YHBEH-03681; No. of pages: 9; 4C: Hormones and Behavior xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Hormones and Behavior journal homepage: www.elsevier.com/locate/yhbeh

Review

Sexual dimorphism in white and brown adipose tissue with obesity and inflammation Ian D. Bloor, Michael E. Symonds ⁎ Early Life Research Unit, Division of Child Health, Obstetrics and Gynaecology, School of Medicine, The University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK

a r t i c l e

i n f o

a b s t r a c t

Available online xxxx

This article is part of a Special Issue “Energy Balance”.

Keywords: Adiposity Obesity Gender Sex Sexual Inflammation BAT WAT

Obesity and its associated comorbidities remain at epidemic levels globally and show no signs of abatement in either adult or child populations. White adipose tissue has long been established as an endocrine signalling organ possessing both metabolic and immune functions. This role can become dysregulated following excess adiposity caused by adipocyte hypertrophy and hyperplasia. In contrast, brown adipose tissue (BAT) is only present in comparatively small amounts in the body but can significantly impact on heat production, and thus could prevent excess white adiposity. Obesity and associated risk factors for adverse metabolic health are not only linked with enlarged fat mass but also are dependent on its anatomical deposition. In addition, numerous studies have revealed a disparity in white adipose tissue deposition prior to and during the development of obesity between the sexes. Females therefore tend to develop a greater abundance of femoral and gluteal subcutaneous fat whereas males exhibit more central adiposity. In females, lower body subcutaneous adipose tissue depots appear to possess a greater capacity for lipid storage, enhanced lipolytic flux and hyperplastic tissue remodelling compared to visceral adipocytes. These differences are acknowledged to contribute to the poorer metabolic and inflammatory profiles observed in males. Importantly, the converse outcomes between sexes disappear after the menopause, suggesting a role for sex hormones within the onset of metabolic complications with obesity. This review further considers how BAT impacts upon on the relationship between excess adiposity, gender, inflammation and endocrine signalling and could thus ultimately be a target to prevent obesity. © 2014 Published by Elsevier Inc.

Contents Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . White adipose tissue . . . . . . . . . . . . . . . . . . . . . . . . . Brown adipose tissue . . . . . . . . . . . . . . . . . . . . . . . . . Sexual dimorphism and adipose tissue depot differences with obesity . . . Subcutaneous adipose tissue vs visceral adipose tissue . . . . . . . . . . Adipose tissue and metabolic comorbidities . . . . . . . . . . . . . . . Sexual dimorphism in BAT deposition . . . . . . . . . . . . . . . . . Obesity, metabolism and BAT . . . . . . . . . . . . . . . . . . . . . Inflammation associated with enhanced WAT mass . . . . . . . . . . . Sex differences in obesity mediated inflammation . . . . . . . . . . . . Effect of the menopause . . . . . . . . . . . . . . . . . . . . . . . Sexual dimorphism of renal disease and HPA axis stimulation with obesity Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author. Fax: +44 115 8230626. E-mail address: [email protected] (M.E. Symonds).

http://dx.doi.org/10.1016/j.yhbeh.2014.02.007 0018-506X/© 2014 Published by Elsevier Inc.

Please cite this article as: Bloor, I.D., Symonds, M.E., Sexual dimorphism in white and brown adipose tissue with obesity and inflammation, Horm. Behav. (2014), http://dx.doi.org/10.1016/j.yhbeh.2014.02.007

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Overview Current body mass index (BMI), which is used to define obesity, suggests that over 30% of all male and females irrespective of age are obese in the USA (CDC, 2013). This incidence has now started to stabilise in this adult population, in association with enhanced public awareness (Flegal et al., 2012; Ogden et al., 2012). However, a worrying statistic in children shows that although obesity rates have plateaued in girls, for boys the prevalence continues to rise (CDC, 2013). These trends are mimicked by the prevalence of comorbidities that can accompany obesity such as the metabolic syndrome and diabetes mellitus type II (T2DM) (Danaei et al., 2011). The development of obesity may be further compounded by suboptimal maternal conditions prior to and during pregnancy (Herring and Oken, 2011). This is due in part to an increased number of pre-gravid females having a high BMI and obese pregnant women are more likely to display gestational diabetes (GDM) (Ferrara, 2007). The development of obesity is attributed to an imbalance in the ratio of energy consumption to expenditure, a response that is driven through a combination of behavioural, socioeconomic and genetic factors (Martinez, 2000). Consequently, the current surge in obesity is a strong implication that behavioural factors, i.e. modern sedentary lifestyles coupled with excessive intake of high fat and/or high carbohydrate foods, especially in poorer social classes, are involved to a greater extent than an individual's genotype (WHO, 2000). It is now established that there are at least three types of adipose tissue (Giralt and Villarroya, 2013), whose function can all be reset with obesity. The focus of the present review will be to consider the relationship between anatomical locations, gender and adipocyte classification in the onset of obesity.

