The adipose tissues (ATs) are endocrine and dynamic organs that display high morphological and functional plasticity. White AT (WAT) was named that way because it presents white adipocytes in its composition. In contrast, brown AT (BAT) has as its main integrant the brown adipocytes [1]. Both ATs play various physiological roles, including energy storage, endocrine regulation, and thermogenesis. As a means of adapting, mammalians developed a mechanism to maintain their body temperatures under unfavorable climates [2]. This process, called adaptative thermogenesis, occurs due to the elevated plasticity of ATs, which allows reversible changes in their morphology and functions [3]. Studies have shown the capacity of progenitor cells as well as mature adipocytes to differentiate into a model that presents similarities with the brown profile, called brite or beige AT [4,5,6]. When this phenomenon occurs in mature adipocytes it is called browning of WAT [4].
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The increase in energy expenditure can act as a therapeutic approach to metabolic syndrome, and also can be associated with poor prognosis of diseases associated with hypermetabolism [15,16,17,18]. For this reason, efforts have been employed to identify the key participants in the regulation of browning. This review aims to present and describe the current studies related to both endogenous and exogenous most relevant agents and their biological mechanisms at biochemical and molecular levels.
On the other hand, the transdifferentiation hypothesis proposes beige cells arise from mature white adipocytes, in a reversible process, after adipogenic stimulus without the participation of a progenitor-like state of cells [37]. The underlying molecular mechanisms for transdifferentiation are under intensive research, but some studies already show that this plasticity process occurs mainly in scWAT depots [29]. Known as browning, this process has gained increasing attention in the research area as an alternative method of energy stimulation. UCP1 expression can be stimulated when white adipocytes are exposed to stimuli, previously referred as to adipogenic stimulus, [20, 27, 29], driven by a set of molecules known as browning markers.
In contrast, the upregulation of UCP1 or even only its activation can perform a paradoxical role in hypermetabolic scenarios and associate with a worse prognosis [76, 77]. It is proven that diet-induced whitening is related to the upregulation of this gene. A greater expression of browning markers (e.g., UCP1, PGC-1α, TBX1) was found in obese human patients mainly in vWAT [78] Besides that, mice affected by cancer-associated cachexia tend to show increased thermogenesis gene expression and BAT activation [79].
The browning process is spontaneously induced by tumor-secreted factors and IL-6 during cachexia development, which can lead to full depletion of AT [80, 81]. Interestingly, the elicitation of browning after burn injury is associated with the hypermetabolic response, as well as an increase in lipolysis and free fatty acid efflux that can outcome in liver steatosis [82, 83]. In addition to the therapeutic impact of the browning process in obesity and metabolic diseases, recent discoveries regarding the impact of UCP1-dependent BAT activity in hypermetabolism conditions should be further investigated in the context of UCP1 to appropriately regulate browning for application in different situations.
Initial studies demonstrated that WAT UCP1 mRNA and protein levels are strongly decreased in β3-AR knockout (KO) mice [30, 93]. In addition, β3-AR agonists are well-known for inducing ectopic UCP1 expression in WAT coupled with a significant mitochondrial enhancement in rodents, and for augmenting glucose homeostatic activity of their BAT [84, 94]. On the other hand, in humans, early efforts to increase browning activation with the use of β3-adrenoreceptor agonists have failed in clinical trials because of their β1- and β2-AR-mediated cardiovascular effects [13, 84, 94]. However, a recent study showed that mirabegron, a selective β3-agonist previously developed for the treatment of overactive bladder, was shown to increase BAT activity as compared to placebo. This study used an oral dose of 200 mg in healthy male subjects, and despite not having severe cardiovascular side effects, they have been shown to increase heart rate and systolic blood pressure [84]. That is the reason long-term studies are warranted to investigate the effectiveness and cardiovascular safety of this type of treatment to induce weight loss and metabolic health improvements.
It is known that the results observed in humans do not always represent the same effects previously described in mice or even contradictory results can be obtained under similar conditions for the same species [138]. Unfortunately, this premise can also be applied to cold-induced browning. Leitner and colleagues showed that in human fewer than half of the BAT deposits is stimulated by cold exposure, hence, the thermogenic function was lower than expected [44].
