Academic Editor: Laureane Masi
Affilation: University of Sao Paulo
Human obesity is now universal and has drawn serious attention of international academia to unravel its pathophysiology and treatment. In recent years, efforts are being made to understand the complex physiology of both white and brown adipose tissue in detail with relevance to obesity. A large number of secretions from the white fat called the adipokines have been recognized that play a definitive role in obesity and its disorders. Innumerable regulators grouped mainly under the transcriptional, hormonal and signaling factors that govern the thermogenic functions of brown fat have been worked out. Based on these revelations, strong suggestions have been made for treating obesity specially by targeting the brown fat as it plays a key role in energy expenditure as well as through behavioral, pharmacological, physiological and surgical approaches. Such findings have been reported in a nutshell in this communication
Human obesity has been documented for at least 25,000 years.
From a physiological view point, obesity is considered to result from a mismatch in energy balance either by an increase in energy intake and/or by a decrease in energy expenditure.
Though, obesity is a mismatch between energy intake and energy output, basically it results from dysfunction of both white and brown fat tissue. Adipose tissue, particularly white fat was a neglected subject till recently when leptin was identified in 1994.
In recent years adipose tissue physiology has taken the center stage of research to address problems related to obesity, diabetes mellitus, insulin resistance, cancer, metabolic syndrome etc.
Listed alphabetically with abbreviations below in the
The location of each adipose tissue (subcutaneous or visceral) itself affects the endocrine function with an unique expression and secretion profiles indicating a high degree of heterogeneity and thereby contribute to disease processes. For example, IL-6 and PAI-1 are secreted more in visceral adipose tissue where as leptin and adinopectin are more from subcutaneous fat tissue. Endocrine secretions from the visceral fat depots are secreted into the portal system and have direct access to liver whereas subcutaneous fat depots secretions are put into the systemic circulation. Local sub-groups of WAT are distributed in visceral, muscle, epicardial, perivascular and kidney areas. Visceral WAT controls local and systemic inflammation while epicardial WAT controls local inflammation and chemotaxis. Muscle WAT is involved in insulin resistance and kidney WAT affects intravascular volume and hypertension. Perivascular WAT is mainly involved with atherosclerosis and hypertension. Such findings may suggest that adipose tissue is perhaps a group of similar but unique endocrine organs.
Many of the secretions come from non-adipocytic portions of the adipose tissue such as vascular, stromal and connective tissues.
Physiological effects of some important adipokines is briefly considered in the following lines.
Leptin has a profound role in the regulation of whole body metabolism by stimulating energy expenditure through elevated sympathetic activity and by controlling the food intake via anorexigenic and orexigenic peptides at the hypothalamus level. In obesity, insulin resistance has been linked to leptin resistance and decreased plasma adiponectin which is reversed by simultaneous administration of leptin and adinopectin. It also plays a role in immune system modulation, sexual development and reproduction. Leptin is also secreted from placenta, gastric fundus mucosa, skeletal muscle and mammary gland.
Adinopectin increases insulin sensitivity, fatty acid oxidation, energy expenditure and reduces the production of glucose by the liver. It has an anti-inflammatory, anti-atherogenic effect and is protective against insulin resistance and reduces the risks of coronary artery disease. It suppresses phagocytic activity and macrophage release of TNF-α, and transformation of macrophages to foam cells
IL-6is secreted by not only adipose tissue but also by brain tissue and skeletal muscle during physical acticity. IL-6 is pro-inflammatory and has a role in tissue injury, lipolysis and it reduces sensitivity to insulin. It decreases adinopectin secretion. But during physical activity, IL-6 secreted from skeletal muscle induces glucose uptake and lipolysis. IL-6 from central nervous system (CNS) decreases body weight and visceral fat by sympathetic activation through increased brown fat activity
An adipocyte renin-angiotensin system (ARAS) located in the intra adipose tissue regulates fat cell mass and energy stores through paracrine/autocrine effects on adipocyte differentiation and lipid storage.Angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) and its receptors (AT1, AT2), and the non-renin-angiotensin enzymes chymase, cathepsins D and G and tonin are all expressed by adipose tissue. Adipose tissue Ang II controls terminal differentiation of preadipocytes to adipocytes through the action of prostacyclin (PGI2) and regulates adipose tissue blood supply. Adipose tissue AGT also influences adipocyte vascular resistance but negatively regulates fat mass by decreasing lipogenesis.It promotesinflammation and insulin resistance and hypertension.However, in humans the role of ARAS in the relation to obesity and hypertension remains to be further explored
In general, most adipokines affect insulin, glucose metabolism and lipid metabolism negatively leading to development of metabolic syndrome features such as increased adiposity, hypertension, diabetes mellitus, cardiovascular effects and inflammatory process with other manifestations.