size was reduced. Furthermore, although adipocyte number remained static, its regulation was shown to be tightly regulated through a high cellular turnover of approximately 8% of adipocytes per year (Spalding et al., 2008). Similar findings have also been demonstrated in experimental rodent models (Bjorntorp et al., 1982). During periods of excess energy intake, adipose tissue remodelling occurs whereby adipocytes increase triglyceride storage leading to expansion of the vacuole that together with adipocyte hypertrophy results in enhanced adipose tissue deposition (Jo et al., 2009). Ultimately, this cellular hypertrophy leads to an imbalanced lipolytic/lipogenic state thereby causing dysfunctional endocrine signalling resulting in an increased risk of obesity related metabolic and inflammatory comorbidities (Vazquez-Vela et al., 2008). Risk factors associated with obesity depend not only on the volume of excess fat but also on its anatomical distribution (Sun et al., 2011), which in humans is greatly affected by gender. WAT acts as both a target for metabolic signals and as an endocrine organ secreting a large number of hormones and proteins as summarised in Table 1 (Ahima and Flier, 2000; Fain et al., 2010; Trayhurn and Beattie, 2001), classified as adipokines. These molecules are therefore involved in a wide range of functions including metabolism, lipid transport, homeostasis and inflammation (Ahima, 2006). In the present article we will focus on the inflammatory and metabolic secretome produced by WAT and how this changes with obesity. For example, the magnitude of expansion in adipose tissue is positively correlated with the expression of tumour necrosis factor-α (TNFα), a classical, multi-functional cytokine involved in pathways regulating inflammation, macrophage recruitment, proliferation, differentiation and apoptosis (Lee and Lee, 2002). Brown adipose tissue

White adipose tissue White adipose tissue (WAT) is categorized as a loose connective tissue with a highly organised vasculature and has a range of functions in addition to structural cushioning, passive insulation and lipid storage (Trayhurn and Beattie, 2001). White adipocytes are unilocular cells containing a large central lipid vacuole, with a flattened nuclei located towards the periphery of the cell membrane. Non-esterified fatty acids (NEFA) accumulate in white adipocytes in the central vacuole and are esterified into triglycerides for storage via the lipoprotein lipase (LPL) pathway (Karpe et al., 1992, 2011). When energy is required, triglycerides undergo lipolysis and are hydrolysed from glycerol to release NEFA into the circulation in quantities depending on current metabolic requirements, predominantly for use by skeletal muscle and liver. This interaction of storage and mobilisation is in constant flux (Yu and Ginsberg, 2005). WAT is widely dispersed within most mammalian species and in this review we will assess data encompassing both human and animal studies. In humans, the two main adipose tissue depots are found in subcutaneous layers and in the central torso area, termed visceral adipose tissue (VAT), which is primarily located around the omental, mesenteric and retroperitoneal areas. In addition, small depots of adipose tissue surround the heart and kidneys and are termed the epi/pericardial and perirenal layers, respectively (Chakrabarty et al., 1988; Sacks and Fain, 2007). The positioning and relative size of these principal depots is also similar in other large mammals, such as the sheep (Symonds et al., 2011). Rodents also possess these depots but relatively large additional deposits of WAT are also located in gonadal, epididymal, inguinal and (the upper) interscapular sites. Initially it was thought that adipocyte cell number was established in utero and during neonatal life, but it is now suspected that the progression of obesity in adults who were not obese in childhood, demonstrate hyperplastic adipose tissue remodelling during childhood and adolescence (Spalding et al., 2008). In this study, obese adults were found to have larger and greater numbers of adipocytes compared to lean subjects. After significant weight loss in these obese individuals, only adipocyte volume rather than population

Adipose tissue is not exclusively white as new-born and hibernating mammals, for example, have a high abundance of brown adipose tissue (BAT) which provides protection from cold exposure by the generation of heat through non-shivering thermogenesis following the activation of uncoupling protein (UCP)1, a mitochondrial trans-membrane bound protein (Cannon and Nedergaard, 2012). Following the release of NEFA, UCP1 acts to allow a free-flow of protons across the inner mitochondrial membrane which results in the generation of heat from the rapid dissipation of oxidation energy (Nicholls, 1983). Unlike WAT, brown adipocytes are highly vascularised, polygonal structures containing multilocular lipid droplets and a high abundance of mitochondria, the organelles which partly provide the cells with their brown colouration. It was originally thought that, in large mammals, when BAT was converted into WAT it disappeared entirely, a process that was initiated immediately after birth (Nedergaard et al., 2007). The presence of functional BAT in adult humans was only considered to occur under certain rare pathological conditions (Cannon and Nedergaard, 2004; Dundamadappa et al., 2007; English et al., 1973; Iyer et al., 2009). However, research in the 1990s identified the “surprising” retention and presence of a small volume of BAT in adult humans by identification of positron emitting tomography computed tomography (PET-CT) hotspots from uptake of 2-fluoro-2-deoxy-D-glucose (FDG), located in the cervical supra-clavicular, supra-adrenal and para-spinal regions (Nedergaard et al., 2007). These findings have now been supported by a variety of additional scanning technologies including thermal imaging and magnetic resonance imaging (MRI) (Iris Chen et al., 2013; Symonds et al., 2012). Recent work has identified the presence of BAT in a number of distinct and diffuse anatomical locations, as reviewed by Sacks and Symonds (2013). A highly topical subject in obesity research, the possibility of targeting BAT for enhanced energy expenditure may hold the key to pharmacological interventions designed to prevent obesity. Additionally the discovery of beige adipocytes which could belong to the same cellular lineage as WAT but possess inducible thermogenic properties (Wu et al., 2012) has offered a further target for obesity

