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Adipocyte biology and obesity-mediated adipose tissue remodeling
Accepted Manuscript Adipocyte biology and obesity-mediated adipose tissue remodeling Anne Kunath, Nora Klöting PII:
S2451-8476(16)30035-5
DOI:
10.1016/j.obmed.2016.10.001
Reference:
OBMED 22
To appear in:
Obesity Medicine
Received Date: 6 September 2016 Accepted Date: 6 October 2016
Please cite this article as: Kunath, A., Klöting, N., Adipocyte biology and obesity-mediated adipose tissue remodeling, Obesity Medicine (2016), doi: 10.1016/j.obmed.2016.10.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Mini-Review
Adipocyte biology and Obesity-mediated adipose tissue remodeling
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Anne Kunath a *, Nora Klöting b German Center for Diabetes Research (DZD), Leipzig, Germany
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Integrated Research and Treatment Center (IFB) AdiposityDiseases, University of Leipzig, Leipzig
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* Corresponding author University of Leipzig German Center for Diabetes Research (DZD) Liebigstraße 19-21 04103 Leipzig Germany Tel.: + 493419713315 FAX: + 493419713409 E-Mail address: [email protected]
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a
ACCEPTED MANUSCRIPT Abstract Obesity has reached epidemic proportions, leading to an increase of associated pathologies such as insulin resistance, cardiovascular disease, some types of cancer and type 2 diabetes. The worldwide obesity epidemic has greatly increased interest in the biology and physiology of adipose tissues (AT), cells specialized in fat storage that all vertebrates
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possess. The last few decades have shown that adipocytes also play a critical role in sensing and responding to changes in systemic energy balance. White fat cells secrete sets of adipokines that influence processes such as food intake, insulin sensitivity, and insulin secretion. Brown adipose tissue instead induces fat accumulation and can produce energy as heat, thereby defending against hypothermia, obesity, and diabetes. There are two
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distinct types of thermogenic fat cells, termed brown and beige adipocytes. Adipocytes exist within AT, where they are in dynamic cross talk with immune cells. AT undergoes a
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continuous remodeling process in a fat-depot specific manner, that normally maintains tissue health, but may spin out of control and lead to adipocyte death in association with the recruitment and activation of macrophages, and systemic insulin resistance. In addition, AT is the major site of vitamin D storage and vitamin D affects directly the expression of the appetite regulating hormone, leptin as well as influencing adipocyte function. This review is intended to serve as an overview of white adipocyte biology and obesity-mediated adipose
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tissue remodeling by microbiome changes.
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Keywords: obesity, WAT, Inflammation, Vitamin D, adipocytes, microbiome
ACCEPTED MANUSCRIPT 1. Background Obesity has reached epidemic proportions. The worldwide obesity epidemic has greatly increased interest in the biology and physiology of adipose tissues (AT). Worldwide more than 1.9 billion adults are influenced by obesity, which represents a fast growing public health problem that contributes to higher mortality through an increase in hypertension,
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stroke, coronary heart disease, type 2 diabetes and some types of cancer (WHO, 2015; (Adams et al., 2006; Bluher, 2013; Hossain Parvez et al; Mensah et al., 2004; Mokdad et al., 2003).
All eukaryotes from yeast to man are able to store calories in the form of lipid droplets, but
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only vertebrates have specialized cells that are recognizable as adipose tissue cells (adipocytes). AT is postulated to be a key player in regulating the process of obesity (Rosen and Spiegelman, 2006). The amount, distribution and changes of body fat have an impact on
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the onset and progression of obesity. Excess of fat is often characterized by a chronic state of low-grade inflammation with progressive immune cell infiltration into AT. AT undergoes a continuous remodeling process that may spin out of control and lead to adipocyte death in association with the recruitment and activation of macrophages, and systemic insulin resistance. There have been several pivotal discoveries that focused our interest on AT. One was the discovery of leptin in 1994 (Zhang et al., 1994). Total inability to produce leptin result
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in profound, early onset obesity with persistently excessive food intake, inappropriately decreased energy expenditure, severe insulin resistance, and genetic background– dependent diabetes (Zhang et al. 1994) (Pelleymounter et al., 1995). Another discovery was the association between inflammation of AT depots and the development of obesity related
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metabolic diseases. Therefore AT is postulated to be a key risk factor in regulating the process of obesity. The amount, distribution and changes of body fat have an impact on the
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onset and progression of obesity. AT is distributed over multiple subcutaneous (SC) and visceral depots, typically accounting for 15 - 30% of total human body weight (F.X. PiSunyer, 1998). This review is intended to give an overview to adipocyte biology function, obesity-mediated AT remodeling and discusses how changes in microbiota and vitamin D status seem to play a potential role in AT function and body weight regulation. 2. Adipose tissue depots and function AT is generally considered either ‘white’, characterized by adipocytes with a single lipid droplet for efficient energy storage, or ‘brown’, characterized by adipocytes with multiple lipid droplets, numerous enlarged mitochondria expressing uncoupling proteins (UCP1) for uncoupled oxidative phosphorylation and nonshivering thermogenesis, and increased vasculature for heat dissipation (Pope et al., 2016). White adipocytes are responsible for
ACCEPTED MANUSCRIPT storing redundant calories as triglycerides within the lipid droplets (Konige et al., 2014). Brown fat is located mainly around the neck and plays an essential role in thermogenesis (Rutkowski et al., 2015). Some fat depots have both white and brown adipocytes and therefore called brite or beige AT (Walden et al., 2012). The appearance of these brite or beige adipocytes may involve transdifferentiation processes of white to beige cells. The ability of adipocytes for lipid uptake and storage in form of triglycerides allows for
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expansion of AT, which significantly influences adipocyte biology. Result of excess triglyceride increase due to a positive energy balance is the growth in size (hypertrophy), whereas the increase in number (hyperplasia) results from the formation of new adipocytes from precursor cells (adipogenesis) (Bjorntorp, 1974). Hypertrophy of adipocytes results in
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loss of insulin sensitivity in lean and obese individuals, whereas AT hyperplasia has been shown to be protective against insulin abnormalities in obesity (Hoffstedt et al., 2010; Kloting and Bluher, 2014). The total amount of fat is distributed in multiple depots in the body, which
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are concentrated in three main areas – subcutaneous, dermal and intraperitoneal fat depots (Cinti, 1999). An excess of intraperitoneal fat is known as central or abdominal obesity and is characterized by excessive fat around the stomach and abdomen.