The details of lipogenesis, lipolysis and the factors controlling adipogensis is well explained in a review article by Proenca et al.
BAT is a multi-depot organ found generally in inter-scapular, subscapular, axillary, paravertebral, mediastinal, periaortic areas and other regions including neck, intercostal vessels, mammary vessels, suprarenals and greater omentum.
As far as the characteristics of WAT and BAT are considered a few major ones can be listed as follows. WAT is unilocular adipocyte (200µm diameter) with lipid storage and mobilization (+++), mitochondria (+), fatty acid oxidation (+), respiratory chain (+), UCP1 (0), PPAR-ˠ coactivator 1α (PGC-1α) (+) while the BAT has the following features; multilocular adipocytes, lipid storage and mobilization (++), mitochondria (+++), fatty acid oxidation (+++), respiratory chain (+++), UCP1 (+++), PGC-1α (+++).
Thermogenesis in the BAT can be explained in brief as follows. BAT is like a burner for the heater. In other words, the function of BAT is to transfer energy from food to heat. The mitochondria in a eukaryotic cell utilize fuels to produce energy in the form of ATP. In the brown fat mitochondria, inward proton conductance that generates ATP (oxidative phosphorylation) takes place as usual, but in addition there is a second proton conductance (proton run back) that does not generate ATP. This alternative route or ‘short-circuit’ conductance depends on a 32-kDa uncoupling protein (UCP), now called UCP1 (previously known as thermogenin) present in the inner membrane of the mitochondria. This protein causes uncoupling of metabolism and generation of ATP so that more heat is produced.
The origin of adipode tissue is very interesting to note as both WAT and BAT and other tissues are believed to arise from a common pluripotent stem cell that gives rise to a mesenchymal precursor cell which has the potential to develop into myoblast, chondroblast, osteoblast and adipocyte. As far as origin of brown adipocytes, it is understood that classical BAT are derived from myogenic factor 5 (Myf 5+) positive progenitor cells similar to skeletal myocytes whereas brite adipocytes have been shown to originate from Myf-negative (Myf 5−) progenitor cells much like white adipocytes. Interestingly, the browning of WAT may also involve trans-differentiation of white-to-brown adipose cells.
Of late, four areas of developments in BAT research have kindled a lot of interest and hopes in the treatment of obesity and related co-morbidities. These include identification of i) active and functional BAT in adult humans, ii) classical and beige /brite types of BAT cells, iii) a number of regulatory factors involved in the control of BAT development and function and iv) a cross-talk between BAT and other peripheral tissues such as skeletal muscle, liver, heart, gut etc.
Positron-emission tomography and computed tomography (PET-CT) scanning, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS), infra-red thermography, enzyme/immuno-histochemistry, radio-immunoassay, blood flow measurements, measurement of noradrenaline stimulated oxygen consumption and so on have provided undeniable evidences for the existence of active and functional BAT in humans. The presence of BAT in humans is well confirmed using radioactive glucose analog18F-flurodeoxyglucoe (18-FDG) with PET scanning.
Thus, both WAT and BAT have become the target to explore the pathophysiology of obesity and its related metabolic disturbances.
BAT not only plays an important role in energy expenditure through its adaptive thermogenic function in body weight regulation and obesity control but also in insulin mediated glucose disposal.
Extraordinary efforts are made by using cellular, molecular, physiological, pharmacological and clinical approaches to investigate the role of brown fat functions and their regulation.
Adipogenesis consists of growth arrest, clonal expansion and terminal differentiation which are governed by four key transcription factors. These include three CCAAT enhancing binding proteins (C/EPB) ˠ, β and δ and PPAR-ˠ. C/EBPα is required for WAT formation while C/EBPβ plays an important role in regulating thermogenic gene expression in BAT. PPAR-ˠ is a master transcription factor required unconditionally for adipogenesis. Its transcriptional activity is regulated at multiple levels. Another factor, forkhead box C2 (FoxC2) induces the formation of brite cells in WAT with increased mitochondria and thermogenic genes and UCP1.
PGC-1α is a cold inducible transcriptional coactivator of PPARˠ found in brown fat. It regulates mitochondrial biogenesis and oxidative metabolism in BAT. Several transcriptional factors such as receptor-interacting protein-140 (RIP140) and the steroid receptor co-activator SRC2/TIF2/GRIP1 function by modulating the activity of PGC-1α.
