Obesity has been linked to a low-grade state of systemic inflammation driven by adipose tissue, with Interleukin (IL)-6, IL-1, IL-8 and Tumour Necrosis Factor (TNF)- playing a major role and subsequently elevating acute phase proteins like C-Reactive Protein (CRP). This creates an inflammatory milieu that has both hypothetical and proven downstream effects. This review will provide an overview of our current knowledge of this pro-inflammatory condition, including how it affects hematologic parameters like platelet, red blood cell and white blood cell counts as well as thrombosis.

Pro-inflammatory State of Obesity

Macrophages and Adipose Tissue: Adipose tissue is a major source of inflammatory mediators, as demonstrated by a wealth of evidence [1]. The most prevalent form of adipose tissue is white, which contains a variety of cell types. The majority are adipocytes, but there are also adipose tissue macrophages, whose relative population size is correlated with the degree of adiposity [2]. According to estimates, up to 40% of the cells in adipose tissue in obese people are macrophages, compared to just 10% in thin people [3]. Furthermore, visceral fat has higher levels of macrophage infiltration than subcutaneous fat. Adipose tissue macrophages are likely bone marrow-derived circulating monocytes that invaded adipose tissue, despite reports that preadipocytes can act as macrophage-like cells [4]. Increasing concentrations of recombinant human leptin have been demonstrated to increase adhesion and transmigration of blood monocytes in a concentration-dependent manner, though all factors attracting immune cells into obese tissues are still not fully understood. Leptin and other chemokines, such as monocyte chemotactic protein-1 and leukotriene B49, also contribute to this.

Adipose Tissue and the Acute Phase Response

Increased production of acute phase proteins, primarily produced by hepatocytes, characterises the acute phase response that follows inflammatory conditions. These acute phase proteins play a number of different roles, including modulating inflammation, blocking proteases and scavenging free radicals. The majority of positive acute phase proteins are primarily regulated by IL-6, which also promotes the synthesis of serum amyloid A, c-reactive protein, haptoglobin, 1-antichymotrypsin, 1-antitrypsin, fibrinogen, complement component C3 and caeruloplasmin [5]. IL-6, IL-1, IL-8 and TNF-12 are examples of cytokines that human adipose tissue can independently manufacture and release and are known to be important inducers of the acute phase response. Although there is some indication that macrophages are the primary source of IL-6 and TNF-alpha which are produced from white adipose tissue, both adipocytes and macrophages contribute to the production of cytokines [6]. The entire list of acute phase reactants and inflammatory mediators found in obesity was compiled by Cottam et al. [3,7].

Obese people have serum and white adipose tissue levels of IL-6 and TNF- that are clearly elevated [8]. According to Mohamed-Ali et al. [13,9], the mass of adipose tissue throughout the body produces 15–35% of systemic IL-6. With weight loss, IL-6 and TNF- levels are also known to fall [10], especially after bariatric surgery [11]. Additionally, it has been observed that people with larger waist-to-hip ratios produce more IL-6 locally in adipose tissue [12]. In contrast to subcutaneous adipose tissue, a higher waist-to-hip ratio frequently denotes more visceral adipose tissue, which has been proven to have an elevated inflammatory status. This confirms the finding that omental adipose tissue releases IL-6 at a rate that is 2-3 times greater than that of its subcutaneous counterpart [13]. It is not unexpected that CRP elevation considerably correlates with the amount of body fat present [14] and also decreases with weight loss as IL-6 regulates CRP production. This correlation has been demonstrated to be stronger in women than in men. Even the adipose tissue itself may create CRP, according to some research [15].

Role of Cytokines and Adipokines

Inflammation is characterised by peripheral blood leukocytosis, which in obesity is probably caused by the chronic low-grade inflammatory condition described in detail above. Through a number of mechanisms, including demargination of intravascular neutrophils, acceleration of bone marrow neutrophil release and augmentation of bone marrow granulopoiesis, pro-inflammatory cytokines like IL-6 and IL-8 are major neutrophilia inducers of leukocytosis.