Beside the main functions of AT as energy storage, mechanical protection and thermal insulator, AT has been recognized as an endocrine organ, which secretes more than 600
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different hormones, so-called adipokines (Bluher, 2014; Kershaw and Flier, 2004; Lehr et al., 2012). Adipokines are involved in regulation of various metabolic processes, for instance appetite and satiety, fat distribution, adipogenesis, energy metabolism, inflammation, which are directly linked to body weight (Bluher, 2014; Bluher and Mantzoros, 2015). Secretion of
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adipokines may be influenced by fat distribution or may contribute to several fat distribution subtypes (Schleinitz et al., 2014). Both AT depots produce and secrete both pro- and antiinflammatory molecules that influence local and systemic inflammation. The balance of pro-
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and anti-inflammatory adipokines is dictated by many different factors, including the nutritional/metabolic status of the host, genetic factors, the presence of infection or systemic inflammation, oxidative stress, smoking status, age, and gender (Bluher, 2016; Mancuso, 2016)
3. Obesity-mediated adipose tissue remodeling Obesity-associated AT remodeling has been first described by Cinti in 2005 as the existence of significant numbers of so-called “crown-like structures (CLS)”, consisting of macrophages surrounding dead adipocytes in both obese mice and humans (Cinti et al., 2005). The high number of CLS is highly correlated to AT inflammation, metabolic disorder as well as considered to be pathological lesions in AT of obese subjects (Aouadi et al., 2013). With
ACCEPTED MANUSCRIPT excess of fat, extreme increases in adipocyte size are accompanied by an elevated frequency of adipocyte death and a phenotypic switch in adipose tissue macrophage (ATMs) polarization and recruitment (Lumeng et al., 2007). The elevated adipocyte death rate could partly be explained by hypoperfusion causing an inadequate supply of oxygen in the face of expanding AT (Patel et al., 2013). Long-term imaging of ATMs in live AT explants have shown that the accumulation of ATMs around a dying adipocyte (formation of CLS), the
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migration of ATMs toward the CLS and out of the CLS, different migratory behaviors of ATMs, and the degradation of dead adipocytes are very dynamic processes (Gericke et al., 2015). High fat feeding (60% of calories as lard) provoke a nearly complete remodeling of the epididymal (visceral) fat depot of male mice. Interestingly, AT of female mice are far less
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susceptible to HF diet–induced adipocyte death and AT remodeling. This gender difference is dramatic in the gonadal (parametrial vs. epididymal), but also holds for SC inguinal fat depots (Strissel et al., 2007). Similar depot differences are observed in genetic obese models
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(Nishimura et al., 2008). The mechanisms underlying depot differences in rates of remodeling are not well understood. DiGirolamo and co-workers showed that next to anatomy, growth characteristics and extra cellular matrix composition differ substantially among fat depots. While the SC fat grows in response to a high fat diet mainly by increasing the number of adipocytes, the hyperplastic capacity of the visceral fat is far lower (DiGirolamo et al., 1998). Despite the close association of adipocyte death with macrophage
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infiltration, it remains unclear to what extent macrophages respond to or contribute to adipocyte death. Lee et al. hypothesized that the small molecules released by dead adipocytes may activate toll-like receptors (TLRs) on the macrophages and neighboring adipocytes, inducing a release of pro-inflammatory factors (Lee et al., 2010).
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In obesity, unusual expression of extra cellular matrix (ECM) components, proteases and fragments derived from adipose tissue-remodeling processes can influence immune cell
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recruitment and activation, actively contributing to inflammation (Catalan et al., 2012). There are obesity induced fat depot differences in adipocyte size and adipose tissue progenitor pool (AP) between SC and VAT (Table1). Therefore, it is not unexpected that plasticity is also differently affected, particularly when stressed by positive energy intake (Pellegrinelli et al., 2016). The percentage of small cells is higher in SC and omental VAT in healthy individuals compared to subjects with diabetes and obesity (Fang et al., 2015). Recently, high fat feeding time course experiments in mice revealed intra-depot differences in immune cell composition in relation to WAT expandability (van Beek et al., 2015). This mice study also suggests that VAT is the primary fat depot that expands during the initial phase of obesity, followed by the SAT and mesenteric VAT. Once the mice had reached a body weight of about 40 grams, gonadal VAT stopped expanding further, in contrast to SAT and mesenteric VAT. Interestingly, reaching this maximal expansion coincides with increased
ACCEPTED MANUSCRIPT adipocyte death rate and formation of CLS, inflammation and tissue dysfunction associated with insulin resistance and liver damage (Strissel et al., 2007). Similarly, another study has suggested that increased visceral mass predominantly results from adipocyte hypertrophy whereas hyperplasia is predominantly seen in SAT (Joe et al., 2009). The resistance to differentiation observed in VAT APs and the fact the cells are more
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prone to cell death than those from SAT, may explain why hypertrophy preferentially occurs in VAT while SAT expands through hyperplasia as a result of the higher progenitor number and/or activity (Pellegrinelli et al., 2016).