PRD1-BF-1-RIZ1 homologous domain-containing protein 16 (PRDM16) is a 140kDa zinc-finger protein that is highly expressed in BAT. It is identified as a molecular switch between myocytes and brown adipocytes. It increases the transcriptional activities of PGC-1α and PPARˠ and the C/EPBs through direct interactions thereby promoting brown fat gene expression, mitochondrial biogenesis and increased cellular respiration. Several regulators such as early B cell factor 2 (EBF2) and microRNAs such as miR-133 and miR-193b are shown to influence PRDM16 activities.
Norepinephrine influences the proliferation of classical brown adipocyte precursors and mediates thermogenic function via β-1 adrenergic receptor and β-3 adrenergic receptor, respectively. Similarly, nitric oxide signalling also activates cGMP dependent protein kinase in brown adipocytes thereby induces UCP1 expression
Transient receptor potential vanilloid (TRPV) signaling involves ion channels that are of four types; TRPV1, TRPV2, TRPV3 and TRPV4. TRPV1 is activated by heat greater than 430C and pungent compounds in chilli peppers. Interestingly, non-pungent capsaicin analogs (capsinoids) activate gastrointestinal TRPV1 and induce thermogenesis in humans and rodents. TRPV4 expressed in adipocytes negatively regulate BAT thermogenic function. Inhibition of TRPV4 activates UCP1 and PGC1α expression in BAT. TRPV2 in BAT when absent or dysfunctional impairs thermogenesis in mouse brown adipose tissue and results in increased body weight and fat upon feeding high fat diet and can not keep constant body temperature when ecposed to cold at 40 C.
Other than thyroid hormones, catecholamines, glucocorticoids and mineralocorticoids, growth hormones and insulin like growth factor-1 (IGF-1), prolactin, insulin, sex hormones and some of the recently identified endogeneous molecules that control BAT functions.
Transforming growth factors (TGF) include bone morphogenetic proteins (BMP) that influence BAT functions. BMP7 treatment of fibroblast cultures or adipogenic precursors induce brown fat regulators like PRDM16. BMP4 similarly activates beige cell differentiation in WAT. BMP8 acts on mature BAT and hypothalamus and positively regulate BAT thermogenesis. Other members of TGF-β family such as myostatin negatively regulate BAT differentiation and thermogenesis.
FGFs are different types and act in an autocrine or paracrine fashion. FGF-21 is secreted from liver and both FGF-19 and FGF-21 promote BAT thermogenic functions. But FGF-19 and FGF-23 are endocrine forms.
Irisin is a polypeptide released by skeletal muscle through increased PGC-1α expression following exercise in both rodents and humans. Irisin showed a powerful browning effect on WAT in mice both in culture and
Cardiac natriuretic peptides (CNP) from atria and ventricle of the heart (ANP, VNP, respectively) and brain natriuretic peptides (BNP) are important endocrine regulators of fluid and hemodynamicfunctions. Cold exposure seem to improve the circulating levels of ANP and BNP and administration of BNP activates the BATthermogenic functions. But, one has to be careful about their effects of on fluid and hemodymanic functions in such situations.
BAT mediated interorgan networking in understanding the functional control of BAT is another interesting facet. For example, norepinephrine produced in the CNS and by the macrophages in the adipose tissue is shown to activate the brown fat development and thermogenic function. TGF- β from the skeletal muscle negatively controls BAT function. As stated earlier, irisin, CNP and IL-6 are also important mediators of BAT function.
Cold exposure not only stimulates tri-iodothyronine (T3) secretion but also releases norepinephrine at sympathetic nerve endings that are plenty in BAT. Such acute cold exposure released norpeinephrine acts via β-3 receptors to increase BAT thermogenic functions. By virtue of a high endogenous expression and activity of intracellular type-2 5’-deiodinase (D2), BAT has the ability to increase substantially the intracellular concentrations of T3 without affecting its circulating concentrations. This will increase the synthesis of UCP1 which turn facilitates the mitochondrial membrane to become leaky to protons rendering the respiration process inefficient.
Brown adipocyte stem/progenitor cells CD34+ in skeletal muscle and human multi-potent adipose derived stem cells (hMADs) in subcutaneous tissue can potentially be induced into BAT externally, expanded and implanted back. Available data suggests that subcutaneous transplantation of embryonic BAT corrected type 1 diabetes in immune-competent mice as was evident by reversal of diabetes symptoms, weight regain and normalization of glucose tolerance.
Along with so many factors as pointed ot above, thecontrolof BAT functions can also be brought about by repressing the translation of PGC1α, inhibition of retinoblastoma (Rb) protein activity, inhibition of RIP140, inhibition of the gender-sensitive α-arrestin domain-containing 3 (ARRDC3) protein, inhibition of retinaldehyde dehydrogenase 1 (ALDH1A1) and so on.
