"Can Soluble-CD163 Discriminate Between Healthy and Unhealthy Obese Individuals?"
Condition: Obesity; Insulin Resistance; Type 2-diabetes; Inflammation
MeSH terms: Obesity; Insulin Resistance; Inflammation
Study type: Observational

Summary: 
      CD163 is a membrane bound receptor primary expressed in monocytes and macrophages. A soluble
      variant of CD163 (sCD163) is present in plasma and is elevated in pathological condition
      activating the monocyte-macrophage system. Recently sCD163 is associated with various
      inflammatory conditions, ex. adipose tissue inflammation and very recently to be a rather
      strong predictor of the development of type 2-diabetes. Only a subset of obese individuals
      develops insulin resistance, type 2-diabetes and related diseases. These healthy obese
      subjects are characterized of less adipose tissue inflammation and less insulin resistance as
      compared to unhealthy obese individuals. Consequently it would be of great importance to
      develop markers that could discriminate between healthy and unhealthy obese subjects. Aim: To
      investigate whether macrophage CD163 is involved in adipose tissue inflammation in obesity
      and thereby to the metabolic complications of metabolic syndrome. To investigate how sCD163
      is regulated by metabolic factors such as obesity, fat distribution, weight loss and diet.
      Methods: Intervention study. 45 morbidly obese subject approved to gastric by-pass. Blood
      samples, MR-spectroscopy, DXA, weight control and fat biopsy are taken before and 12 month
      after surgery. Correlations studies: to investigate the influence of diet and weight loss on
      CD163 and sCD163. Perspective: To study the role of macrophages infiltration and activation
      for adipose tissue inflammation and to determine whether the macrophage marker, s-CD163,
      together with other markers will be able better to identify obese individuals who are at
      increased risk for developing complications such as diabetes
    

Detailed description: 
      It is recognized that low grade inflammation is a key player in the development of
      atherosclerosis and insulin resistance (Haslam, James 2005). Circulating levels of
      inflammatory markers such as high sensitive C-reactive protein (hsCRP) and interleukin (IL)-6
      are found to be increased in subjects with cardiovascular disease (CVD) and type 2-diabetes
      (Dandona, Aljada & Bandyopadhyay 2004). We and others have shown that obesity, and in
      particular abdominal obesity, is associated with persistent increased level of inflammatory
      markers (Bruun et al. 2007, Christiansen et al. 2010a) . Thus this low grade of inflammation
      may represent "the common soil" for the pathogenesis of atherosclerosis and insulin
      resistance and represent the link between these metabolic disturbances and obesity.

      Besides its function as a storage organ, the adipose tissue (AT) exerts a complex role in the
      organism. In obesity the adipose tissue is infiltrated by an increased amount of macrophages,
      and particular these macrophages express and release a wide range of hormones and cytokines,
      collectively called adipokines, which biological functions are shown to include involvement
      in glucose metabolism, lipid metabolism, adipocyte differentiation, immunity, vasculature and
      neuron development and eating behavior (Trayhurn, Wood 2004).

      Among the adipokines expressed in the AT are pro-inflammatory cytokines as TNFα, IL-6,
      pro-inflammatory chemokines as IL-8, MCP-1, MIP1α, thrombotic factors as plasminogen
      inhibitor 1 (PAI-1), and AT specific proteins as adiponectin and leptin.

      Hypertrophied adipocytes, as seen in obese subjects and associated with insulin resistance
      are shown to display a distinct gene expression of inflammatory markers compared to small
      human adipocytes and it is shown that adipocyte size is an important determinant of adipokine
      secretion. Moreover an positive association between the grade of obesity and the expression
      of pro-inflammatory cytokines as TNFα, IL-6, IL-8, has been found whereas and an inverse
      association between adiponectin and obesity has been reported (Kern et al. 2003, Bruun et al.
      2003).In accordance with these observations, we have found the AT expression of MCP-1 was
      up-regulated in obese subjects (Christiansen, Richelsen & Bruun 2005) whereas the AT
      expression of adiponectin in obese subjects (mean BMI 40 kg/m2 ) was found down-regulated
      with 50% as compared to lean subjects (mean BMI 22 kg/m2) (Christiansen et al. 2010b).

