An update on the secretory functions of brown, white, and beige adipose tissue: Towards therapeutic applications.

Adipose tissue, including white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue, is vital in modulating whole-body energy metabolism. While WAT primarily stores energy, BAT dissipates energy as heat for thermoregulation. Beige adipose tissue is a hybrid form of adipose tissue that shares characteristics with WAT and BAT. Dysregulation of adipose tissue metabolism is linked to various disorders, including obesity, type 2 diabetes, cardiovascular diseases, cancer, and infertility. Both brown and beige adipocytes secrete multiple molecules, such as batokines, packaged in extracellular vesicles or as soluble signaling molecules that play autocrine, paracrine, and endocrine roles. A greater understanding of the adipocyte secretome is essential for identifying novel molecular targets in treating metabolic disorders. Additionally, microRNAs show crucial roles in regulating adipose tissue differentiation and function, highlighting their potential as biomarkers for metabolic disorders. The browning of WAT has emerged as a promising therapeutic approach in treating obesity and associated metabolic disorders. Many browning agents have been identified, and nanotechnology-based drug delivery systems have been developed to enhance their efficacy. This review scrutinizes the characteristics of and differences between white, brown, and beige adipose tissues, the molecular mechanisms involved in the development of the adipocytes, the significant roles of batokines, and regulatory microRNAs active in different adipose tissues. Finally, the potential of WAT browning in treating obesity and atherosclerosis, the relationship of BAT with cancer and fertility disorders, and the crosstalk between adipose tissue with circadian system and circadian disorders are also investigated.

Brown adipose tissue-derived metabolites and their role in regulating metabolism.

The discovery and rejuvenation of metabolically active brown adipose tissue (BAT) in adult humans have offered a new approach to treat obesity and metabolic diseases. Beyond its accomplished role in adaptive thermogenesis, BAT secretes signaling molecules known as "batokines", which are instrumental in regulating whole-body metabolism via autocrine, paracrine, and endocrine action. In addition to the intrinsic BAT metabolite-oxidizing activity, the endocrine functions of these molecules may help to explain the association between BAT activity and a healthy systemic metabolic profile. Herein, we review the evidence that underscores the significance of BAT-derived metabolites, especially highlighting their role in controlling physiological and metabolic processes involving thermogenesis, substrate metabolism, and other essential biological processes. The conversation extends to their capacity to enhance energy expenditure and mitigate features of obesity and its related metabolic complications. Thus, metabolites derived from BAT may provide new avenues for the discovery of metabolic health-promoting drugs with far-reaching impacts. This review aims to dissect the complexities of the secretory role of BAT in modulating local and systemic metabolism in metabolic health and disease.

Physical activity and batokines.

Brown and beige adipose tissue share similar functionality, being both tissues specialized in producing heat through nonshivering thermogenesis and also playing endocrine roles through the release of their secretion factors called batokines. This review elucidates the influence of physical exercise, and myokines released in response, on the regulation of thermogenic and secretory functions of these adipose tissues and discusses the similarity of batokines actions with physical exercise in the remodeling of adipose tissue. This adipose tissue remodeling promoted by autocrine and paracrine batokines or physical exercise seems to optimize its functionality associated with better health outcomes.

Adipose tissue adipokines and lipokines: Functions and regulatory mechanism in skeletal muscle development and homeostasis.

Skeletal muscle plays important roles in normal biological activities and whole-body energy homeostasis in humans. The growth and development of skeletal muscle also directly influence meat production and meat quality in animal production. Therefore, regulating the development and homeostasis of skeletal muscle is crucial for human health and animal production. Adipose tissue, which includes white adipose tissue (WAT) and brown adipose tissue (BAT), not only functions as an energy reserve but also has attracted substantial attention because of its role as an endocrine organ. The novel signalling molecules known as "adipokines" and "lipokines" that are secreted by adipose tissue were identified through the secretomic technique, which broadened our understanding of the previously unknown crosstalk between adipose tissue and skeletal muscle. In this review, we summarize and discuss the secretory role of adipose tissues, both WAT and BAT, as well as the regulatory roles of various adipokines and lipokines in skeletal muscle development and homeostasis. We suggest that adipokines and lipokines have potential as drug candidates for the treatment of skeletal muscle dysfunction and related metabolic diseases and as promising nutrients for improving animal production.

Brown adipose tissue as an endocrine organ: updates on the emerging role of batokines.

