Adipose tissue fibrosis in obesity and after drastic weight loss

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Extra cellular matrix: composition and pathophysiology

The protein composition and dynamics of the extracellular matrix (ECM) is crucial for the functioning of adipocytes. Adipocytes, as endothelial cells, are surrounded by a thick ECM referred to as basal lamina (Pierleoni, Verdenelli et al. 1998). While a strong ECM is the principal function of bone and cartilage, the basal lamina in adipocytes may be more important for cell survival. ECM components of adipocytes have been studied mostly by immunohistochemistry and RT-PCR. These components are represented by different types of collagens and collagen-related proteins, such as cell surface integrins, fibronectin, elastin, laminin, proteoglycans, tenascin-C, several matrix metalloproteinases (MMP), tissue inhibitors of matrix metalloproteinases (TIMP) and some more. It is important to note that some of these proteins are not produced only by the adipocytes, but also by cells of the stromal vascular fraction containing preadipocytes, capillary endothelial cells, infiltrated monocytes/macrophages, and a population of multipotent stem cells (Mariman and Wang 2010). More than 30 collagens are known, but the most present in adipose tissue Col 1, 4 and 6 are also the best characterized (Nakajima, Yamaguchi et al. 1998) (Khan, Muise et al. 2009). Specific collagens and their regulators have a role during the physiological process of adipogenesis, when the adipocyte changes the cell shape from fibroblastic to spherical shape, changing in level and type, in parallel with level of cytoskeletal components (Pierleoni, Verdenelli et al. 1998), (Spiegelman and Ginty 1983). Obviously, ECM components intervene during the adaptive response of adipose to cellular alterations due to expansion/reduction as well. In obesity, in both rodents and humans, expanding AT displays increases in components of the ECM, including collagen VI and thrombospondin, parallel to considerable tissue remodeling and increase in inflammatory macrophages (Varma, Yao-Borengasser et al. 2008) (Spencer, Yao-Borengasser et al. 2010) (Pasarica, Gowronska-Kozak et al. 2009) (Divoux, Tordjman et al. 2010) (Sun, Tordjman et al. 2013). ECM composition and ECM regulatory proteins, such as glycoconjugates, important in influencing the rate of assembly, size, and structure of collagen fibrils, are currently studied in conditions of broad biomedical importance from arthritis to tissue repair, from tumor invasion to cardiovascular disease (Kadler, Hill et al. 2008).

Extra cellular matrix: a dynamic structure

Next to protein composition of ECM, its dynamics is of crucial importance for adipocyte functioning. ECM is in fact under constant turnover. During ECM remodeling, physiological or pathological, proteins have their specific roles of mediating the balanced result between constructive and destructive enzymes together with their enhancers and inhibitors. An example of this complemented balance can be given by lumican and decorin. Despite the fact that both are collagen cross-linking proteins, these two enzymes have been found to have opposing roles in fibrosis (Pasarica, Gowronska-Kozak et al. 2009) (Khan, Muise et al. 2009). Another classical example important for ECM regulation is represented by the balance between MMPs and TIMPs. In vivo research on MMPs provides contradicting results, indicating the complexity of MMP activity that depends on relative concentrations of different MMPs, their substrate specificity, and the activity of their inhibitors (TIMPs), (TIMPs), and the fibrinolytic system comprising plasminogen/plasmin and their activators (tissue-type plasminogen activator and urokinasetype activator (Christiaens, Scroyen et al. 2008) (Demeulemeester, Collen et al. 2005) (Lijnen, Maquoi et al. 2002). Another interesting ECM component is a membrane-anchored metalloproteinase MMP14, which was proved to be important for a proper WAT development using null mice (MT1-MMP). Using null mice, MT1-MMP was proved to be important for a proper WAT development (Chun, Hotary et al. 2006). Null mice were in fact lipodystrophic and in a 3-dimensional (3-D) ECM context, during adipocyte maturation, MT1-MMP was required to modulate pericellular collagen rigidity. However, besides the physiological activity of ECM, there are pathological conditions in which ECM accumulation is deregulated, as in obese WAT. In that case the same protease, MT1-MMP, cannot properly control the formation of a rigid network of collagen fibrils and consequently contribute to restrain adipocyte expansion. Other ECM components can participate to pathological remodeling and tissue stiffening. For example lysyl oxidase (Lox) and the LOX family of secreted amine oxidases have been observed increased in many fibrotic diseases due to their role in rigid cross-linking of elastin and collagens (Sivakumar, Gupta et al. 2008) (Kagan and Li 2003) (Csiszar 2001) (Smith-Mungo and Kagan 1998). Finally, it is important to acknowledge the role of proteases in contributing to tissue remodeling through a variety of different mechanisms (Cheng, Shi et al. 2012). For example it has been shown that cathepsins can be secreted within the extracellular spaces and directly affect collagen turnover and degradation, as it is the case for cathepsin S (Shi, Munger et al. 1992). The cathepsin biology and their significance in ECM remodeling in the development and progression of various pathological conditions continue receiving scientific attention in search of successful therapeuctics.