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Table1. Differences of WAT depots undergoes remodeling in obesity SAT vs VAT
Adipocyte hypertrophy
<
Production of inflammatory factors Crown like structure
<
<
Fibrosis deposition with decreased
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tissue plasticity Expansion
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Remodeling process
SVF differentiation capacity
>
> >
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SVF = stromal vascular fraction, SAT = subcutaneous adipose tissue,
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VAT = visceral adipose tissue
4. AT Inflammation, adipocyte cross-talk and turnover As mentioned, expansion of white AT (WAT) leads to apoptosis of hypertrophic adipocytes and release of large fat droplets, which are toxic to the surrounding cells and leads to increased infiltration of macrophages in the WAT in obese individuals. Infiltration of macrophages into AT increases proportionally with increased BMI, body fat mass and adipocyte hypertrophy and represents a reversible process in obese patients losing weight (Bluher, 2013; Cancello et al., 2005; Harman-Boehm et al., 2007). These M1 macrophages (“classically activated”) assume an inflammatory phenotype, which is characterized by the expression of inflammatory cytokines, whereas anti-inflammatory M2 macrophages
ACCEPTED MANUSCRIPT (“alternatively activated”) play a role in tissue remodeling (Rosen and Spiegelman, 2014). Lumeng et al. indicated that the ATM phenotype changed from an anti-inflammatory M2 state to a proinflammatory M1 state, during body weight gain (Lumeng et al., 2007). ATM play critical roles in the establishment of the chronic inflammatory state and metabolic disorders including Type 2 diabetes and insulin resistance (Koppaka et al., 2013). Expanded AT mass contributes to increased production and release of inflammation-related factors in obesity.
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Obesity increases numbers of macrophages in AT compared with AT of lean individuals (Weisberg et al., 2003). The number of ATM is the strongest predictor of insulin-resistant obesity (Kloting et al., 2010) and is depending on the location of the fat depot. Visceral AT with higher number of immune cells suggests that antigens derived from the gut may
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contribute to T-cell activation and recruitment into visceral AT (Sell et al., 2012). ATM emigrate out of so called CLS, consisting of macrophages surrounding dead adipocytes (Cinti et al., 2005), to become resident in the interstitium, which confirm CLS as a new
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source of ATM (Haase et al., 2014). Inflammatory state of obesity with progressive immune cell infiltration into AT plays a key role in metabolic disorders which are linked to obesity. In Obesity the production of adipokines are increased, which leads to inflammation of adipose tissue by extensive macrophages infiltration. Therefore adipokines become important role in the control of immune cells infiltrating AT.
Adipocytes share their microenvironment with multiple cell types, such as stromal-vascular
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cells (SVF), blood vessels, lymph nodes and nerves that interact to coordinate adipose functions (Hausman et al., 2001). This crosstalk between adipocytes and macrophages establishes and maintains the chronic inflammation state in obese AT through persistently recruiting new macrophages/monocytes from circulation. Adipokines and chemokines are
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key mediators linking the adipocytes and ATMs and regulating AT inflammation. Obesity not only recruits more macrophages, but also upregulates the expression of chemokines and
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their receptors in AT from obese mice and humans (Bai and Sun, 2015). Time course studies in rodents have shown that, under high fat diet conditions, almost 80% of the adipocytes in the epididymal (visceral) AT died and were replaced within a few weeks (Strissel et al., 2007). Human studies estimate that the lifespan of a SC adipocyte in humans is about 10 years (Spalding et al., 2008). Interestingly, BMI and weight loss do not alter the adipocyte turnover rates indicating that adipocyte number is tightly regulated, static during adulthood and the relative rates of adipocyte death seems to be equal between lean and obese. Often, obese individuals have more adipocytes; therefore the absolute number of dead or dying adipocytes at any time point is higher and could contribute to the chronic inflammatory state.