Brown adipose tissue (BAT) remains active in adults, oxidizing fatty acids or glucose and releasing energy in the form of heat. Brown adipocytes and enhanced thermogenesis are targets for treating obesity and its comorbidities. BAT shows high synthesis activity and secretes several signaling molecules. The brown adipokines, or batokines, take action in an autocrine, paracrine, and endocrine manner. Batokines have a role in the homeostasis of the cardiovascular system, central nervous system, white adipose tissue, liver, and skeletal muscle and exert beneficial effects on BAT. The systemic function of batokines gives BAT an endocrine organ profile. Besides, the batokines Fibroblast Growth Factor-21, Vascular Endothelial Growth Factor A, Bone Morphogenetic Protein 8, Neuregulin 4, Myostatin, and Interleukin-6 emerge as targets to treat obesity and its comorbidities, deserving attention. This review outlines the role of six emerging batokines on BAT and their cross-talk with other organs, focusing on their physiological significance and diet-induced changes.

Disease progression promotes changes in adipose tissue signatures in type 2 diabetic (db/db) mice: The potential pathophysiological role of batokines.

Unlike the white adipose tissue (WAT) which mainly stores excess energy as fat, brown adipose tissue (BAT) has become physiologically important and therapeutically relevant for its prominent role in regulating energy metabolism. The current study makes use of an established animal model of type 2 diabetes (T2D) db/db mice to determine the effect of the disease progression on adipose tissue morphology and gene regulatory signatures. Results showed that WAT and BAT from db/db mice display a hypertrophied phenotype that is consistent with increased expression of the pro-inflammatory cytokine, tumor necrosis factor-alpha (Tnf-α). Moreover, BAT from both db/db and non-diabetic db/+ control mice displayed an age-related impairment in glucose homeostasis, inflammatory profile, and thermogenic regulation, as demonstrated by reduced expression of genes like glucose transporter (Glut-4), adiponectin (AdipoQ), and uncoupling protein 1 (Ucp-1). Importantly, gene expression of the batokines regulating sympathetic neurite outgrowth and vascularization, including bone morphogenic protein 8b (Bmp8b), fibroblast growth factor 21 (Fgf-21), neuregulin 4 (Nrg-4) were altered in BAT from db/db mice. Likewise, gene expression of meteorin-like (Metrnl), growth differentiation factor 15 (Gdt-15), and C-X-C motif chemokine-14 (Cxcl-14) regulating pro- and anti-inflammation were altered. This data provides some new insights into the pathophysiological mechanisms involved in BAT hypertrophy (or whitening) and the disturbances of batokines during the development and progression of T2D. However, these are only preliminary results as additional experiments are necessary to confirm these findings in other experimental models of T2D.

Brain-to-BAT - and Back?: Crosstalk between the Central Nervous System and Thermogenic Adipose Tissue in Development and Therapy of Obesity.

The body of mammals harbors two distinct types of adipose tissue: while cells within the white adipose tissue (WAT) store surplus energy as lipids, brown adipose tissue (BAT) is nowadays recognized as the main tissue for transforming chemical energy into heat. This process, referred to as 'non-shivering thermogenesis', is facilitated by the uncoupling of the electron transport across mitochondrial membranes from ATP production. BAT-dependent thermogenesis acts as a safeguarding mechanism under reduced ambient temperature but also plays a critical role in metabolic and energy homeostasis in health and disease. In this review, we summarize the evolutionary structure, function and regulation of the BAT organ under neuronal and hormonal control and discuss its mutual interaction with the central nervous system. We conclude by conceptualizing how better understanding the multifaceted communicative links between the brain and BAT opens avenues for novel therapeutic approaches to treat obesity and related metabolic disorders.

Immune Cells in Thermogenic Adipose Depots: The Essential but Complex Relationship.

Brown adipose tissue (BAT) is a unique organ in mammals capable of dissipating energy in form of heat. Additionally, white adipose tissue (WAT) can undergo browning and perform thermogenesis. In recent years, the research community has aimed to harness thermogenic depot functions for new therapeutic strategies against obesity and the metabolic syndrome; hence a comprehensive understanding of the thermogenic fat microenvironment is essential. Akin to WAT, immune cells also infiltrate and reside within the thermogenic adipose tissues and perform vital functions. As highly plastic organs, adipose depots rely on crucial interplay with these tissue resident cells to conserve their healthy state. Evidence has accumulated to show that different immune cell populations contribute to thermogenic adipose tissue homeostasis and activation through complex communicative networks. Furthermore, new studies have identified -but still not fully characterized further- numerous immune cell populations present in these depots. Here, we review the current knowledge of this emerging field by describing the immune cells that sway the thermogenic adipose depots, and the complex array of communications that influence tissue performance.