Adipose tissue fibrosis in obesity and after drastic weight loss

Fibrosis is the common pathological outcome of many chronic inflammatory diseases in the context of the liver, lung, kidney and several other tissues. The term fibrosis has been defined as the formation of fibrous tissue as a reparative or reactive process. In the “healthy” adipose tissue, remodeling is a complex process characterized by dynamic changes in cellular composition and function (Itoh, Suganami et al. 2011). Instead until now fibrosis in WAT has been explained as the initial response to adipocyte hypertrophy. In particular, our team demonstrated the ECM accumulation in human obesity through the method of picrosirius red staining of WAT (Henegar, Tordjman et al. 2008), and also the importance of macrophage-preadipocyte interactions in WAT fibrosis development or maintenance (Keophiphath, Achard et al. 2009). As the collagen content increases, the overall rigidity of adipose tissue also increase.
This rigidity in WAT, as in other tissues, may impair angiogenesis, so that adipocytes surrounded by
fibrotic tissue cannot be adequately oxygenated, becoming more susceptible to necrosis (Trayhurn,
Wang et al. 2008). Signals emerging from hypertophic (dysfunctional) or dying adipocytes could influence the formation of fibrous structure around the cells. Fibrosis in WAT has been presented as the hallmark response of metabolically challenged adipocytes and in particular collagen 6 has been shown to have a key role in limiting WAT expansion and consequently influencing insulin sensitivity (Pasarica, Gowronska-Kozak et al. 2009) (Khan, Muise et al. 2009). Adipose tissue inflammation and immune cell accumulation have been observed in obesity as well as during dynamic weight loss (due to caloric restriction or fasting), in relation with increased lipolytic activity (Kosteli, Sugaru et al. 2010). However, differently from obesity, adipose tissue remodeling and the potential contribution of WAT macrophages in the process has not been fully investigated after drastic weight loss (Kosteli, Sugaru et al. 2010). In 2010, our team showed that human WAT fibrosis, in particular peri-cellular fibrosis, could be a process able to limit the lipolytic activity of adipocytes, possibly a mechanism preventing an excess weight loss after bariatric surgery (Divoux, Tordjman et al. 2010). During drastic weight loss, dysfunction or death in adipocytes is also found, as suggested by perilipin-negative adipocytes engulfed in fibrosis, similarly to what has been reported in obesity for the adipocytes surrounded by crown-like structures of macrophages (Cinti, Mitchell et al. 2005). Consequently WAT fibrosis could be a response to signals emerging from adipocytes within the specific inflammatory milieu. In this view, fibrosis is considered a pathologically deregulated healing response to inflammation-induced destruction and injury of tissue, as summarized in Figure 18. During obesity, dead adipocytes as identified by perilipin-negative staining are found surrounded by macrophages in crown-like structures (Cinti, Mitchell et al. 2005). After drastic weight loss, perilipin-negative adipocytes are also found engulfed in fibrosis (Divoux, Tordjman et al. 2010). Consequently WAT fibrosis could be a response to signals emerging from dead adipocytes.

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A cross-road between metabolism and immunity

In our body there are “organs” considered key for their plastic endocrine functions, like the above presented adipose tissue and the more recently identified gut microbiota (Brown and Hazen 2015). Both systems are exposed to nutritional fluctuation and participate in maintaining body homeostasis converting dietary molecules into hormonal (WAT) and hormone-like (metabolites from microbiota) signals. Excess or defects of energy flux can dysregulate the delicate balance of interactions between metabolism and immunity in both “organs” (Exley, Hand et al. 2014) (Kau, Ahern et al. 2011).
In the context of metabolic disorders, adipose tissue has been particularly studied, being at the junction of immune and metabolic co-regulation. WAT efficiently monitors metabolic homeostasis through the release of adipokines. These adipocyte-specific secretory proteins are now recognized participants in the regulation of immune responses through their own pro- and anti-inflammatory activities (Ouchi, Parker et al. 2011). In addition, the intrinsic presence of various immune cells, innate and adaptive, tightens up the immune-metabolic role of adipose tissue (Makki, Froguel et al. 2013). However, the interest in gut microbial communities has been rapidly increasing recently due to the impact that microbial metabolites can have in physiological and/or pathological processes. Adipose tissue and host receptors have the primary function of establishing the connection between metabolic and immune systems.