Please cite this article as: Bloor, I.D., Symonds, M.E., Sexual dimorphism in white and brown adipose tissue with obesity and inflammation, Horm. Behav. (2014), http://dx.doi.org/10.1016/j.yhbeh.2014.02.007

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Table 1 Adipokines and proteins secreted by white adipose tissue and their main functional roles (Ahima and Flier, 2000; Fain, 2010; Fain et al., 2004; Trayhurn and Beattie, 2001; Trayhurn and Wood, 2005). Adipokine

Function

Adipocyte lipid binding protein Adipocyte trypsin Adiponectin Angiotensin Apelin C-reactive protein Cholesteryl ester transfer protein Hormone sensitive lipase Insulin-like growth factor Interleukin 1β (IL-1β) Interleukin 6 (IL-6) Interleukin 8 (IL-8) Interleukin 10 (IL-10) Interleukin 18 (IL-18) Leptin Lipoprotein lipase Macrophage migration inhibitory factor β (MIF-β) Metallothionein Monobutyrin Monocyte chemotactic protein 1 (MCP-1) Perilipin Peroxisome proliferator-activated protein-γ (PPAR-γ) Plasminogen activator inhibitor-1 (PAI-1) Resistin Retinol binding protein Steroid hormones Transforming growth factor-β Tumour necrosis factor-α (TNF-α) Uncoupling proteins Visfatin Zinc-alpha2-glycoprotein

Regulates systemic glucose and lipid metabolism Immune stress response Regulates glucose level and metabolism of lipids in energy production Blood vessel constriction, release of vasopressin & aldosterone which increase blood pressure Regulation of body fluid homeostasis Inflammatory response, insulin resistance Mediates the transfer of cholesteryl esters and triglycerides between lipoprotein particles Hydrolysis of triglycerides for NEFA mobilisation Insulin effects & cell growth/development Inflammatory response Immune stress response, insulin resistance Immune stress response Anti-inflammatory effect Inflammatory response Regulates energy uptake/expenditure (appetite and metabolism) Mediates lipid uptake Immune stress response Immune stress response Vasodilatation of the microvessel Immune stress response Regulates lipid metabolism Lipid metabolism, vascular homeostasis, inflammation Vascular homeostasis Inflammatory response, insulin resistance Lipid metabolism Lipid metabolism, insulin resistance Cell adhesion and migration, growth and differentiation Immune stress response, insulin resistance Energy balance and thermoregulation Insulin resistance Lipid metabolism

Fig. 1. Summary of the sex dimorphism in white adipose tissue (WAT) and brown adipose tissue (BAT) deposition. During weight gain, pre-menopausal females develop fat mass in femoral and gluteal lower body depots compared to males who develop visceral fat (Lemieux et al., 1993). Lower body depots possess better lipid handling properties and a healthier metabolic profile. In addition approximately 50% of abdominal fat in females is stored within the central compartment compared to 98% in males (Pou et al., 2007). To date no evidence between sex differences with obesity in BAT deposition has been reported. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Image sourced and adapted from Vitale et al. (2009).

Please cite this article as: Bloor, I.D., Symonds, M.E., Sexual dimorphism in white and brown adipose tissue with obesity and inflammation, Horm. Behav. (2014), http://dx.doi.org/10.1016/j.yhbeh.2014.02.007