Progressive brown adipocyte dysfunction: Whitening and impaired nonshivering thermogenesis as long-term obesity complications.

Chronic obesity damages the cytoarchitecture of brown adipose tissue (BAT), leading to whitening of brown adipocytes and impaired thermogenesis, characterizing BAT dysfunction. Understanding the pathways of whitening progression can bring new targets to counter obesity. This study aimed to evaluate the chronic effect (12, 16, and 20 weeks) of a high-fat diet (50% energy as fat) upon energy expenditure, thermogenic markers, and pathways involved in BAT whitening in C57BL/6J mice. Sixty adult male mice comprised six nutritional groups, where the letters refer to the diet type (control, C or high-fat, HF), and the numbers refer to the period (in weeks) of diet administration: C12, HF12, C16, HF16, C20, and HF20. After sacrifice, biochemical, molecular, and stereological analyses addressed the outcomes. The HF groups had overweight, oral glucose intolerance, and hyperleptinemia, resulting in progressive whitening of BAT and decreased numerical density of nuclei per area of tissue compared to age-matched control groups. In addition, the whitening maximization was related to altered batokines gene expression, decreased nonshivering thermogenesis, and body temperature, resulting in low energy expenditure. The HF20 group showed enlarged adipocytes with stable and dysfunctional lipid droplets, followed by inflammation and ER stress. In conclusion, chronic HF diet intake caused time-dependent maximization of whitening with defective nonshivering thermogenesis. Long-term BAT dysfunction includes down-regulated vascularization markers, upregulated inflammasome activation, and ER stress markers.

Batokines: Mediators of Inter-Tissue Communication (a Mini-Review).

PURPOSE OF REVIEW: This review highlights aspects of brown adipose tissue (BAT) communication with other organ systems and how BAT-to-tissue cross-talk could help elucidate future obesity treatments. RECENT FINDINGS: Until recently, research on BAT has focused mainly on its thermogenic activity. New research has identified an endocrine/paracrine function of BAT and determined that many BAT-derived molecules, termed "batokines," affect the physiology of a variety of organ systems and cell types. Batokines encompass a variety of signaling molecules including peptides, metabolites, lipids, or microRNAs. Recent studies have noted significant effects of batokines on physiology as it relates whole-body metabolism and cardiac function. This review will discuss batokines and other BAT processes that affect the liver, cardiovascular system, skeletal muscle, immune cells, and brown and white adipose tissue. Brown adipose tissue has a crucial secretory function that plays a key role in systemic physiology.

12,13-diHOME as a new therapeutic target for metabolic diseases.

Lipokines are bioactive compounds, derived from adipose tissue depots, that control several molecular signaling pathways. Recently, 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), an oxylipin, has gained prominence in the scientific literature. An increase in circulating 12,13-diHOME has been associated with improved metabolic health, and the action of this molecule appears to be mediated by brown adipose tissue (BAT). Scientific evidence indicates that the increase in serum levels of 12,13-diHOME caused by stimuli such as physical exercise and exposure to cold may favor the absorption of fatty acids by brown adipose tissue and stimulate the browning process in white adipose tissue (WAT). Thus, strategies capable of increasing 12,13-diHOME levels may be promising for the prevention and treatment of obesity and metabolic diseases. This review explores the relationship of 12,13-diHOME with brown adipose tissue and its role in the metabolic health context, as well as the signaling pathways involved between 12,13-diHOME and BAT.

Impaired brown adipose tissue is differentially modulated in insulin-resistant obese wistar and type 2 diabetic Goto-Kakizaki rats.

Brown adipose tissue (BAT) is a potential target to treat obesity and diabetes, dissipating energy as heat. Type 2 diabetes (T2D) has been associated with obesogenic diets; however, T2D was also reported in lean individuals to be associated with genetic factors. We aimed to investigate the differences between obese and lean models of insulin resistance (IR) and elucidate the mechanism associated with BAT metabolism and dysfunction in different IR animal models: a genetic model (lean GK rats) and obese models (diet-induced obese Wistar rats) at 8 weeks of age fed a high-carbohydrate (HC), high-fat (HF) diet, or high-fat and high-sugar (HFHS) diet for 8 weeks. At 15 weeks of age, BAT glucose uptake was evaluated by 18F-FDG PET under basal (saline administration) or stimulated condition (CL316,243, a selective ß3-AR agonist). After CL316, 243 administrations, GK animals showed decreased glucose uptake compared to HC animals. At 16 weeks of age, the animals were euthanized, and the interscapular BAT was dissected for analysis. Histological analyses showed lower cell density in GK rats and higher adipocyte area compared to all groups, followed by HFHS and HF compared to HC. HFHS showed a decreased batokine FGF21 protein level compared to all groups. However, GK animals showed increased expression of genes involved in fatty acid oxidation (CPT1 and CPT2), BAT metabolism (Sirt1 and Pgc1-α), and obesogenic genes (leptin and PAI-1) but decreased gene expression of glucose transporter 1 (GLUT-1) compared to other groups. Our data suggest impaired BAT function in obese Wistar and GK rats, with evidence of a whitening process in these animals.