ACCEPTED MANUSCRIPT 5. Microbiome and obesity Changes in microbiota play a potential role in body weight regulation, development of metabolic disorders and obesity (Cox et al., 2015; Rosenbaum et al., 2015; Villanueva-Millan et al., 2015). Mechanisms how the composition of gut microbiota influences the development of obesity are barely understood, but intestinal microbiome is beginning to be recognized as
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one of the major important risk factors of obesity. The human gut microbiota consists of trillions of microbial cells and is dominated by four phyla (Actinobacteria, Firmicutes, Proteobacteria, Bacteriodetes), which varies between different body sites and among individuals depending on diet, stress, medication, geographical location and other factors (Bailey, 2014; Hamady and Knight, 2009; Morgan et
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al., 2013). Highest number of microorganisms has been observed in the intestinal tract, which comprises more than 10.000 different phylotypes (Harris et al., 2012). The microbiota
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may be regarded as an entero-endocrine organ, because it is able to change the production of molecules that affect energy metabolism including weight gain, weight loss and fat mass storage (Tehrani et al., 2012). In a study by Elli et al. fecal microbial profiles of obese subjects and their lean relatives were compared and the existence of a kind of “familial fingerprint” of the intestinal bacteria was concluded, because the core intestinal flora was family specific (Elli et al., 2010). The homology of the intestinal microbiota was stronger between blood-related subjects than between individuals with identical phenotypes (Elli et al.,
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2010). Study of Turnbaugh et al. confirmed the homology by the result that intestinal bacterial phyla were much closer in blood-related individuals than in unrelated subjects, which was independent from body weight (Turnbaugh et al., 2009). Possible mechanisms of the impact from intestinal microbiome to obesity include low-grade
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inflammation, energy expenditure and storage and hormonal regulation between the intestinal microbiome and the host. Several mice studies have shown that obese mice have
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significant increased body fat through the increased capacity of the microbiome to harvest energy from diet (Ley et al., 2005; Turnbaugh et al., 2006). Further, the authors demonstrated that colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota' (Ley et al., 2005; Turnbaugh et al., 2006). Studies based on gut microbiome exhibit correlations between the composition of commensal bacteria residing in the human gut and the development of obesity and insulin resistance (Turnbaugh et al., 2009; Zhang et al., 2013). An experimental study, which transplanted fecal microbiota from adult twin pairs discordant for obesity into germ-free mice, replicated BMI differences of the twins in mice (Ridaura et al., 2013). These results emphasize the strong microbiota-by-diet interaction (Ridaura et al., 2013). Investigating the effect of microbiota composition change from recipients with metabolic syndrome that obtained intestinal microbiota from lean donors showed that
ACCEPTED MANUSCRIPT increased gut microbiota diversity is associated with improved insulin resistance (Vrieze et al., 2012). Obese Individuals with higher microbial gene richness present more low-grade inflammation and insulin resistance than obese subjects with lower microbial richness (Cotillard et al., 2013). Studies in mice revealed that increased intestinal permeability of individuals with obesity results in migration of bacteria into AT, which leads to inflammation and insulin resistance.
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The presence of bacteria in human adipose tissue and underlying mechanisms leading to the development of insulin resistance is still remaining unclear. Gut microbiota is an additional contributing factor to the pathophysiology of obesity.
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6. Vitamin D action in adipocytes
Vitamin D is a micronutrient required for the growth and development of human bodies. AT is
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a reservoir for vitamin D (about 60% of total vitamin D) in human subjects and rats (Blum et al., 2008). Interestingly, visceral fat contains about 20 % more vitamin D than subcutaneous AT (SAT) (Beckman et al., 2013). Several studies have demonstrated that vitamin D deficiency is closely associated with not only total fat content, but also the specific pattern of fat distribution. Sorkin et al. and others demonstrated a negative correlation between serum vitamin D levels and visceral fat area (Sorkin et al., 2014; Thompson et al., 2016).
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Interestingly, research showed that Vitamin D affects directly the expression of the appetite regulating hormone, leptin (Kong et al., 2013). Vitamin D binds its cognate receptor, the vitamin D receptor (VDR), to exert its biological functions. VDRs are expressed in adipocytes. In adipocytes, vitamin D appears to inhibit the active form of adipogenic
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transcription factors and fat accumulation during the differentiation phase (Ding et al., 2012). Moreover, since there are Vitamin D Response elements (VDREs) in the insulin gene, it is proposed that vitamin D modulates insulin synthesis in the pancreatic beta cells as well
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(Maestro et al., 2003). Vitamin D insufficiency leads to activation of phospholipase C in adipocytes, which, in turn, leads to an increase in intracellular calcium. The increased calcium flux in adipocytes, which stimulates fatty acid synthase, may increase lipogenesis and inhibit lipolysis (Zemel, 2002). Vitamin D may increase peripheral insulin action by stimulating the expression of insulin receptors, which subsequently leads to improvement of obesity and obesity related disorders, such as fatty liver (Takiishi et al., 2010). Other targets of vitamin D action are immune cells, and control function of maturation and/or growth of T cells, B cells and dendritic cells, to generate a more tolerant and anti-inflammatory response profile (Almerighi et al., 2009; Chen et al., 2007; Jeffery et al., 2009; Verma and Hussain, 2016). Some human studies have provided strong support for beneficial impacts of VD supplementation, but still well-designed clinical studies are urgently needed to demonstrate
ACCEPTED MANUSCRIPT real valuable utility for limiting obesity (Landrier et al., 2016). Taken together, there is strong evidence that Vitamin D deficiency and VDR expression in adipocytes is linked to obesity. 8. Conclusion In summary of the current literature, the physiologic functions attributed to adipose tissue are expanding. WAT is characterized by its capacity to adapt and expand in response to surplus
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energy through processes of adipocyte hypertrophy and/or recruitment and proliferation of precursor cells in combination with vascular and extracellular matrix remodeling. AT undergoes a continuous remodeling process in a fat-depot specific manner, that normally maintains tissue health, but may spin out of control and lead to adipocyte death in
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association with the recruitment and activation of macrophages, and systemic insulin resistance. Changes in microbiota and vitamin D status seem to play a potential role in AT
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function and body weight regulation.
ACCEPTED MANUSCRIPT Conflict of interest The authors declare no conflict of interest.
Acknowledgements
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We apologize to those whose work was not directly cited because of space constraints. We thank Dr. Henrike Heyne for reading an earlier version of the manuscript and providing useful comments. Funding
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This work was supported by SFB1052 B4 (to NK), FKZ01E01501 (to NK) and 82DZD00601
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(to AK).
Figure legend
Figure 1. Overview of Obesity-mediated adipose tissue remodeling. Physiological functions of Vitamin D and microbiome changes contribute to obese white adipocytes.