Table of contents :

A. Contexte du projet
1. Les altérations du tissu adipeux dans les maladies métaboliques
2. Les altérations de l’intestin et du microbiote intestinal dans les malacies métaboliques
B. Objectifs et principaux résultats
1. Etude I: L’adaptation du tissu adipeux à un stress métabolique induit par l’isomère trans10, cis12 de l’acide
linoléique engage des macrophages anti-inflammatoires.
Résultats complémentaires
2. Etude II: Effet de deux souches de probiotiques sur la prise de poids et le statut glycémique chez la souris
rendue obèse par un régime hyperlipidique.
3. Conclusion générale
C. Contribution à des publications présentées en annexe
1. Publication 2
2. Publication 3
3. Publication 4
A. Metabolic diseases
1. Metabolic syndrome
2. Overweight and obesity
3. Diabetes mellitus type II
4. Lypodistrophic syndromes
B. Metabolic diseases: the available models
1. Mouse models of obesity
Leptin-deficient mice
Leptin receptor-deficient mice
High fat diet-induced obesity
2. Lipodystrophic mouse models
PPARγ-deficient mice
Transgenic aP2-SREBP-1c mice
A-ZIP/F-1 mice
C. The metabolic organs
1. Adipose tissue: functions and dysfunctions
Metabolic and endocrine functions
Adipose tissue plasticity
Adipose tissue immunity and inflammation
2. Liver: functions and dysfunctions
Metabolic functions
Non-alcoholic fatty liver disease
3. Intestine: functions and dysfunctions
4. Muscle: functions and dysfunctions
D. Metabolic diseases: Innate and adaptive immunity
1. Innate immunity
Mast cells
Dendritic cells
Natural killer cells
2. Adaptive immunity
Natural killer T- cells
Helper T- cells
Gamma delta T- cells
B lymphocytes
3. Immunological memory
4. Immunity and inflammation: chemokines and other recruitment factors
E. Adipose tissue: cellular and structural alterations in obesity
1. Adipocytes: functions and dysfunctions
2. Extra cellular matrix: composition and pathophysiology
3. Extra cellular matrix: a dynamic structure
4. Adipose tissue fibrosis in obesity and after drastic weight loss
F. A cross-road between metabolism and immunity
1. Nutrient-sensing and metabolism
2. Toll like receptors (TLRs)
3. G-protein coupled receptors (GCPRs)
G. Conjugated fatty acids: the t10,c12-CLA model
1. Conjugated fatty acids
Conjugated linoleic acid (CLA)
CLA isomers: experimental effects
2. A murine model of lypoatrophic syndrome: t10, c12 CLA
Adipose tissue and t10, c12 CLA
Liver and t10, c12 CLA
Intestine and t10, c12 CLA
Pancreas and t10, c12 CLA
Muscle and t10, c12 CLA
Immunity and t10,c12-CLA
H. Intestinal microflora and metabolic diseases
1. Microbiota composition: functions and dysfunctions
2. Symbiosis between the host and the microbiota
3. Microflora modulation: potential therapeutics
4. Effectiveness of probiotic and prebiotic interventions
A. Hypothesis and models used
B. Study I: Adipose tissue plasticity in response to short-term trans 10, cis12 conjugated linoleic acid (CLA)
adimistration in mice
D. Complementary results of study I
1. WAT nutrient-sensing in response to CLA
2. WAT plasticity in response to CLA
3. Effects of CLA adminsitration on transcription factors of the IRF family
4. Effects of CLA administration on the intestine: barrier function
5. Effects of CLA administration on the intestine: microbiota
6. Reversibility: permeability and intestinal ecology
7. Effects of CLA administration on the liver
8. Are the CLA effects on WAT indirectly mediated by macrophages?
E. Conclusions
A. Purpose
B. The experimental model
1. Methods
2. Effects of probiotics on body weight and adiposity
3. Effects of probiotics on glycemic status
4. Effects of probiotics on plasma variables
C. Conclusions
A. Contribution of adipose tissue to metabolic deregulation
B. Adipose tissue plasticity and metabolic consequences
C. The future of probiotics to improve metabolic status?
D. Conclusions


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