Rubén Cereijo

An endocrine role for brown adipose tissue

White adipose tissue is recognized as both a site of energy storage and an endocrine organ that produces a myriad of endocrine factors called adipokines. Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis in mammals. The amount and activity of brown adipocytes are associated with protection against obesity and associated metabolic alterations. These effects of BAT are traditionally attributed to its capacity for the oxidation of fatty acids and glucose to sustain thermogenesis. However, recent data suggest that the beneficial effects of BAT could involve a previously unrecognized endocrine role through the release of endocrine factors. Several signaling molecules with endocrine properties have been found to be released by brown fat, especially under conditions of thermogenic activation. Moreover, experimental BAT transplantation has been shown to improve glucose tolerance and insulin sensitivity mainly by influencing hepatic and cardiac function. It has been proposed that these effects are due to the release of endocrine factors by brown fat, such as insulin-like growth factor I, interleukin-6, or fibroblast growth factor-21. Further research is needed to determine whether brown fat plays an endocrine role and, if so, to comprehensively identify which endocrine factors are released by BAT. Such research may reveal novel clues for the observed association between brown adipocyte activity and a healthy metabolic profile, and it could also enlarge a current view of potential therapeutic tools for obesity and associated metabolic diseases.

Brown adipose tissue as a secretory organ

Brown adipose tissue (BAT) is the main site of adaptive thermogenesis and experimental studies have associated BAT activity with protection against obesity and metabolic diseases, such as type 2 diabetes mellitus and dyslipidaemia. Active BAT is present in adult humans and its activity is impaired in patients with obesity. The ability of BAT to protect against chronic metabolic disease has traditionally been attributed to its capacity to utilize glucose and lipids for thermogenesis. However, BAT might also have a secretory role, which could contribute to the systemic consequences of BAT activity. Several BAT-derived molecules that act in a paracrine or autocrine manner have been identified. Most of these factors promote hypertrophy and hyperplasia of BAT, vascularization, innervation and blood flow, processes that are all associated with BAT recruitment when thermogenic activity is enhanced. Additionally, BAT can release regulatory molecules that act on other tissues and organs. This secretory capacity of BAT is thought to be involved in the beneficial effects of BAT transplantation in rodents. Fibroblast growth factor 21, IL-6 and neuregulin 4 are among the first BAT-derived endocrine factors to be identified. In this Review, we discuss the current understanding of the regulatory molecules (the so-called brown adipokines or batokines) that are released by BAT that influence systemic metabolism and convey the beneficial metabolic effects of BAT activation. The identification of such adipokines might also direct drug discovery approaches for managing obesity and its associated chronic metabolic diseases.

Fibroblast growth factor-21 is expressed in neonatal and pheochromocytoma-induced adult human brown adipose tissue.

OBJECTIVE In rodents, brown (BAT) and white (WAT) adipose tissues are targets and expression sites for fibroblast growth factor-21 (FGF21). In contrast, human WAT expresses negligible levels of FGF21. We examined FGF21 expression in human BAT samples, including the induced BAT found in adult patients with pheochromocytoma, and interscapular and visceral BAT from newborns. METHODS The expression of FGF21 and uncoupling protein-1 (UCP1, a brown adipocyte marker), was determined by quantitative real-time-PCR and immunoblotting. The transcript levels of marker genes for developmentally-programmed BAT (zinc-finger-protein of the cerebellum-1, ZIC1) and inducible-BAT (cluster of differentiation-137, CD137) were also determined. RESULTS FGF21 and UCP1 are significantly expressed in visceral adipose tissue from pheochromocytoma patients, but not in visceral fat from healthy individuals. In neonates, FGF21 and UCP1 are both expressed in visceral and interscapular fat, and their expression levels show a significant positive correlation. Marker gene expression profiles suggest that inducible BAT is present in visceral fat from pheochromocytoma patients and neonates, whereas developmentally-programmed BAT is present in neonatal interscapular fat. CONCLUSIONS Human BAT, but not WAT, expresses FGF21. The expression of FGF21 is especially high in inducible, also called beige/brite, neonatal BAT, but it is also found in the interscapular, developmentally-programmed, BAT of neonates.