Notably, the use of cold as a browning inducer has been carefully applied not only because of the side effects that can be displayed at the whole-body level but also due to the contradictory effect observed in humans. If on one hand, the anti-inflammatory and immunosuppressive role mediated by cold and cold-induced browning is beneficial in healthy individuals, for ill people these same effects may become harmful. In contrast, intriguing research has brought a new perspective on temperature-based browning. Li and colleagues discovered that a hydrogel-based photothermal therapy leads to a successful increase of beige activation in both mice and humans. The therapy consists of increasing the local temperature, around 41C, without evident stress on skin or adjacent tissues [142]. This promising study succeeds previous findings that pointed to the occurrence of WAT browning after burn injury [143, 144]. The characterization of possible inducers of browning is a strongly growing field since the applicability of these inducers as therapy in humans has proven to be a major clinical hurdle. However, even under promising advances is clear that further investigation regarding the mechanisms triggered by this stimulus pathway should be conducted.
Physical exercising is already associated with improvements in several processes related to the cardiovascular system, skeletal muscle, and ATs [193]. Following this, several studies show that physical activity provides better quality of life [194] and helps in the treatment of several metabolic diseases and obesity [195] through increasing AT lipolysis, vascularization, blood flow, and promoting the secretion of hormones and adipokines [196]. Among the main adipokines, FGF21 (Fibroblast growth factor 21) and leptin stand out, which act in an autocrine/paracrine manner, regulating WAT browning process [197]. After physical activities, the adipokine leptin stimulates activity in the sympathetic nerve and together with insulin act synergistically in different neuronal subsets of proopiomelanocortin (POMC) inducing browning of WAT through decreased hypothalamic inflammation caused by exercise [198]. During exercise, the increase in glucagon, which already has thermogenic potential [199], and the decrease in insulin in the liver lead to FGF21 secretion [200].
The myokine myostatin (Mstn), a growth factor that limits muscle growth and development, is negatively involved in the WAT browning process, as Mstn-deficient mice showed high expression of genes associated with FA oxidation, mitochondrial biogenesis, lipid transport together with the positive regulation of PGC-1α and UCP1, this mechanism occurs through the phosphorylation of AMPK, necessary for the activation of PGC1α and FNDC5 [199]. Metrnl, the gene encoding for Meteorin-like protein, is a myokine known to be induced by resistance exercise dependently on PGC-1α4. Metrnl regulates genes involved in thermogenesis, as it is capable of promoting the activation of M2 macrophages by inciting the expression of IL-4 and thus triggering the production of catecholamines [206], responsible for favoring thermogenesis in AT [207]. Beta-Aminoisobutyric acid is another myokine that has increased levels during exercise and can induce the brown adipocyte phenotype in human-induced pluripotent stem cells during differentiation to mature white adipocytes [146].
Although the studies conducted in mice seem promising, the effect of exercise on WAT browning in humans has proven to be controversial. A survey conducted with sedentary subjects participating in a 12-week bicycle-training program showed scWAT increased expression of UCP1, carnitine palmitoyltransferase 1B (CPT1B), TBX1 [15]. However, other studies have not achieved similar effects. Tsiloulis and colleagues collected scWAT of obese men after 6 weeks of physical training and the mRNA levels of UCP1, CD137, CITED, TBX1, LHX8, and TCF21 were not altered [211]. Many factors may be involved in this diversity of results since the duration, frequency, and degree of intensity are associated with these effects. Thus, more human studies need to be conducted as many questions still need to be clarified.
The fish oil is rich in n-3 polyunsaturated fatty acids (PUFAs), components that are associated with the formation of beige adipocytes, among them is eicosapentaenoic acid (EPA). Mice fed different diets, including with EPA, for 8 weeks showed increased expression of β3-AR, PGC-1α, and UCP1 and exhibited high expression of PPAR [227], though this effect is controversial since another animal study investigating a diet containing pure EPA (3.6% as EPA ethyl ester) did not show the expression of beige adipocyte marker genes of inguinal and visceral WAT, but only in BAT [228]. Docosahexaenoic acid (DHA) (1.2%) together with EPA (2.4%) increased oxygen consumption and rectal temperature, as well as UCP1 and β3AR levels via the central nervous system. However, knockout mice for TRPV1 did not achieve the same effect, showing that such events were mediated by SNS, TRPV1, and catecholamines [229]. Conjugated linoleic acids (CLAs) also showed potential to induce browning process in the WAT [230]. 2ff7e9595c
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