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prevention. It is now understood that some white adipocytes can undergo a ‘browning’ transformation through either transdifferentiation in response to exposure of cold and β3-adrenergic agonist stimulation and/or from the differentiation and maturation of precursor white preadipocytes (Vitali et al., 2012; Wang et al., 2013). Beige fat cells have been postulated to possess a dual function, in that they not only can store lipids in periods of excess energy intake similarly to white adipocytes but also can dissipate energy when initiated by either cold exposure, stimulatory metabolic hormones, pharmacologic activators or sympathetic stimuli (Wu et al., 2013). Sexual dimorphism and adipose tissue depot differences with obesity The gender dimorphism in the development of WAT is best described in humans, with females possessing more fat than males irrespective of ethnicity, BMI and age (Gallagher et al., 2000). As summarised in Fig. 1, pre-menopausal females accumulate more subcutaneous WAT that is located primarily in peripheral and lower body areas, (i.e. subcutaneous, gluteal and femoral regions) (Lemieux et al., 1993; Ross et al., 1993), whereas males develop a higher abundance of visceral WAT in the upper body regions (Kvist et al., 1988; Lemieux et al., 1993). Significant fat redistribution occurs in females during and after the menopause, when a transition of lower SAT to central adiposity occurs, suggesting the potential role of sex hormones in this process (Lovejoy and Sainsbury, 2009). Increased visceral adiposity is associated with obesity, and often linked to the progression of metabolic related conditions. This reflects the very different metabolic profiles and characteristics between subcutaneous and visceral adipocytes (Wajchenberg, 2000) that could ultimately determine the magnitude of obesity related disease. Subcutaneous adipose tissue vs visceral adipose tissue SAT is comprised of well organised, tightly packed spherical adipocytes, whereas VAT is highly vascularised with disorganised, irregular shaped lobules (Sniderman et al., 2007). Females possess larger subcutaneous than visceral adipocytes, suggesting a lower storage capacity in visceral depots for triglycerides, creating higher lipid saturation, increased lipolysis and greater susceptibility for dysfunction (Tchoukalova et al., 2008). Similarly, as reviewed by Tchernof et al. (2006), SAT cells were larger and more abundant than visceral adipocytes in the female population, whereas VAT was more active and displayed increased lipolysis and a higher sensitivity to lipolytic stimuli via antagonism of the β-adrenergic receptor compared with subcutaneous adipocytes. Current evidence proposes adipocyte hyperplasia rather than hypertrophy occurs in females during fat mass expansion (Drolet et al., 2008). This observation was reported in gluteal but not VAT depots, although hypertrophy did occur in gluteal depots in the presence of obesity. Females have a higher proportion of early differentiated adipocytes compared to males in SAT, especially in the femoral depot (Tchoukalova et al., 2010). This in tandem with the findings that femoral subcutaneous preadipocytes exhibit higher resistance to cytokine mediated apoptosis when matched with abdominal SAT, proposes a lower utilisation and cellular turnover in lower body SAT compared to upper abdominal depots (Tchoukalova et al., 2010). In females the volume of subcutaneous fat is more strongly correlated with total body fat mass compared with males. During adipogenesis WAT mass increases in both genders. This process is amplified in males, particularly in VAT and abdominal SAT depots (Tchoukalova et al., 2008). As reviewed by White et al., further comparisons of adipocytes from females (including pre- and post-menopausal subjects) revealed adipocyte hypertrophy only occurs in VAT compared with hyperplasia and hypertrophy in abdominal SAT (Drolet et al., 2008; White and Tchoukalova, 2013; Lemieux et al., 1993). In summary, proliferation of SAT in females, results in the expansion of fat mass through a

combination of adipogenesis, lipolysis and adipocyte hypertrophy, allowing for SAT to store larger amounts of lipids and thus reducing the opportunity for NEFA accumulation in visceral compartments, as shown in Table 2. Adipose tissue and metabolic comorbidities Epidemiological studies on cardiovascular and metabolic disease have identified that the abundance of both SAT and VAT are significantly correlated with blood pressure, plasma concentrations of glucose, triglycerides and high-density lipoprotein cholesterol which lead to increased risks of developing hypertension, T2DM and related metabolic comorbidities (Fox et al., 2007). Women, however, display a stronger relationship between VAT volume and the development of these risk factors than men (Fox et al., 2007). Therefore, perhaps females have acquired a protective strategy of promoting adipose accumulation in their other fat depots which ultimately exhibit weaker associations with cardiometabolic risk factors. In another study, subcutaneous abdominal adipose tissue was only associated with a small number of obesity related risk factors (e.g. plasma triglycerides), whereas VAT and BMI, in particular waist circumference, showed a much greater risk association with adverse cardiometabolic health (Porter et al., 2009). However, in the presence of obesity, enlarged SAT has a reduced lipolytic function resulting in less triglyceride turnover, that could assist in the maintenance of excess central, rather than peripheral fat (Ryden et al., 2013). In an obese state, adipocyte sensitivity to insulin becomes impaired, predominantly through down-regulation of the insulin responsive glucose transporter, GLUT4 (Pedersen et al., 1991). Insulin receptor binding is reduced which leads to decreased phosphorylation of downstream substrates and suppresses gene expression of GLUT4 (Kahn and Flier, 2000), leading to hyperinsulinaemia. This increase in circulating insulin acts on lower body white adipocytes to suppress NEFA release, which is not observed in upper body fat (Stolic et al., 2002). In contrast, because VAT exhibits greater resistance to insulin's anti-lipolytic effects compared with both abdominal and lower body SAT, lipolysis and NEFA release are all elevated from central fat deposits even with higher insulin (Guo et al., 1999; Jensen, 1995; Meek et al., 1999; Nielsen et al., 2004; Tchkonia et al., 2013). Additionally, excess circulating NEFA originating from the dysfunctional lipolytic flux in central WAT inhibits insulin action on skeletal muscle glucose uptake and suppresses hepatic glucose production. Ultimately this compounds the development of hyperinsulinaemia, resulting in insulin resistance (Boden et al., 1994). The rate of lipolysis varies between each fat depot, and as highlighted by (Tchkonia et al., 2013), females display a higher NEFA flux than males commencing in adolescence (Adler-Wailes et al., 2013). With obesity, upper body SAT releases higher amounts of NEFA than the lower body in females (Jensen, 1995), which contributes up to 60% of basal systemic NEFA (Nielsen et al., 2004). This compares with ~ 15% in lean individuals (Guo et al., 1999; Meek et al., 1999; Nielsen et al., 2004). In severely obese males, however, hypertrophic adipocytes from VAT demonstrate a greater association with metabolic abnormalities than similar sized adipocytes from abdominal SAT (Hoffstedt et al., 2010). This contrasts with recent findings that with increased adipocyte size, lipolytic activity increases irrespective of its origin (Laurencikiene et al., 2011; Tchkonia et al., 2013). Dysfunction of both lower and upper body SAT mediates the expansion of VAT, increases lipotoxicity and augments systemic inflammation (Nielsen et al., 2004), further emphasising the benefits of normally functioning SAT as observed in females. In rodents, subcutaneous lipectomy results in enlargement of VAT, hyperinsulinaemia, decreased insulin sensitivity and increased inflammatory cytokine secretion maladaptations that can be reversed with re-implantation (Ishikawa et al., 2006; Mauer et al., 2001; Weber et al., 2000). Gender differences are also observed with lipectomy induced fat loss in mice where females, but not males, conserved a greater abundance of SAT but showed

