Browning of the white adipose tissue regulation: new insights into nutritional and metabolic relevance in health and diseases

Abstract

Adipose tissues are dynamic tissues that play crucial physiological roles in maintaining health and homeostasis. Although white adipose tissue and brown adipose tissue are currently considered key endocrine organs, they differ functionally and morphologically. The existence of the beige or brite adipocytes, cells displaying intermediary characteristics between white and brown adipocytes, illustrates the plastic nature of the adipose tissue. These cells are generated through white adipose tissue browning, a process associated with augmented non-shivering thermogenesis and metabolic capacity. This process involves the upregulation of the uncoupling protein 1, a molecule that uncouples the respiratory chain from Adenosine triphosphate synthesis, producing heat. β-3 adrenergic receptor system is one important mediator of white adipose tissue browning, during cold exposure. Surprisingly, hyperthermia may also induce beige activation and white adipose tissue beiging. Physical exercising copes with increased levels of specific molecules, including Beta-Aminoisobutyric acid, irisin, and Fibroblast growth factor 21 (FGF21), which induce adipose tissue browning. FGF21 is a stress-responsive hormone that interacts with beta-klotho. The central roles played by hormones in the browning process highlight the relevance of the individual lifestyle, including circadian rhythm and diet. Circadian rhythm involves the sleep-wake cycle and is regulated by melatonin, a hormone associated with UCP1 level upregulation. In contrast to the pro-inflammatory and adipose tissue disrupting effects of the western diet, specific food items, including capsaicin and n-3 polyunsaturated fatty acids, and dietary interventions such as calorie restriction and intermittent fasting, favor white adipose tissue browning and metabolic efficiency. The intestinal microbiome has also been pictured as a key factor in regulating white tissue browning, as it modulates bile acid levels, important molecules for the thermogenic program activation. During embryogenesis, in which adipose tissue formation is affected by Bone morphogenetic proteins that regulate gene expression, the stimuli herein discussed influence an orchestra of gene expression regulators, including a plethora of transcription factors, and chromatin remodeling enzymes, and non-coding RNAs. Considering the detrimental effects of adipose tissue browning and the disparities between adipose tissue characteristics in mice and humans, further efforts will benefit a better understanding of adipose tissue plasticity biology and its applicability to managing the overwhelming burden of several chronic diseases.

Keywords: Browning; Life-style; UCP1; White adipose tissue.

Fig. 1

Brown adipocyte regulation by exogenous agents. Thyroid hormones act on thermogenesis through interaction with their Thyroid receptors (TR) and the G-protein-coupled receptor (GPCR). TRα promotes an increase in adrenergic signaling while TRβ acts to stimulate uncoupling protein 1 (UCP1). β3 receptor (β3-AR) is expressed constitutively on the surface of the adipocyte and acts to regulate the transcription and activation of genes related to mitochondrial biogenesis, brown adipocyte differentiation, and lipid storage. This receptor can be activated through cold, which is the main mechanism for activating browning, agonist drugs, or diet. Chronic exposure to cold and food intake, such as curcumin and fish oil, promotes thermogenesis by releasing catecholamines from the central nervous system (CNS) that bind to β-AR, thus initiating a signaling cascade. An increase in the concentration of cAMP is elicited which consequently leads to the enhanced activity of protein kinase A (PKA) which promotes the cAMP-response element-binding protein (CREB). This pathway is related to the transcription of thermogenic genes such as peroxisome proliferator-activated receptor γ (PPARγ), Type II iodothyronine deiodinase (DIO2), PR domain containing 16 (PRDM16), Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and Cell death-inducing DNA fragmentation factor-like effector A (CIDEA). The other dietary components can participate in the induction of browning through the modulation of the gut microbiota promoting the increase of the expression of thermogenic genes. The release of growth factor 21 (FGF21) is mediated by the practice of physical exercises and physiological changes. FGF21 will interact with its FGFR receptor and that activation induces a self-phosphorylation of the FGFR that mediates the activation of pathways related to increased expression of UCP1

Fig. 2

The impact of circadian rhythm and different diets on the WAT browning modulation. The secretion of melatonin, a circadian rhythm regulating neurohormone, is mediated by the release of Norepinephrine (NE), which binds to β-adrenergic receptors. Adrenergic activation is one of the main mechanisms of WAT browning induction and BAT activation. Intermittent fasting (IF) associates with weight reduction, improved metabolic status due to increased glycemic tolerance, decreased white adipocyte hypertrophy and AT inflammation, and augmented expression of thermogenic genes (such as UCP1) and recruitment of beige adipocytes. IF is also modulates the intestinal microbiome composition and diversity, a shift closely related to the induction of browning in the WAT. Caloric restriction (CR) is also associated with weight loss, promotes greater recruitment of beige adipocytes through the participation of M2 macrophage and eosinophil infiltration and in WAT. Finally, obesity-inducing diets correlate with increased lipid accumulation, WAT unhealthy expansion and dysregulation. Abnormal expansion of WAT promotes ER stress, greater induction of adipose cell apoptosis and inflammation through NF-κB transcription factor activation and increased pro-inflammatory cytokines secretion

Fig. 3

WAT browning transcriptional regulation. The transcriptional regulation of the WAT beiging process involves the action of a plethora of specific proteins and nucleic acids. This orchestra of trans-acting factors modulates genes associated with oxidative capacity, mitochondrial biogenesis and non-shivering thermogenesis. While the action of some factors, such as PGC-1α, IRF4, PRDM16, ZFP516, EHMT1 and RNAs, copes with WAT browning, TLE3, ZFP423, and the NuRD complex, another set of RNAs e others inhibit this process, favoring adipogenesis and white adipocyte differentiation