      Thus, adipose tissue inflammation resulting in dysfunction of the adipose tissue may be the
      important factor relating obesity to insulin resistance, metabolic syndrome, diabetes, and
      cardiovascular diseases.

      CD163:

      CD-163 is a membrane bound receptor primary expressed in monocytes and macrophages. CD163 was
      originally described as a hemoglobin scavenger receptor since it is involved in removing
      hemoglobin released from ruptured red blood cells (Moestrup, Moller 2004). A soluble variant
      of CD-163 (s-CD-163) is present in plasma and is elevated in pathological condition
      activating the monocyte-macrophage system.

      Recently s-CD-163 is associated with various inflammatory conditions (Moestrup, Moller 2004),
      and very recently to be a rather strong predictor of the development of type 2 diabetes in a
      large Danish cohort (Moller et al. 2011). Thus, s-CD-163 may be a marker both related to
      inflammation as well as to metabolic conditions maybe linking low grade inflammation and
      metabolic abnormalities, and furthermore, may be a marker of the obese state with
      complications.

      Only a subset of overweight and obese individuals develops insulin resistance, type 2
      diabetes and related diseases (Stefan et al. 2008, Bluher 2010). These "healthy" obese
      subjects are characterized of less adipose tissue inflammation and less insulin resistance as
      compared to unhealthy obese individuals. Consequently it would be of great importance to
      develop markers or predictors that could discriminate between "healthy" and unhealthy obese
      subjects in order to made a better selection for more invasive treatment such as e.g.
      surgery, pharmacotherapy etc.

      Research Plan:

        1. Is CD163 pathophysiologically involved in adipose tissue inflammation in obesity?
           Adipose tissue (AT) is taken from various regions in lean to very obese subjects - from
           either subcutaneous fat biopsies (lean subjects), surgery (obese subjects - BMI> 30),
           and from bariatric surgery (gastric bypass) in the very obese subjects (BMI > 40) - both
           subcutaneous and visceral AT are investigated in parallel in the very obese individuals.

           In the adipose tissue the amount of macrophages will be determined by both biochemical
           (e.g. CD68) and microscopically methods (immunohistochemistry). Moreover, the gene
           expression (PCR) and protein (Western blot) of CD163 will be detected in AT and related
           to the expression and protein of a number of other proinflammatory adipokines.

        2. Is s-CD163 a marker of adipose tissue inflammation and metabolic disturbances? Blood
           samples from the individuals in project 1 will also be obtained and s-CD163 measured (in
           house sandwich ELISA kit (Moller, Hald & Moestrup 2002)). These values will be related
           to the amount of macrophages in AT and the expression of CD136 in AT. Moreover, the
           insulin sensitivity determined by the HOMA model will be performed, and s-CD163 related
           to the HOMA score.

        3. Is s-CD163 affected by weight loss, and dietary changes ( e.g. the effect of fructose
           (proinflammatory) and the effect of resveratrol (antiinflammatory)?

             1. Weight loss will be induced by bariatric surgery (bypass) in very obese subjects
                (BMI > 40). S-CD163 and changes in insulin sensitivity (HOMA) and other
                inflammatory markers (e.g. hsCRP, IL-6, TNF, MCP-1, adiponectin etc.) will be
                measured before and after 6 and 12 months after surgery. From power calculations it
                is planned to include 45 very obese subjects in this study - half of them with type
                2 diabetes.

             2. We have performed dietary investigations with fructose (soft drinks taken for 6
                months in 50 overweight and obese subjects) which induces ectopic fat accumulation
                in the liver determined by MR-spectroscopy and insulin resistance, and dietary
                intervention with resveratrol which reduces liver fat and has antiinflammatory
                effects. In frozen plasma samples from these studies s-CD163 will be measured in
                order to get insight in the dietary effect of fructose and resveratrol on this and
                related markers.
    

Intervention name(s): gastric bypass
Intervention type(s): Procedure
Intervention description(s): Low grade inflammation in adipose tissue before and after gastric bypass
Other intervention name(s): Soluble-CD163
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The cohorts will be selected from the department of Endokrinology at Aarhus University
        Hospital.
      
Biospecimen description: 
      Blood, adipose tissue
    
Keywords: Obesity; Soluble-CD163; Macrophage; Inflammation