Please cite this article as: Bloor, I.D., Symonds, M.E., Sexual dimorphism in white and brown adipose tissue with obesity and inflammation, Horm. Behav. (2014), http://dx.doi.org/10.1016/j.yhbeh.2014.02.007

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Table 2 Summary of the human sex dimorphism differences in adipose tissue exhibited between lower body femoral and gluteal (SAT) and upper body visceral fat (VAT). Females Lower body fat storage

Males Upper body fat storage

References

Increased number of adipocytes

–

Larger adipocytes

Smaller adipocytes

Hyperplastic and hypertrophic tissue remodelling during obesity Increased number of preadipocytes Reduced activity, mobilisation and lipolysis Reduced apoptotic cellular turnover Predisposition for lipid storage in lower body fat

Hypertrophic tissue remodelling during obesity – Increased activity, mobilisation and lipolysis Increased apoptotic cellular turnover Increased central fat mass and lipid storage in obesity

–

Increased metabolic dysfunction

Tchernof et al. (2006) Tchoukalova et al. (2008) Tchernof et al. (2006) Tchoukalova et al. (2008) Drolet et al. (2008) Tchoukalova et al. (2010) Tchoukalova et al. (2008) Tchoukalova et al. (2010) Lemieux et al. (1993) Tchernof et al. (2006) Tchoukalova et al. (2008) Tchernof et al. (2006)

a reduced capacity to regrow VAT (Shi et al., 2007). This adaptation in females was attributed to decreased energy expenditure mediated through decreased sympathetic activation of BAT thermogenesis. These data all highlight the variation in lipid handling and metabolic influence between genders with depot location being critical and exacerbated with obesity. Sexual dimorphism in BAT deposition In humans, there is currently insufficient data to determine whether a disparity exists between genders in BAT deposition. Males and females appear to possess a similar regional distribution of BAT, although when detected using FDG PET-CT, it was more prominent in the cervicalsupraclavicular region in females, at a ratio of 2:1, compared to males (Cypess et al., 2009). This is explained primarily by the greater sensitivity to cold exposure by females (Quevedo et al., 1998), but it is uncertain whether the same explanation accounts for the reduction of BAT mass in ageing, as assessed by FDG PET-CT, that occurs more rapidly in males (Pfannenberg et al., 2010). In rodents the response of BAT to adrenergic stimulation mediated by overfeeding with a high fat–high sugar diet, is enhanced in females and could be mediated by reduced expression of the alpha2A-adrenoceptor (Rodriguez et al., 2001). This is involved in the inhibition and suppression of noradrenaline's action including its effect on lipolysis, although it is not considered to be a major regulator of BAT mass. Adult female rats have also been shown to retain larger mitochondria with a higher cristae density than males, which may further explain differences in BAT capacity between genders (Rodriguez-Cuenca et al., 2002). How BAT responds in the presence of obesity is unknown (Fig. 1), although in humans the amount of detectable BAT with cold exposure is inversely correlated to WAT mass and BMI (Vijgen et al., 2011). Whether this is due to WAT expansion and encroachment in to brown depot locales or a deleterious cellular and molecular effect mediated by white hypertrophic adipocytes with obesity has not been determined. Currently very limited data exists of any sexual dimorphism with obesity on BAT for any species. Obesity, metabolism and BAT There is still a dearth of knowledge in the endocrine function of BAT, especially the small depots that remain in adults. A growing body of rodent work suggests that BAT could possess beneficial metabolic effects mediated by the production and release of endocrine signals, particularly during periods of increased thermogenesis (Villarroya et al., 2013). UCP1 knock-out mice exhibit increased weight gain in comparison to wild-type controls but only when housed under thermoneutral temperatures. However, during cold exposure these same subjects do not gain weight and use the extra energy to maintain body temperature through increased shivering, perhaps masking the obesogenic effect of UCP1 deficiency (Feldmann et al., 2009), although these findings are not consistently observed (Harms and Seale, 2013). Increasing BAT and beige