Brown/Beige adipose tissues and the emerging role of their secretory factors in improving metabolic health: The batokines.

Brown and beige adipose tissues are the primary sites for adaptive non-shivering thermogenesis. Although they have been known principally for their thermogenic effects, in recent years, it has emerged that, just like white adipose tissue (WAT), brown and beige adipose tissues also play an important role in the regulation of metabolic health through secretion of various brown adipokines (batokines) in response to various physiological cues. These secreted batokines target distant organs and tissues such as the liver, heart, skeletal muscles, brain, WAT, and perform various local and systemic functions in an autocrine, paracrine, or endocrine manner. Brown and beige adipose tissues are therefore now receiving increasing levels of attention with respect to their effects on various other organs and tissues. Identification of novel secreted factors by these tissues may help in the discovery of drug candidates for the treatment of various metabolic disorders such as obesity, type-2 diabetes, skeletal deformities, cardiovascular diseases, dyslipidemia. In this review, we comprehensively describe the emerging secretory role of brown/beige adipose tissues and the metabolic effects of various brown/beige adipose tissues secreted factors on other organs and tissues in endocrine/paracrine manners, and as well as on brown/beige adipose tissue itself in an autocrine manner. This will provide insights into understanding the potential secretory role of brown/beige adipose tissues in improving metabolic health.

An update on brown adipose tissue biology: a discussion of recent findings.

Brown adipose tissue (BAT) has been encouraged as a potential treatment for obesity and comorbidities due to its thermogenic activity capacity and contribution to energy expenditure. Some interventions such as cold and ß-adrenergic drugs are able to activate BAT thermogenesis as well as promote differentiation of white adipocytes into brown-like cells (browning), enhancing the thermogenic activity of these cells. In this mini-review, we discuss new mechanisms related to BAT and energy expenditure. In this regard, we will also discuss recent studies that have revealed the existence of important secretory molecules from BAT "batokines" that act in autocrine, paracrine, and endocrine mechanisms, which in turn may explain some of the beneficial roles of BAT on whole body glucose and fat metabolism. Finally, we will discuss new insights related to BAT thermogenesis with an additional focus on the distinct features of BAT metabolism between rodents and humans.

Brown Adipose Tissue: A Metabolic Regulator in a Hypothalamic Cross Talk?

Since the discovery of functionally competent, energy-consuming brown adipose tissue (BAT) in adult humans, much effort has been devoted to exploring this tissue as a means for increasing energy expenditure to counteract obesity. However, despite promising effects on metabolic rate and insulin sensitivity, no convincing evidence for weight-loss effects of cold-activated human BAT exists to date. Indeed, increasing energy expenditure would naturally induce compensatory feedback mechanisms to defend body weight. Interestingly, BAT is regulated by multiple interactions with the hypothalamus from regions overlapping with centers for feeding behavior and metabolic control. Therefore, in the further exploration of BAT as a potential source of novel drug targets, we discuss the hypothalamic orchestration of BAT activity and the relatively unexplored BAT feedback mechanisms on neuronal regulation. With a holistic view on hypothalamic-BAT interactions, we aim to raise ideas and provide a new perspective on this circuit and highlight its clinical relevance.

Age-Dependent Changes of Adipokine and Cytokine Secretion From Rat Adipose Tissue by Endogenous and Exogenous Toll-Like Receptor Agonists.

