adipose tissue (BAT) has an extraordinary metabolic capacity to burn excess stored energy and holds great promise in combating obesity and related diseases. This unique ability to nullify the effects of extra energy intake of these specialized tissues has provided attractive perspectives for the therapeutic potential of BAT in humans. Browning of white adipose tissue by promoting the expression and activity of key mitochondrial uncoupling protein 1 (UCP1) represents an exciting new strategy to combat obesity via enhanced energy dissipation. Members of the transforming growth factor-beta (TGF-β) superfamily including myostatin and follistatin have recently been demonstrated to play a key role in regulating white adipose browning both in in-vitro and in-vivo animal models and thereby present attractive avenues for exploring the therapeutic potential for the treatment of obesity and related metabolic diseases.

The global prevalence of obesity and related cardiometabolic disease continues to increase through the 21st century. Whilst multi-factorial, obesity is ultimately caused by chronic caloric excess. However, despite numerous interventions focussing on reducing caloric intake these either fail or only elicit short-term changes in body mass. There is now a focus on increasing energy expenditure instead which has stemmed from the recent ‘re-discovery’ of cold-activated brown adipose tissue (BAT) in adult humans and inducible ‘beige’ adipocytes. Through the unique mitochondrial uncoupling protein 1 (UCP1), these thermogenic adipocytes are capable of combusting large amounts of chemical energy as heat and in animal models can prevent obesity and cardiometabolic disease. At present, human data does not point to a role for thermogenic adipocytes in regulating body weight or fat mass but points to a pivotal role in regulating metabolic health by improving insulin resistance as well as glucose and lipid homeostasis. This review will therefore focus on the metabolic benefits of BAT activation and the mechanisms and signalling pathways by which these could occur including improvements in insulin signalling in peripheral tissues, systemic lipid and cholesterol metabolism and cardiac and vascular function.

β-adrenergic receptors (βARs) are well established for conveying the signal from catecholamines to adipocytes. Acting through the second messenger cyclic adenosine monophosphate (cAMP) they stimulate lipolysis and also increase the activity of brown adipocytes and the ‘browning’ of adipocytes within white fat depots (so-called ‘brite’ or ‘beige’ adipocytes). Brown adipose tissue mitochondria are enriched with uncoupling protein 1 (UCP1), which is a regulated proton channel that allows the dissipation of chemical energy in the form of heat. The discovery of functional brown adipocytes in humans and inducible brown-like (‘beige’ or ‘brite’) adipocytes in rodents have suggested that recruitment and activation of these thermogenic adipocytes could be a promising strategy to increase energy expenditure for obesity therapy. More recently, the cardiac natriuretic peptides and their second messenger cyclic guanosine monophosphate (cGMP) have gained attention as a parallel signaling pathway in adipocytes, with some unique features. In this review, we begin with some important historical work that touches upon the regulation of brown adipocyte development and physiology. We then provide a synopsis of some recent advances in the signaling cascades from β-adrenergic agonists and natriuretic peptides to drive thermogenic gene expression in the adipocytes and how these two pathways converge at a number of unexpected points. Finally, moving from the physiologic hormonal signaling, we discuss yet another level of control downstream of these signals: the growing appreciation of the emerging roles of non-coding RNAs as important regulators of brown adipocyte formation and function. In this review, we discuss new developments in our understanding of the signaling mechanisms and factors including new secreted proteins and novel non-coding RNAs that control the function as well as the plasticity of the brown/beige adipose tissue as it responds to the energy needs and environmental conditions of the organism.

Beige (or brite, “brown in white”) adipocytes are uncoupling protein 1 (UCP1)-positive cells residing in white adipose depots that, depending on the conditions, behave either as classic white adipocytes, storing energy as lipids, or as brown adipocytes, dissipating energy from oxidative metabolism as heat through non-shivering thermogenesis. Because of their thermogenic potential and, therefore, possible usage to treat metabolic diseases such as obesity and type 2 diabetes, beige cells have attracted the attention of many scientists worldwide aiming to develop strategies to safely recruit and activate their thermogenic activity. Indeed, in recent years, a large variety of conditions, molecules (including nutrients) and signaling pathways were reported to promote the recruitment of beige adipocytes. Despite of those advances, the true contribution of beige adipocyte thermogenesis to whole-body energy expenditure is still not completely defined. Herein, we discuss some important aspects that should be considered when studying beige adipocyte biology and the contribution to energy balance and whole-body metabolism.

Understanding the impact of regular exercise training on uncoupling protein 1 (UCP1) activity in classical brown adipose tissue ( C BAT) is vital to our knowledge of whole-body thermogenic activity. The purpose of this systematic review was to evaluate the available experimental evidence on the effect of regular exercise training on UCP1 expression in C BAT. We performed a literature search using PubMed (1966–2016), Scopus, and EMBASE (1974–2016). Studies in any language that examined the effect of regular exercise training on UCP1 expression in C BAT, and not white adipose tissue (WAT), were eligible. Reviews, editorials, and conference proceedings were excluded. Nine studies fulfilled the set criteria. Risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. The quality of reporting the results in the included studies was assessed using the 38-item checklist of the Animal Research Reporting of In Vivo Experiments (ARRIVE). Based on the evidence available and a comprehensive analysis of different confounding factors, we conclude that regular exercise training does not represent a major stimulus of UCP1 expression in C BAT. However, regular exercise training may induce adaptive responses to C BAT thermogenic activity in cases where: (i) animals consume a high-fat diet, (ii) exercise is combined with cold exposure, and (iii) animals show endogenously low UCP1 levels. Finally, it is important to note an inconsistency in the results from the analysed studies, which may be attributed to a number of confounding factors, increased risk of bias, as well as low quality of reporting the results.

Obstructive sleep apnea (OSA) has a strong association with cardiovascular and metabolic abnormalities, although the mechanism driving this association is not well established. NOV/CCN3, a multifunctional extracellular matrix protein, may play a mechanistic and/or prognostic role in these associations. We hypothesized that patients with OSA, which primarily affects obese individuals, will have increased levels of NOV, and that NOV can serve as a biomarker in patients to predict OSA as well as metabolic and cardiac risk. Ten morbidly obese and 10 healthy lean subjects underwent overnight polysomnography (PSG) and clinical evaluation. Blood samples were analyzed for NOV levels, adiponectin and IL-6. OSA was found in nine obese subjects and three lean subjects. NOV levels were significantly higher in the OSA vs. no OSA group (2.1 ± 0.9 vs. 1.3 ± 0.8, p < 0.03). NOV levels were significantly higher in the obese vs. lean group (2.2 ± 0.3 vs. 1.4 ± 0.2-fold change, p < 0.03). Among lean subjects, NOV levels were significantly higher in the OSA vs. no OSA group (2.1 ± 0.9 vs. 1.0 ± 0.4, p < 0.05). NOV and AHI were positively correlated (ρ = 0.49, p = 0.033). IL-6 and adiponectin differences in obese vs. lean and OSA vs. no OSA were consistent with an inflammatory phenotype in obese subjects and OSA subjects. NOV is a novel biomarker of the presence and severity of OSA and a potential marker of future cardiovascular and metabolic disease in OSA patients.