fat activity in mice has also been shown to limit weight gain and improve their metabolic profile. For example, augmenting BAT activity via cold exposure has been demonstrated to improve lipid clearance and triglyceride rich lipoprotein uptake in BAT cells in obese rodents reducing hyperlipidaemia (Bartelt et al., 2011). In addition, the ‘beigeing’ or ‘browning’ of white adipocytes as mediated using the hormone irisin or transgenic over-expression of PRDM16, improves glucose tolerance and lipid handling whilst preventing insulin resistance (Harms and Seale, 2013; Seale et al., 2007, 2011). BAT also secretes retinol binding protein 4, which when produced by WAT is a positive regulatory factor in controlling insulin resistance and glucose metabolism (Rosell et al., 2012). Although its endocrine and paracrine functions are not fully elucidated, it seems BAT activity and its association with systemic metabolism are linked and represents an obvious therapeutic target for obesity treatment. Inflammation associated with enhanced WAT mass Hypertrophic white adipocytes increase the production and secretion of adipokines into the circulation, with adipokine gene expression positively correlated with adipocyte size (Skurk et al., 2007). Obesity and hyperinsulinaemia both stimulate the immune system, with raised insulin having a pleiotropic role to further promote lipid storage. The mechanisms mediating obesity induced insulin resistance remain complex and it is unsure whether insulin resistance is causally or negatively associated with obesity (Miles and Jensen, 2005). Epidemiological data supports the former notion that insulin resistance is driven by increased VAT and BMI, with weight loss and reduction of central fat resulting in improved insulin sensitivity (Goodpaster et al., 1999). TNFα is one of the most prominent inflammatory cytokines secreted by enlarged WAT and is a molecule that promotes insulin resistance by inhibiting tyrosine phosphorylation of the insulin receptor substrate-1, thereby decreasing insulin stimulated glucose uptake (Hotamisligil, 2003; Hotamisligil et al., 1993). Production of another established molecule involved in the inflammatory cascade, C-reactive protein (CRP) is not only positively correlated to fat mass (Visser et al., 1999), but is also considered an independent biomarker in the development of cardiovascular disease (Trayhurn and Wood, 2005). Immunological adipokines from the interleukin (IL6, IL18, IL10) family, are both pro- and antiinflammatory molecules. Their secretion is up-regulated with obesity and thus their release is increased in the circulation (Eder et al., 2009; Juge-Aubry et al., 2005; Roytblat et al., 2000). The same responses occur with the monocyte and macrophage recruiting molecules monocyte chemoattractant protein-1 (MCP1) and its receptor chemokine C–C motif receptor 2 (CCR2) (Kanda et al., 2006; Sartipy and Loskutoff, 2003). Compared with WAT from lean subjects, mRNA and protein expression of numerous pro-inflammatory molecules and classic cytokines, including transforming growth factor 1 beta (TGF1β), plasminogen activator inhibitor-1 (PAI-1), inducible nitric oxide synthase (iNOS) and intercellular adhesion molecule (ICAM) are all raised with

Please cite this article as: Bloor, I.D., Symonds, M.E., Sexual dimorphism in white and brown adipose tissue with obesity and inflammation, Horm. Behav. (2014), http://dx.doi.org/10.1016/j.yhbeh.2014.02.007