There are reports on animal experiments that have shown an over-expression of monoacylglycerol lipase (MGL) in the forebrain of transgenic mice that decreases the production of 2-arachidonoyl-sn-glycerol (2-AG) resulting in leanness, increased energy cost of activity, enhanced thermogenesis in BAT suggesting the critical role of endocannabinoid system. In another study, favorable inflammation profile with a lower C-reactive protein (CRP) and alpha-1 antitrypsin level has shownthat CRP could play a protective role against obesity and cardiometabolic risks. Yet, another study claims that obese mice lacked a protein called collagen VI fared much better metabolically.
Different strategies for treating obesity such as modifying diet, increasing physical activity (behavioral approach), utilizing weight loss medications (pharmacological approach), cold exposure (physiological approach) as well as recommending surgical procedures in appropriate patients could be considered.
As pointed out earlier, it is suggested that transcriptional factors such as PRDM16 and other associated co-regulators PGC -1α and C-terminal binding protein (CtBP1/2) which controls the switch from WAT to BAT are potential targets for the development of obesity related treatments.
Studies on cold exposure in BAT research is varied and and less standardized. BAT utilises both carbohydrates and lipids during cold exposure to increase thermogenesis via β-3 adrenergic receptor. The cold exposure methods used include air exposure in environmental chambers, water immersion, liquid-conditioned suit, limb cooling methods, individualized cooling and water perfused mattress or garment. The temperature used also varies from 16-190C. Water cooling has been suggested as the most preferred method. But, the individualized cooling at the lowest temperature for non-shivering conditions may be the most promising approach. Though, this area of cold exposure treatment looks a natural way, it needs proper design and standardised protocols to optimise the benefits before conclusively pronouncing it as an efficient method.
Similar to cold exposure, exercise and use of nonpungent capsaicin in diet are known to stimulate BAT thermogenesis by enhancing mitochondrial UCP1 production to promote the heat production. Of late, very interestingly, the role played by the gut microbiome in energy balance is reported. It has been shown that there is an intimate relationship between the gut flora and BAT thermogenesis. It is possible that the bacteria in the gut flora is affected by the diet and may alter the metabolic functions of the host. Cold exposure in such situations can influence the microbial flora and help losing the extra fat as well as improve the gastrointestinal absorptive functions.
Therefore, it appears that several communication pathways linking the brain, skeletal muscle, gut and other organs including the heart and liver involve short-term and long-term signals that may help to balance the energy intake and expenditure. Thus, BAT being a major site for mammalian non-shivering thermogenesis could be a promising target for prevention and treatment of human obesity.
To address obesity and related problems, reducing total adipose mass is the important strategy. It may be achievable by considering various ways and means. For example, virtually all known adipose tissue secreted proteins are dysregulated when the WAT mass is markedly altered; either increased in the obese state or decreased in lipoatrophy. Therefore, an in-depth understanding of molecular actions of adipokines and modifying adipokine gene expression, targeting the mechanisms involved in macrophage recruitment, understanding the signaling pathways in target tissues such as the brain, skeletal muscle and elsewhere would certainly provide some ways of dealing with the problem. But, the key challenges will be to identify all of the secreted proteins by WAT to establish the function of each secreted protein and to assess the pathophysiological consequences of changes in adipocyte protein production.
Recent observations of BAT being functional in adult humans provides a rationale for its stimulation to increase energy expenditure through adaptive thermogenesis for an anti-obesity strategy. A large body of data available suggest that targeting endocrine hormones for BAT modulation can yield a positive answer for successful prevention and management of human obesity. Therefore, further understanding of the physiological link between various endocrine/autocrine/paracrine hormones and BAT is necessary for the development of new therapeutic options.
However, there are some suggestions that one should take in treating all obese individuals as there are some divides in opinion. Human studies have shown that some groups of individuals called ‘healthy obese’ who can maintain cardiovascular and metabolic health are genetically programmed to carry extra fat. Some poorly understood or entirely unknown benefits of mild or moderate obesity may be in-built for them and one has to be very cautious in weight loss goals in such individuals. It is better to be overweight or even obese and physically active rather than sedentary and normal weight as the goal of optimum health is not to be ‘thin’ but to be as ‘healthy’ as one can regardless of body weight. Therefore, obesity treatment should be directed at the metabolic syndrome
All in all, obesity is a multidimensional metabolic disorder and is rarely cured once it sets in. Hence, long term treatment should be planned with combined therapy that involves behavioural and physiogical approaches for effectiveness. It may be good to avoid pharmacological and surgical approaches in such situations. Overall, the scientific world eagerly awaits further advanced studies to document possible metabolic interventions using BAT as a primary target to prevent and manage obesity.