Leptin and other adipokines might possibly be involved. In obese Pima Indians, Wilson et al. [16] found a positive, albeit indirect, connection between fasting plasma leptin concentrations and white blood cell count. They discovered that plasma leptin concentration was significantly correlated with leukocyte count in overweight and obese subjects and that leptin (at high levels, but levels which are observed in obesity) significantly stimulated the appearance of granulocyte-macrophage colonies, the precursor for monocytes and granulocytes. In addition, they discovered that leptin levels in women were considerably greater than in men and this difference maintained even after correcting for BMI. A murine model has demonstrated that treatment with a synthetic fragment of leptin resulted in a two-fold increase in the number of hematopoietic stem cells with an associated increase in the number of granulocyte/macrophage colony-forming units produced by bone marrow cells. Furthermore, it has been demonstrated that human and mouse hematopoietic stem cells express the leptin receptor. It is evident that leptin regulates hematopoiesis through an indirect, multifactorial mechanism. Despite being classified as non-hematopoietic because they primarily differentiate into osteogenic, chondrogenic and adipogenic progeny, bone marrow mesenchymal stromal cells have been shown to be leptin receptor positive. These cells also directly express hematopoietic stem cell niche factors like stem cell factor and Cxcl12, indicating that they contribute to the organigram. 

In conclusion, leptin and other chemokines help bone marrow-derived monocytes migrate into adipose tissue, which leads to an increase in IL-6, TNF- and other cytokines in obesity. The following increase in acute phase proteins, such as CRP, accounts for the persistent low-grade inflammation that results, which in turn affects hematologic parameters and the risk of thrombosis, as will be detailed later. It is unclear from the available literature whether there is a cycle at work in which bone marrow-derived monocytes are likely both the source and the target of pro-inflammatory signals. Further study is necessary on this subject since it might reveal additional therapeutic targets that are upstream of the acute phase response.

1. Banks, R. et al. "The acute phase protein response in patients receiving subcutaneous IL-6." Clinical & Experimental Immunology, vol. 102, no. 1, 1995, pp. 217–223.

2. Calabro, P. et al. "Release of C-reactive protein in response to inflammatory cytokines by human adipocytes: Linking obesity to vascular inflammation." Journal of the American College of Cardiology, vol. 46, no. 6, 20 Sept. 2005, pp. 1112–1113.

3. Cottam, D.R. et al. "The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: Implications and effects of weight loss." Obesity Surgery, vol. 14, no. 5, May 2004, pp. 589–600.

4. Cousin, B. et al. "A role for preadipocytes as macrophage-like cells." FASEB Journal, vol. 13, no. 2, Feb. 1999, pp. 305–312.

5. Curat, C.A. et al. "From blood monocytes to adipose tissue-resident macrophages: Induction of diapedesis by human mature adipocytes." Diabetes, vol. 53, no. 5, May 2004, pp. 1285–1292.

6. Fain, J.N. et al. "Comparison of the release of adipokines by adipose tissue, adipose tissue matrix and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans." Endocrinology, vol. 145, no. 5, May 2004, pp. 2273–2282.

7. Fantuzzi, G. "Adipose tissue, adipokines and Inflammation." Journal of Allergy and Clinical Immunology, vol. 115, no. 5, May 2005, pp. 911–919.

8. Farhangi, M.A. et al. "White blood cell count in women: Relation to inflammatory biomarkers, haematological profiles, visceral adiposity and other cardiovascular risk factors." Journal of Health, Population and Nutrition, vol. 31, no. 1, Mar. 2013, pp. 58–64.

9. Ford, E.S. "Body mass index, diabetes and c-reactive protein among U.S. adults." Diabetes Care, vol. 22, no. 12, Dec. 1999, pp. 1971–1977.

10. Herishanu, Y. et al. "leukocytosis in obese individuals: possible link in patients with unexplained persistent neutrophilia." European Journal of Haematology, vol. 76, no. 6, June 2006, pp. 516–520.

11. Kern, P.A. et al. "The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss and relationship to lipoprotein lipase." Journal of Clinical Investigation, vol. 95, no. 5, May 1995, pp. 2111–2119.

12. Kopp, C.W. et al. "Weight loss reduces tissue factor in morbidly obese patients." Obesity Research, vol. 11, no. 8, Aug. 2003, pp. 950–956.

13. Mohamed-Ali, V. et al. "Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo." Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 12, Dec. 1997, pp. 4196–4200.

14. Park, H.S. et al. "Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-Alpha and IL-6." Diabetes Research and Clinical Practice, vol. 69, no. 1, July 2005, pp. 29–35.

15. Weisberg, S.P. et al. "Obesity is associated with macrophage accumulation in adipose tissue." Journal of Clinical Investigation, vol. 112, no. 12, Dec. 2003, pp. 1796–1808.

16. Wilson, C.A. et al. "Relationship of the white blood cell count to body fat: Role of leptin." British Journal of Haematology, vol. 99, no. 2, Nov. 1997, pp. 447–451.