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obesity (Fried et al., 1998; Perreault and Marette, 2001; Vgontzas et al., 1997; Weisberg et al., 2003). A number of studies have investigated the link between cytokines and obesity. For example, mRNA abundance of MCP-1 and TNFα correlates with total fat mass (Fain, 2010). Furthermore, in a gene expression study of IL6, CCR2 and MIF, VAT possessed higher expression compared to SAT in obese subjects (Alvehus et al., 2010; Fain et al., 2004; Mazurek et al., 2003). Plasma concentrations of these markers are therefore used clinically to define and characterise the metabolic phenotype with obesity (Phillips and Perry, 2013). Cytokines and immune signalling molecules all play pleiotropic roles and in conjunction with adipokine cross-talk drive the recruitment and synthesis of supplementary regulating immune cells, i.e. macrophages, monocytes, leukocytes and T-cells (Nishimura et al., 2009a,b). Ultimately they perpetuate a feedback loop of increased immune cell recruitment and infiltration driving further cytokine secretion and creating the lowgrade inflammation found with obesity. Infiltration of VAT by immune cell response activators, have an important role in the pathogenesis of obesity comorbidities such as insulin resistance (Kintscher et al., 2008). Hypertrophic adipocytes have been linked to the activation of apoptosis and presence of crown-like structures (Murano et al., 2008; Sharkey et al., 2009), which may be another mechanism for cumulative macrophage signalling and recruitment. It is further hypothesised that the non-fat cell fraction of adipose tissue plays a greater role in adipokine expression than adipocytes (Fain, 2010). This could contribute to the microcirculatory dysfunction and hypoxia caused by adipocyte enlargement in obesity. Hypoxia in adipose tissue stimulates vascular synthesis and remodelling via up-regulation of the vascular endothelial growth factor (VEGF) gene, allowing for endothelial growth leading to additional immune cell infiltration and signalling, further maintaining a chronic inflammatory response (Ye, 2011). Sex differences in obesity mediated inflammation As previously discussed, different anatomical locations of WAT are heterogeneous between genders and in their metabolic profiles. Currently only a limited amount work exists in the field, but comparative studies analysing the effect of gender on the relationship between depots and their inflammatory profiles have identified that enlarged VAT contributes to elevated IL6 and CRP plasma concentrations (Beasley et al., 2009). The same study also demonstrated a trend for increased subcutaneous femoral adiposity in females resulting in reduced circulating concentrations of these inflammatory molecules (Beasley et al., 2009). VAT therefore appears to be a predictor of inflammatory protein concentration and hence obese females may display a reduced or protective obesity linked inflammatory profile compared to males due to their different adipose tissue distribution. Obesity in females does result in an amplified inflammatory condition compared to lean females, regardless of adipose tissue deposition (Fain, 2010). Beasley et al. (2009) demonstrated the increased visceral fat mass was positively associated with elevated IL6, TNFα and CRP regardless of race or gender. A caveat of this study however, was that the analysed population were all elderly (N 69 years old) and thus after the age at which adipose tissue redistribution occurs in postmenopausal females, meaning no difference in inflammatory profiles with genders would be expected. Associations between VAT, sex steroids and inflammation in males have established that plasma concentrations of 17β-estradiol were strongly linked to visceral adiposity, but not with SAT mass (Gautier et al., 2013). Elevated CRP, glucose, triglycerides, insulin and IL6 concentrations were also negatively correlated to plasma testosterone, which were reduced in obese subjects, suggesting a role for central fat mediated inflammation contributing to the hypogonadism displayed with the metabolic syndrome (Gautier et al., 2013; Laaksonen et al., 2003). The association between obesity in males, reduced circulating testosterone and increased risk of developing CVD and the metabolic syndrome is well documented (Corona et al.,

2009; Kang, 2013). Nevertheless, obese males with reduced circulating testosterone do not display raised estradiol concentrations (Mogri et al., 2013) until old age, where they become elevated in elderly men through an elevation in aromatase activity that converts testosterone to estradiol (Leder, 2007). Effect of the menopause In morbidly obese women, those who demonstrated upper body obesity exhibited elevated plasma testosterone and estrone, yet lower body obesity was characterised by higher 17β-estradiol concentrations (Kirschner et al., 1990). Raised 17β-estradiol was inversely correlated to VAT mass and circulating inflammatory signalling molecules, but after the menopause these relationships were diminished with the reduction of oestrogen and increased appetite plus central adipose tissue expansion (Fuente-Martin et al., 2013). Furthermore, the menopause is associated with decreased energy expenditure and lipid oxidation leading to enhanced total fat mass primarily deposited in VAT (Lovejoy et al., 2008). This augmented fat deposition is thought to be driven by an absence of sex hormones, for example, oestrogen deficient female rats demonstrate a hyperphagic response with a specific macronutrient increase in dietary fat consumption (Lovejoy et al., 2008). Not all studies agree with this finding, however, as Heine et al. showed that in oestrogen receptor-α knockout in both sexes and ovariectomy models in female rats, visceral WAT mass increased as a result of decreased energy expenditure rather than increased calorie consumption (Heine et al., 2000). It is likely that the greater WAT accumulation seen in combination with a reduction or removal of female sex hormones is mediated through both increased food consumption and decreased physical activity as observed in the human population (O'Rahilly and Farooqi, 2008). In premenopausal females, femoral adipocytes show greater LPL activity and thus a higher storage volume for lipids than VAT, yet central adipocytes exhibit greater lipolytic responsiveness and sensitivity than lower body fat. After the menopause, however, the loss of oestrogen removes these inter-depot differences, leading to the heightened development of central adiposity (Rebuffe-Scrive et al., 1986). The difference in adipose tissue effects observed between males and female with sex hormones is salient, and perhaps the gender disparity exhibited in inflammatory mediated obesity is regulated by sex hormone action on the hypothalamus to a greater extent than is currently understood. Further studies are now needed to help elucidate the effect of sex steroids on hypothalamic modulated adipose tissue deposition and their link to obesity related metabolic disease. Sexual dimorphism of renal disease and HPA axis stimulation with obesity The elevated chronic inflammatory status observed in obesity alongside its associated comorbidities is hypothesised to be a mechanism behind a more widespread systemic injury, targeting important organ systems within the body (Rocha and Libby, 2009). Moderate obesity in young adult sheep leads to enhanced inflammatory gene expression in the kidneys coupled with hypercellular invasion and expansion in the glomerular structure (Bloor et al., 2012). However, these responses were not observed in females, who appeared to be protected by an up-regulation in cortisol synthesis and glucocorticoid expression (Bloor et al., 2012), indicating a role for HPA axis activation in this observed sexual disparity. Across species, cortisol has been shown to decrease the synthesis of pro-inflammatory cytokines, molecules which are known to contribute to HPA activation, indicating the potential cross-talk between HPA axis activation and the chronic inflammatory condition linked to obesity (Bose et al., 2009). The difference in glucocorticoid action in females may be established in early life, as young sheep, for example, display elevated resting plasma cortisol, ACTH and enhanced adrenocortical response in comparison to males, suggesting