The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes.

The thermogenic activity of brown adipose tissue (BAT) and browning of white adipose tissue are important components of energy expenditure. Here we show that GPR120, a receptor for polyunsaturated fatty acids, promotes brown fat activation. Using RNA-seq to analyse mouse BAT transcriptome, we find that the gene encoding GPR120 is induced by thermogenic activation. We further show that GPR120 activation induces BAT activity and promotes the browning of white fat in mice, whereas GRP120-null mice show impaired cold-induced browning. Omega-3 polyunsaturated fatty acids induce brown and beige adipocyte differentiation and thermogenic activation, and these effects require GPR120. GPR120 activation induces the release of fibroblast growth factor-21 (FGF21) by brown and beige adipocytes, and increases blood FGF21 levels. The effects of GPR120 activation on BAT activation and browning are impaired in FGF21-null mice and cells. Thus, the lipid sensor GPR120 activates brown fat via a mechanism that involves induction of FGF21.

Thermogenic brown and beige/brite adipogenesis in humans

Abstract Evidence from rodents established an important role of brown adipose tissue (BAT) in energy expenditure. Moreover, to sustain thermogenesis, BAT has been shown to be a powerful sink for draining and oxidation of glucose and triglycerides from blood. The potential of BAT activity in protection against obesity and metabolic syndrome is recognized. Recently, an unexpected presence and activity of BAT has been found in adult humans. Here we review the most recent research in this field and, specifically, how new findings apply to humans. Moreover, we seek to clarify the underlying biological processes occurring beyond the burst of new nomenclature in the field. The cell type responsible for thermogenesis, the brown adipocyte, arises from complex developmental processes. In addition to ‘classical’ brown adipocytes, present in developmentally programmed BAT depots, there are brown adipocytes, named ‘brite’ (from ‘brown-in-white’) or ‘beige’, which appear in response to thermogenic stimuli in white fat due to the so-called ‘browning’ process. Beige/brite cells appear to be important components of BAT depots in adult humans. In addition to the known control of BAT activity by the sympathetic nervous system, metabolic and hormonal signals originating in muscle or liver (e.g. irisin, FGF21) are recognized as activators of BAT and beige/brite adipocytes.

Toward an Understanding of How Immune Cells Control Brown and Beige Adipobiology

Immune cells were recently found to have an unexpected involvement in controlling the thermogenic activity of brown and beige adipose tissue. Here, we review how macrophages, eosinophils, type 2 innate lymphoid cells, and T lymphocytes are linked to this process. In particular, the recruitment of alternatively activated macrophages and eosinophils is associated with brown fat activation and white fat browning. Conversely, pro-inflammatory immune cell recruitment represses the thermogenic activity of brown and beige adipose tissues via cytokines that inhibit noradrenergic signaling. Macrophages also influence the noradrenergic tone by degrading norepinephrine locally and by inhibiting sympathetic innervation over time.

Oncostatin m impairs brown adipose tissue thermogenic function and the browning of subcutaneous white adipose tissue

Since oncostatin m (OSM) is elevated in adipose tissue in conditions of obesity and type 2 diabetes in mice and humans, the aim of this study was to determine whether this cytokine plays a crucial role in the impairment of brown adipose tissue (BAT) activity and browning capacity that has been observed in people with obesity.

Adipokines and the Endocrine Role of Adipose Tissues.