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CLS = crown-like structures, ATMs = adipose tissue macrophages
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Figure1 . Overview of Obesity-mediated adipose tissue remodeling
Vitamin D
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Microbiome
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Pro-inflammation
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Obese adipocyte Adipokine imbalance CLS, ATMs ECM imbalance Pro-inflammatory stage
Adipogenesis Fat accumulation Adipokine secretion Leptin secretion Apoptosis
S2451-8476(16)30035-5
DOI:
10.1016/j.obmed.2016.10.001
Reference:
OBMED 22
To appear in:
Obesity Medicine
Received Date: 6 September 2016 Accepted Date: 6 October 2016
Please cite this article as: Kunath, A., Klöting, N., Adipocyte biology and obesity-mediated adipose tissue remodeling, Obesity Medicine (2016), doi: 10.1016/j.obmed.2016.10.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Adipocyte biology and Obesity-mediated adipose tissue remodeling
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Anne Kunath a *, Nora Klöting b German Center for Diabetes Research (DZD), Leipzig, Germany
b
Integrated Research and Treatment Center (IFB) AdiposityDiseases, University of Leipzig, Leipzig
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* Corresponding author University of Leipzig German Center for Diabetes Research (DZD) Liebigstraße 19-21 04103 Leipzig Germany Tel.: + 493419713315 FAX: + 493419713409 E-Mail address: [email protected]
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a
ACCEPTED MANUSCRIPT Abstract Obesity has reached epidemic proportions, leading to an increase of associated pathologies such as insulin resistance, cardiovascular disease, some types of cancer and type 2 diabetes. The worldwide obesity epidemic has greatly increased interest in the biology and physiology of adipose tissues (AT), cells specialized in fat storage that all vertebrates
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possess. The last few decades have shown that adipocytes also play a critical role in sensing and responding to changes in systemic energy balance. White fat cells secrete sets of adipokines that influence processes such as food intake, insulin sensitivity, and insulin secretion. Brown adipose tissue instead induces fat accumulation and can produce energy as heat, thereby defending against hypothermia, obesity, and diabetes. There are two
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distinct types of thermogenic fat cells, termed brown and beige adipocytes. Adipocytes exist within AT, where they are in dynamic cross talk with immune cells. AT undergoes a
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continuous remodeling process in a fat-depot specific manner, that normally maintains tissue health, but may spin out of control and lead to adipocyte death in association with the recruitment and activation of macrophages, and systemic insulin resistance. In addition, AT is the major site of vitamin D storage and vitamin D affects directly the expression of the appetite regulating hormone, leptin as well as influencing adipocyte function. This review is intended to serve as an overview of white adipocyte biology and obesity-mediated adipose
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tissue remodeling by microbiome changes.
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Keywords: obesity, WAT, Inflammation, Vitamin D, adipocytes, microbiome
ACCEPTED MANUSCRIPT 1. Background Obesity has reached epidemic proportions. The worldwide obesity epidemic has greatly increased interest in the biology and physiology of adipose tissues (AT). Worldwide more than 1.9 billion adults are influenced by obesity, which represents a fast growing public health problem that contributes to higher mortality through an increase in hypertension,
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stroke, coronary heart disease, type 2 diabetes and some types of cancer (WHO, 2015; (Adams et al., 2006; Bluher, 2013; Hossain Parvez et al; Mensah et al., 2004; Mokdad et al., 2003).
All eukaryotes from yeast to man are able to store calories in the form of lipid droplets, but
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only vertebrates have specialized cells that are recognizable as adipose tissue cells (adipocytes). AT is postulated to be a key player in regulating the process of obesity (Rosen and Spiegelman, 2006). The amount, distribution and changes of body fat have an impact on
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the onset and progression of obesity. Excess of fat is often characterized by a chronic state of low-grade inflammation with progressive immune cell infiltration into AT. AT undergoes a continuous remodeling process that may spin out of control and lead to adipocyte death in association with the recruitment and activation of macrophages, and systemic insulin resistance. There have been several pivotal discoveries that focused our interest on AT. One was the discovery of leptin in 1994 (Zhang et al., 1994). Total inability to produce leptin result
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in profound, early onset obesity with persistently excessive food intake, inappropriately decreased energy expenditure, severe insulin resistance, and genetic background– dependent diabetes (Zhang et al. 1994) (Pelleymounter et al., 1995). Another discovery was the association between inflammation of AT depots and the development of obesity related
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metabolic diseases. Therefore AT is postulated to be a key risk factor in regulating the process of obesity. The amount, distribution and changes of body fat have an impact on the
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onset and progression of obesity. AT is distributed over multiple subcutaneous (SC) and visceral depots, typically accounting for 15 - 30% of total human body weight (F.X. PiSunyer, 1998). This review is intended to give an overview to adipocyte biology function, obesity-mediated AT remodeling and discusses how changes in microbiota and vitamin D status seem to play a potential role in AT function and body weight regulation. 2. Adipose tissue depots and function AT is generally considered either ‘white’, characterized by adipocytes with a single lipid droplet for efficient energy storage, or ‘brown’, characterized by adipocytes with multiple lipid droplets, numerous enlarged mitochondria expressing uncoupling proteins (UCP1) for uncoupled oxidative phosphorylation and nonshivering thermogenesis, and increased vasculature for heat dissipation (Pope et al., 2016). White adipocytes are responsible for
ACCEPTED MANUSCRIPT storing redundant calories as triglycerides within the lipid droplets (Konige et al., 2014). Brown fat is located mainly around the neck and plays an essential role in thermogenesis (Rutkowski et al., 2015). Some fat depots have both white and brown adipocytes and therefore called brite or beige AT (Walden et al., 2012). The appearance of these brite or beige adipocytes may involve transdifferentiation processes of white to beige cells. The ability of adipocytes for lipid uptake and storage in form of triglycerides allows for
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expansion of AT, which significantly influences adipocyte biology. Result of excess triglyceride increase due to a positive energy balance is the growth in size (hypertrophy), whereas the increase in number (hyperplasia) results from the formation of new adipocytes from precursor cells (adipogenesis) (Bjorntorp, 1974). Hypertrophy of adipocytes results in
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loss of insulin sensitivity in lean and obese individuals, whereas AT hyperplasia has been shown to be protective against insulin abnormalities in obesity (Hoffstedt et al., 2010; Kloting and Bluher, 2014). The total amount of fat is distributed in multiple depots in the body, which
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are concentrated in three main areas – subcutaneous, dermal and intraperitoneal fat depots (Cinti, 1999). An excess of intraperitoneal fat is known as central or abdominal obesity and is characterized by excessive fat around the stomach and abdomen.