Please cite this article as: Bloor, I.D., Symonds, M.E., Sexual dimorphism in white and brown adipose tissue with obesity and inflammation, Horm. Behav. (2014), http://dx.doi.org/10.1016/j.yhbeh.2014.02.007

I.D. Bloor, M.E. Symonds / Hormones and Behavior xxx (2014) xxx–xxx

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Fig. 2. Summary of potential HPA pathway activation between sexes with obesity. In females, deposition of accumulated white adipose tissue in lower and upper body subcutaneous depots prevents visceral depot to act as an increased stressed signal in HPA dysfunction, leading to transition of decreased deposition of lower and upper body subcutaneous adipose tissue (SAT) depots to raised central adiposity development. In obese males, a positive feedback loop of increasing central fat expansion, insulin resistance and systemic inflammation stimulates further possible HPA dysfunction, which is not observed in females. Additional protection from this feedback cycle in obese females may occur from the elevated generation of cortisol to suppress cytokine synthesis and systemic inflammation. Solid arrows represent action, dotted arrows represent no action, black arrows represent ↑ — increase, ↓ — decrease, ↔ — no change, ? — unknown. ACTH — adrenocorticotropic hormone; CRH — corticotropin releasing hormone. Image sourced and adapted from Vitale et al. (2009).

augmented HPA function from an early age (Gardner et al., 2006). Renal tissue from females is also acknowledged to show a reduced progression rate of kidney disease attributed to the actions of oestrogen and its receptors compared to males (Silbiger and Neugarten, 2008). Bloor et al. (2013) have also demonstrated in sheep that males possess smaller adipocytes in peri-renal adipose tissue compared to females, yet this difference in size and volume is removed with juvenile onset obesity, suggesting an increased lipid storage capacity in central adipocytes surrounding important organs for males which may contribute towards the enhanced disease progression exhibited by male kidneys. In human models of enhanced central adiposity, activity of the HPA is increased, evidence that visceral obesity is a form of systemic stress (Mathieu et al., 2009; Pasquali et al., 2006; Syed and Weaver, 2005). Enhanced HPA dysfunction is also postulated to drive redistribution of body adipose tissue towards enlargement of the intra-abdominal depot (Duclos et al., 2005; Stewart et al., 1999). Exposure of omental and SAT to glucocorticoids increases LPL mRNA expression and activity in males. Females showed an inverse response of increased lipolysis and lipogenesis activity between SAT and VAT in the presence of glucocorticoids and insulin (Fried et al., 1993). The mechanisms and interactions of obesity, gender, glucocorticoids and inflammation are varied, complex and not completely understood. It is likely that imbalances in HPA activity mediated by the stress of obesity and glucocorticoid action are positively associated with the adverse metabolic outcomes linked to excess adiposity. The potential obesity mediated gender dimorphism in HPA activation is summarised in Fig. 2.

Summary A wealth of data has been reported supporting the existence of sexual dimorphism in the human population with the presence of obesity. Clarifying the multifaceted and complicated nature of regulation in adipose tissue deposition and its endocrine role in controlling the inflammatory and metabolic network is still uncertain. Both WAT and BAT appear to maintain dynamic endocrine roles which are linked to their anatomical locations, with different depots possessing diverse metabolic and inflammatory signalling profiles which also appear to be concomitant with hypothalamic regulation via sex hormone action and glucocorticoids. These relationships become all the more complex when the recent discovery of beige adipocytes is taken into account, a finding which further obfuscates the nature and developmental lineage of adipocytes and their precursors and thus questions the subsequent impact on the metabolic and endocrine function of these tissues. Acknowledgments The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007–2013), project EarlyNutrition under grant agreement no. 289346. Conflict of interest The authors have no conflicts of interest to declare.

Please cite this article as: Bloor, I.D., Symonds, M.E., Sexual dimorphism in white and brown adipose tissue with obesity and inflammation, Horm. Behav. (2014), http://dx.doi.org/10.1016/j.yhbeh.2014.02.007

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Please cite this article as: Bloor, I.D., Symonds, M.E., Sexual dimorphism in white and brown adipose tissue with obesity and inflammation, Horm. Behav. (2014), http://dx.doi.org/10.1016/j.yhbeh.2014.02.007