The last two decades have witnessed a shift in the consideration of white adipose tissue as a mere repository of fat to be used when food becomes scarce to a true endocrine tissue releasing regulatory signals, the so-called adipokines, to the whole body. The control of eating behavior, the peripheral insulin sensitivity, and even the development of the female reproductive system are among the physiological events controlled by adipokines. Recently, the role of brown adipose tissue in human physiology has been recognized. The metabolic role of brown adipose tissue is opposite to white fat; instead of storing fat, brown adipose tissue is a site of energy expenditure via adaptive thermogenesis. There is growing evidence that brown adipose tissue may have its own pattern of secreted hormonal factors, the so-called brown adipokines, having distinctive biological actions on the overall physiological adaptations to enhance energy expenditure.

Thermogenic activation represses autophagy in brown adipose tissue.

Background:Brown adipose tissue (BAT) thermogenesis is an adaptive process, essential for energy expenditure and involved in the control of obesity. Obesity is associated with abnormally increased autophagy in white adipose tissue. Autophagy has been proposed as relevant for brown-vs-white adipocyte differentiation; however, its role in the response of BAT to thermogenic activation is unknown.Methods:The effects of thermogenic activation on autophagy in BAT were analyzed in vivo by exposing mice to 24 h cold condition. The effects of norepinephrine (NE), cAMP and modulators of lysosomal activity were determined in differentiated brown adipocytes in the primary culture. Transcript expression was quantified by real-time PCR, and specific proteins were determined by immunoblot. Transmission electron microscopy, as well as confocal microscopy analysis after incubation with specific antibodies or reagents coupled to fluorescent emission, were performed in BAT and cultured brown adipocytes, respectively.Results:Autophagy is repressed in association with cold-induced thermogenic activation of BAT in mice. This effect was mimicked by NE action in brown adipocytes, acting mainly through a cAMP-dependent protein kinase A pathway. Inhibition of autophagy in brown adipocytes leads to an increase in UCP1 protein and uncoupled respiration, suggesting a repressing role for autophagy in relation to the activity of BAT thermogenic machinery. Under basal conditions, brown adipocytes show signs of active lipophagy, which is suppressed by a cAMP-mediated thermogenic stimulus.Conclusions:Our results show a noradrenergic-mediated inverse relationship between autophagy and thermogenic activity in BAT and point toward autophagy repression as a component of brown adipocyte adaptive mechanisms to activate thermogenesis.

Resistin and visfatin in steatotic and non-steatotic livers in the setting of partial hepatectomy under ischemia-reperfusion

BACKGROUND & AIMS This study examined whether the regulation of resistin and visfatin could reduce damage and improve regeneration in both steatotic and non-steatotic livers undergoing partial hepatectomy under ischemia-reperfusion, a procedure commonly applied in clinical practice to reduce bleeding. METHODS Resistin and visfatin were pharmacologically modulated in lean and obese animals undergoing partial hepatectomy under ischemia-reperfusion. RESULTS No evident role for these adipocytokines was observed in non-steatotic livers. However, obese animals undergoing liver surgery showed increased resistin in liver and plasma, without changes in adipose tissue, together with visfatin downregulation in liver and increment in plasma and adipose tissue. Endogenous resistin maintains low levels of visfatin in the liver by blocking its hepatic uptake from the circulation, thus regulating the visfatin detrimental effects on hepatic damage and regenerative failure. Indeed, the administration of anti-resistin antibodies increased hepatic accumulation of adipocyte-derived visfatin, exacerbating damage and regenerative failure. Interestingly, treatment with anti-visfatin antibodies protected steatotic livers, and similar results were obtained with the concomitant inhibition of resistin and visfatin. Thus, when visfatin was inhibited, the injurious effects of anti-resistin antibodies disappeared. Herein we show that upregulation of visfatin increased NAD levels in the remnant steatotic liver, whereas visfatin inhibition decreased them. These later observations suggest that visfatin may favour synthesis of NAD instead of DNA and induces alterations in amino acid metabolism-urea cycle and NO production, overall negatively affecting liver viability. CONCLUSIONS Our results indicate the clinical potential of visfatin blocking-based therapies in steatotic livers undergoing partial hepatectomy with ischemia-reperfusion.