Beside the main functions of AT as energy storage, mechanical protection and thermal insulator, AT has been recognized as an endocrine organ, which secretes more than 600
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different hormones, so-called adipokines (Bluher, 2014; Kershaw and Flier, 2004; Lehr et al., 2012). Adipokines are involved in regulation of various metabolic processes, for instance appetite and satiety, fat distribution, adipogenesis, energy metabolism, inflammation, which are directly linked to body weight (Bluher, 2014; Bluher and Mantzoros, 2015). Secretion of
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adipokines may be influenced by fat distribution or may contribute to several fat distribution subtypes (Schleinitz et al., 2014). Both AT depots produce and secrete both pro- and antiinflammatory molecules that influence local and systemic inflammation. The balance of pro-
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and anti-inflammatory adipokines is dictated by many different factors, including the nutritional/metabolic status of the host, genetic factors, the presence of infection or systemic inflammation, oxidative stress, smoking status, age, and gender (Bluher, 2016; Mancuso, 2016)
3. Obesity-mediated adipose tissue remodeling Obesity-associated AT remodeling has been first described by Cinti in 2005 as the existence of significant numbers of so-called “crown-like structures (CLS)”, consisting of macrophages surrounding dead adipocytes in both obese mice and humans (Cinti et al., 2005). The high number of CLS is highly correlated to AT inflammation, metabolic disorder as well as considered to be pathological lesions in AT of obese subjects (Aouadi et al., 2013). With
ACCEPTED MANUSCRIPT excess of fat, extreme increases in adipocyte size are accompanied by an elevated frequency of adipocyte death and a phenotypic switch in adipose tissue macrophage (ATMs) polarization and recruitment (Lumeng et al., 2007). The elevated adipocyte death rate could partly be explained by hypoperfusion causing an inadequate supply of oxygen in the face of expanding AT (Patel et al., 2013). Long-term imaging of ATMs in live AT explants have shown that the accumulation of ATMs around a dying adipocyte (formation of CLS), the
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migration of ATMs toward the CLS and out of the CLS, different migratory behaviors of ATMs, and the degradation of dead adipocytes are very dynamic processes (Gericke et al., 2015). High fat feeding (60% of calories as lard) provoke a nearly complete remodeling of the epididymal (visceral) fat depot of male mice. Interestingly, AT of female mice are far less
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susceptible to HF diet–induced adipocyte death and AT remodeling. This gender difference is dramatic in the gonadal (parametrial vs. epididymal), but also holds for SC inguinal fat depots (Strissel et al., 2007). Similar depot differences are observed in genetic obese models
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(Nishimura et al., 2008). The mechanisms underlying depot differences in rates of remodeling are not well understood. DiGirolamo and co-workers showed that next to anatomy, growth characteristics and extra cellular matrix composition differ substantially among fat depots. While the SC fat grows in response to a high fat diet mainly by increasing the number of adipocytes, the hyperplastic capacity of the visceral fat is far lower (DiGirolamo et al., 1998). Despite the close association of adipocyte death with macrophage
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infiltration, it remains unclear to what extent macrophages respond to or contribute to adipocyte death. Lee et al. hypothesized that the small molecules released by dead adipocytes may activate toll-like receptors (TLRs) on the macrophages and neighboring adipocytes, inducing a release of pro-inflammatory factors (Lee et al., 2010).
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In obesity, unusual expression of extra cellular matrix (ECM) components, proteases and fragments derived from adipose tissue-remodeling processes can influence immune cell
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recruitment and activation, actively contributing to inflammation (Catalan et al., 2012). There are obesity induced fat depot differences in adipocyte size and adipose tissue progenitor pool (AP) between SC and VAT (Table1). Therefore, it is not unexpected that plasticity is also differently affected, particularly when stressed by positive energy intake (Pellegrinelli et al., 2016). The percentage of small cells is higher in SC and omental VAT in healthy individuals compared to subjects with diabetes and obesity (Fang et al., 2015). Recently, high fat feeding time course experiments in mice revealed intra-depot differences in immune cell composition in relation to WAT expandability (van Beek et al., 2015). This mice study also suggests that VAT is the primary fat depot that expands during the initial phase of obesity, followed by the SAT and mesenteric VAT. Once the mice had reached a body weight of about 40 grams, gonadal VAT stopped expanding further, in contrast to SAT and mesenteric VAT. Interestingly, reaching this maximal expansion coincides with increased
ACCEPTED MANUSCRIPT adipocyte death rate and formation of CLS, inflammation and tissue dysfunction associated with insulin resistance and liver damage (Strissel et al., 2007). Similarly, another study has suggested that increased visceral mass predominantly results from adipocyte hypertrophy whereas hyperplasia is predominantly seen in SAT (Joe et al., 2009). The resistance to differentiation observed in VAT APs and the fact the cells are more
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prone to cell death than those from SAT, may explain why hypertrophy preferentially occurs in VAT while SAT expands through hyperplasia as a result of the higher progenitor number and/or activity (Pellegrinelli et al., 2016).