White adipose tissue but recently also brown adipose tissue have emerged as endocrine organs. Age-associated obesity is accompanied by prolonged and elevated lipopolysaccharide (LPS)-induced sickness symptoms and increased cytokine and adipokine levels in the circulation partially originating from adipose tissue. In the present study, ex vivo fat explants were used to investigate how the exogenous pathogen-associated molecular pattern (PAMP) LPS or the endogenous danger-associated molecular patterns (DAMPs) high mobility group box-1 protein (HMGB1) and biglycan modulate the release of cytokines and adipokines/batokines and, thus, could influence systemic and/or local inflammation. The response of adipose tissue (epididymal, retroperitoneal, subcutaneous, and brown) was compared between young lean and old obese rats (2 vs. 24 months old). LPS induced a strong interleukin (IL)-6 and tumor necrosis factor (TNF) alpha release into the supernatant of all adipose tissue types investigated. HMGB1 (subcutaneous) and biglycan (retroperitoneal) led to an increased release of IL-6 and TNFalpha (HMGB1) and decreased visfatin and adiponectin (biglycan) secretion from epididymal adipose tissue (young rats). Visfatin was also decreased by HMGB1 in retroperitoneal adipose tissue of old rats. We found significantly higher leptin (all fat pads) and adiponectin (subcutaneous) levels in supernatants of adipose tissue from old compared to young rats, whereas visfatin secretion showed the opposite. The expression of the biglycan receptor Toll-like receptor (TLR) 2 as well as the LPS and HMGB1 receptors TLR4 and receptor for advanced glycation end products (RAGE) were reduced with age (TLR4/RAGE) and by stimulation with their ligands (subcutaneous). Overall, we revealed that adipokines/adipose-tissue released cytokines show some modulation of their release caused by mediators of septic (batokines) and sterile inflammation with potential implication for acute and chronic disease. Moreover, aging may increase or decrease the release of fat-derived mediators. These data show that DAMPS and LPS locally modulate cytokine secretion while only DAMPS but not LPS can locally alter adipokine secretion during inflammation.

Proteomics-Based Comparative Mapping of the Secretomes of Human Brown and White Adipocytes Reveals EPDR1 as a Novel Batokine.

Adipokines secreted from white adipose tissue play a role in metabolic crosstalk and homeostasis, whereas the brown adipose secretome is less explored. We performed high-sensitivity mass-spectrometry-based proteomics on the cell media of human adipocytes derived from the supraclavicular brown adipose and from the subcutaneous white adipose depots of adult humans. We identified 471 potentially secreted proteins covering interesting categories such as hormones, growth factors, extracellular matrix proteins, and proteins of the complement system, which were differentially regulated between brown and white adipocytes. A total of 101 proteins were exclusively quantified in brown adipocytes, and among these was ependymin-related protein 1 (EPDR1). EPDR1 was detected in human plasma, and functional studies suggested a role for EPDR1 in thermogenic determination during adipogenesis. In conclusion, we report substantial differences between the secretomes of brown and white human adipocytes and identify novel candidate batokines that can be important regulators of human metabolism.

The role of brown and beige adipose tissue in glycaemic control.

For the past decade, brown adipose tissue (BAT) has been extensively studied as a potential therapy for obesity and metabolic diseases due to its thermogenic and glucose-consuming properties. It is now clear that the function of BAT goes beyond heat production, as it also plays an important endocrine role by secreting the so-called batokines to communicate with other metabolic tissues and regulate systemic energy homeostasis. However, despite numerous studies showing the benefits of BAT in rodents, it is still not clear whether recruitment of BAT can be utilized to treat human patients. Here, we review the advances on understanding the role of BAT in metabolism and its benefits on glucose and lipid homeostasis in both humans and rodents. Moreover, we discuss the latest methodological approaches to assess the contribution of BAT to human metabolism as well as the possibility to target BAT, pharmacologically or by lifestyle adaptations, to treat metabolic disorders.

Adipose Tissue-Derived Signatures for Obesity and Type 2 Diabetes: Adipokines, Batokines and MicroRNAs.

: Obesity is one of the main risk factors for type 2 diabetes mellitus (T2DM). It is closely related to metabolic disturbances in the adipose tissue that primarily functions as a fat reservoir. For this reason, adipose tissue is considered as the primary site for initiation and aggravation of obesity and T2DM. As a key endocrine organ, the adipose tissue communicates with other organs, such as the brain, liver, muscle, and pancreas, for the maintenance of energy homeostasis. Two different types of adipose tissues-the white adipose tissue (WAT) and brown adipose tissue (BAT)-secrete bioactive peptides and proteins, known as "adipokines" and "batokines," respectively. Some of them have beneficial anti-inflammatory effects, while others have harmful inflammatory effects. Recently, "exosomal microRNAs (miRNAs)" were identified as novel adipokines, as adipose tissue-derived exosomal miRNAs can affect other organs. In the present review, we discuss the role of adipose-derived secretory factors-adipokines, batokines, and exosomal miRNA-in obesity and T2DM. It will provide new insights into the pathophysiological mechanisms involved in disturbances of adipose-derived factors and will support the development of adipose-derived factors as potential therapeutic targets for obesity and T2DM.