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Table1. Differences of WAT depots undergoes remodeling in obesity SAT vs VAT
Adipocyte hypertrophy
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Production of inflammatory factors Crown like structure
<
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Fibrosis deposition with decreased
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tissue plasticity Expansion
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Remodeling process
SVF differentiation capacity
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> >
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SVF = stromal vascular fraction, SAT = subcutaneous adipose tissue,
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VAT = visceral adipose tissue
4. AT Inflammation, adipocyte cross-talk and turnover As mentioned, expansion of white AT (WAT) leads to apoptosis of hypertrophic adipocytes and release of large fat droplets, which are toxic to the surrounding cells and leads to increased infiltration of macrophages in the WAT in obese individuals. Infiltration of macrophages into AT increases proportionally with increased BMI, body fat mass and adipocyte hypertrophy and represents a reversible process in obese patients losing weight (Bluher, 2013; Cancello et al., 2005; Harman-Boehm et al., 2007). These M1 macrophages (“classically activated”) assume an inflammatory phenotype, which is characterized by the expression of inflammatory cytokines, whereas anti-inflammatory M2 macrophages
ACCEPTED MANUSCRIPT (“alternatively activated”) play a role in tissue remodeling (Rosen and Spiegelman, 2014). Lumeng et al. indicated that the ATM phenotype changed from an anti-inflammatory M2 state to a proinflammatory M1 state, during body weight gain (Lumeng et al., 2007). ATM play critical roles in the establishment of the chronic inflammatory state and metabolic disorders including Type 2 diabetes and insulin resistance (Koppaka et al., 2013). Expanded AT mass contributes to increased production and release of inflammation-related factors in obesity.
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Obesity increases numbers of macrophages in AT compared with AT of lean individuals (Weisberg et al., 2003). The number of ATM is the strongest predictor of insulin-resistant obesity (Kloting et al., 2010) and is depending on the location of the fat depot. Visceral AT with higher number of immune cells suggests that antigens derived from the gut may
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contribute to T-cell activation and recruitment into visceral AT (Sell et al., 2012). ATM emigrate out of so called CLS, consisting of macrophages surrounding dead adipocytes (Cinti et al., 2005), to become resident in the interstitium, which confirm CLS as a new
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source of ATM (Haase et al., 2014). Inflammatory state of obesity with progressive immune cell infiltration into AT plays a key role in metabolic disorders which are linked to obesity. In Obesity the production of adipokines are increased, which leads to inflammation of adipose tissue by extensive macrophages infiltration. Therefore adipokines become important role in the control of immune cells infiltrating AT.
Adipocytes share their microenvironment with multiple cell types, such as stromal-vascular
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cells (SVF), blood vessels, lymph nodes and nerves that interact to coordinate adipose functions (Hausman et al., 2001). This crosstalk between adipocytes and macrophages establishes and maintains the chronic inflammation state in obese AT through persistently recruiting new macrophages/monocytes from circulation. Adipokines and chemokines are
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key mediators linking the adipocytes and ATMs and regulating AT inflammation. Obesity not only recruits more macrophages, but also upregulates the expression of chemokines and
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their receptors in AT from obese mice and humans (Bai and Sun, 2015). Time course studies in rodents have shown that, under high fat diet conditions, almost 80% of the adipocytes in the epididymal (visceral) AT died and were replaced within a few weeks (Strissel et al., 2007). Human studies estimate that the lifespan of a SC adipocyte in humans is about 10 years (Spalding et al., 2008). Interestingly, BMI and weight loss do not alter the adipocyte turnover rates indicating that adipocyte number is tightly regulated, static during adulthood and the relative rates of adipocyte death seems to be equal between lean and obese. Often, obese individuals have more adipocytes; therefore the absolute number of dead or dying adipocytes at any time point is higher and could contribute to the chronic inflammatory state.
ACCEPTED MANUSCRIPT 5. Microbiome and obesity Changes in microbiota play a potential role in body weight regulation, development of metabolic disorders and obesity (Cox et al., 2015; Rosenbaum et al., 2015; Villanueva-Millan et al., 2015). Mechanisms how the composition of gut microbiota influences the development of obesity are barely understood, but intestinal microbiome is beginning to be recognized as
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one of the major important risk factors of obesity. The human gut microbiota consists of trillions of microbial cells and is dominated by four phyla (Actinobacteria, Firmicutes, Proteobacteria, Bacteriodetes), which varies between different body sites and among individuals depending on diet, stress, medication, geographical location and other factors (Bailey, 2014; Hamady and Knight, 2009; Morgan et
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al., 2013). Highest number of microorganisms has been observed in the intestinal tract, which comprises more than 10.000 different phylotypes (Harris et al., 2012). The microbiota
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may be regarded as an entero-endocrine organ, because it is able to change the production of molecules that affect energy metabolism including weight gain, weight loss and fat mass storage (Tehrani et al., 2012). In a study by Elli et al. fecal microbial profiles of obese subjects and their lean relatives were compared and the existence of a kind of “familial fingerprint” of the intestinal bacteria was concluded, because the core intestinal flora was family specific (Elli et al., 2010). The homology of the intestinal microbiota was stronger between blood-related subjects than between individuals with identical phenotypes (Elli et al.,
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2010). Study of Turnbaugh et al. confirmed the homology by the result that intestinal bacterial phyla were much closer in blood-related individuals than in unrelated subjects, which was independent from body weight (Turnbaugh et al., 2009). Possible mechanisms of the impact from intestinal microbiome to obesity include low-grade
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inflammation, energy expenditure and storage and hormonal regulation between the intestinal microbiome and the host. Several mice studies have shown that obese mice have
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significant increased body fat through the increased capacity of the microbiome to harvest energy from diet (Ley et al., 2005; Turnbaugh et al., 2006). Further, the authors demonstrated that colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota' (Ley et al., 2005; Turnbaugh et al., 2006). Studies based on gut microbiome exhibit correlations between the composition of commensal bacteria residing in the human gut and the development of obesity and insulin resistance (Turnbaugh et al., 2009; Zhang et al., 2013). An experimental study, which transplanted fecal microbiota from adult twin pairs discordant for obesity into germ-free mice, replicated BMI differences of the twins in mice (Ridaura et al., 2013). These results emphasize the strong microbiota-by-diet interaction (Ridaura et al., 2013). Investigating the effect of microbiota composition change from recipients with metabolic syndrome that obtained intestinal microbiota from lean donors showed that
ACCEPTED MANUSCRIPT increased gut microbiota diversity is associated with improved insulin resistance (Vrieze et al., 2012). Obese Individuals with higher microbial gene richness present more low-grade inflammation and insulin resistance than obese subjects with lower microbial richness (Cotillard et al., 2013). Studies in mice revealed that increased intestinal permeability of individuals with obesity results in migration of bacteria into AT, which leads to inflammation and insulin resistance.
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The presence of bacteria in human adipose tissue and underlying mechanisms leading to the development of insulin resistance is still remaining unclear. Gut microbiota is an additional contributing factor to the pathophysiology of obesity.
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6. Vitamin D action in adipocytes
Vitamin D is a micronutrient required for the growth and development of human bodies. AT is
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a reservoir for vitamin D (about 60% of total vitamin D) in human subjects and rats (Blum et al., 2008). Interestingly, visceral fat contains about 20 % more vitamin D than subcutaneous AT (SAT) (Beckman et al., 2013). Several studies have demonstrated that vitamin D deficiency is closely associated with not only total fat content, but also the specific pattern of fat distribution. Sorkin et al. and others demonstrated a negative correlation between serum vitamin D levels and visceral fat area (Sorkin et al., 2014; Thompson et al., 2016).
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Interestingly, research showed that Vitamin D affects directly the expression of the appetite regulating hormone, leptin (Kong et al., 2013). Vitamin D binds its cognate receptor, the vitamin D receptor (VDR), to exert its biological functions. VDRs are expressed in adipocytes. In adipocytes, vitamin D appears to inhibit the active form of adipogenic
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transcription factors and fat accumulation during the differentiation phase (Ding et al., 2012). Moreover, since there are Vitamin D Response elements (VDREs) in the insulin gene, it is proposed that vitamin D modulates insulin synthesis in the pancreatic beta cells as well
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(Maestro et al., 2003). Vitamin D insufficiency leads to activation of phospholipase C in adipocytes, which, in turn, leads to an increase in intracellular calcium. The increased calcium flux in adipocytes, which stimulates fatty acid synthase, may increase lipogenesis and inhibit lipolysis (Zemel, 2002). Vitamin D may increase peripheral insulin action by stimulating the expression of insulin receptors, which subsequently leads to improvement of obesity and obesity related disorders, such as fatty liver (Takiishi et al., 2010). Other targets of vitamin D action are immune cells, and control function of maturation and/or growth of T cells, B cells and dendritic cells, to generate a more tolerant and anti-inflammatory response profile (Almerighi et al., 2009; Chen et al., 2007; Jeffery et al., 2009; Verma and Hussain, 2016). Some human studies have provided strong support for beneficial impacts of VD supplementation, but still well-designed clinical studies are urgently needed to demonstrate
ACCEPTED MANUSCRIPT real valuable utility for limiting obesity (Landrier et al., 2016). Taken together, there is strong evidence that Vitamin D deficiency and VDR expression in adipocytes is linked to obesity. 8. Conclusion In summary of the current literature, the physiologic functions attributed to adipose tissue are expanding. WAT is characterized by its capacity to adapt and expand in response to surplus
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energy through processes of adipocyte hypertrophy and/or recruitment and proliferation of precursor cells in combination with vascular and extracellular matrix remodeling. AT undergoes a continuous remodeling process in a fat-depot specific manner, that normally maintains tissue health, but may spin out of control and lead to adipocyte death in
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association with the recruitment and activation of macrophages, and systemic insulin resistance. Changes in microbiota and vitamin D status seem to play a potential role in AT
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function and body weight regulation.
ACCEPTED MANUSCRIPT Conflict of interest The authors declare no conflict of interest.
Acknowledgements
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We apologize to those whose work was not directly cited because of space constraints. We thank Dr. Henrike Heyne for reading an earlier version of the manuscript and providing useful comments. Funding
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This work was supported by SFB1052 B4 (to NK), FKZ01E01501 (to NK) and 82DZD00601
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(to AK).
Figure legend
Figure 1. Overview of Obesity-mediated adipose tissue remodeling. Physiological functions of Vitamin D and microbiome changes contribute to obese white adipocytes.
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CLS = crown-like structures, ATMs = adipose tissue macrophages
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Figure1 . Overview of Obesity-mediated adipose tissue remodeling
Vitamin D
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Microbiome
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Pro-inflammation
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Obese adipocyte Adipokine imbalance CLS, ATMs ECM imbalance Pro-inflammatory stage
Adipogenesis Fat accumulation Adipokine secretion Leptin secretion Apoptosis