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New Therapeutic Avenues

The interplay between metabolic dysregulation and inflammation can have an important role to play in our understanding of a variety of chronic conditions – particularly obesity-related diseases – and open up new pathways for the development of more effective therapeutics.

Adipose tissue has evolved from simply being a means for storing energy that can be released in times of need. The intrinsic biochemical mechanisms present in this tissue can provide calories, in the form of triglycerides and free fatty acids, in response to metabolic demands. It is clear, however, that humans in Western cultures have overburdened this process to a great extent. Accumulation of massive amounts of body fat in adipose tissues has led to an epidemic of obesity.With obesity comes an associated morbidity and mortality due to diabetes, cardiovascular disease, cancer and pulmonary disorders. The problem has become so severe that the current generation of Americans may be the first to have a lifespan shorter than their parents.

The association between obesity and these disorders has led to the search for a common mechanism to explain these observations. Over the past several years it has become increasingly clear that the accumulation of vast amounts of fat in adipose tissue is linked to significant alterations in the immune system. Understanding the interplay between immune regulation and metabolic derangement in the form of insulin resistance, metabolic syndrome and Type 2 diabetes (T2D) has taken on greater significance and has led to a concept that has been referred to as immunometabolism (1). This article is intended to provide a broad overview of some of the more pertinent findings that explore the relationship between intermediary metabolism and immune regulation.

The Inflammatory Response

The concept of inflammation conjures up a vision of host defences designed to ward off invading pathogens or insults. This system relies on a delicate balance between effector cells, humoural responses and regulatory cells, which are designed to quickly resolve threats to the host with minimal residual damage. The inflammatory response to invading pathogens is associated with large systemic increases in cytokines, chemokines and acute phase proteins such as C reactive protein (CRP), haptoglobin, fibrinogen, plasminogen activator inhibitor (PAI), and serum amyloid. In addition, large numbers of leukocytes are recruited to the site of inflammation, followed by some degree of resolution or repair, such as fibrosis.

The inflammatory response induced by obesity retains many of these features, presented as a low level, chronic process, essentially raising the steady state level of many of these key players. For example, childhood obesity is a risk factor for the development of metabolic derangements and asthma, and obese children as young as three years of age show increases in many markers of inflammation.Many of these same markers are elevated in patients with T2D. Other studies have shown that elevated levels of IL-1β, IL-6 and CRP can predict the development of T2D in populations. A number of clinical trials are ongoing or have been completed that attempt to treat diabetes using an anti-inflammatory approach. Three approaches – using salicylates, anti-IL-1 and anti-TNF agents – have been attempted.While the data obtained with agents designed to neutralise TNF have not demonstrated improvement in blood glucose levels,  interference with the IL-1 signalling pathway and the use of salicylates have shown decreases in blood glucose in small clinical trials (2,3).

The promising use of anti-cytokine therapy leads one to consider the source of those cytokines and how they might contribute to metabolic derangements such as insulin resistance and T2D. In addition to leukocytes, adipose tissue itself has a considerable repertoire of secretory products, collectively known as adipokines, which play important roles in energy metabolism and the inflammatory process. Approximately 50 different adipokines have been identified. Some of these, such as TNF-α, IL-6, IL-18 and resistin are pro-inflammatory, while others, such as adiponectin are antiinflammatory. The adipokines profile for visceral fat is different from that of subcutaneous fat. Further, the adipokine secretory profile for a given tissue bed can be modified by structural changes to that tissue or by diet.

Adiponectin: A Promising Candidate

Adiponectin has emerged as an important player in immunometabolism. It is synthesised by adipocytes and has insulinsensitising and anti-inflammatory properties, and circulates in normal humans at relatively high levels. Surprisingly, adiponectin levels inversely correlate with visceral fat accumulation. In patients with T2D, adiponectin levels are decreased, and high levels of adiponectin predict decreased incidence for the development of T2D.

Studies in genetically modified mice have provided a good deal of insight into the role of adiponectin in human health and disease. As mentioned, obese individuals have lower levels of adiponectin and are also at increased risk for coronary artery disease, insulin resistance, hypertension and stroke. Inactivation of the adiponectin gene in mice results in animals which appear phenotypically normal, but are prone to developing more severe complications when exposed to certain stresses. For example, animals deficient in adiponectin (APN-KO) show a decreased ability to unload cholesterol from lipid-laden macrophages (4). APN-KO animals are also more sensitive to ischemia-reperfusion injury and to cardiac pressure overload (5-7). Further, crossing APN over-expressing animals with ob/ob mice normalises glucose tolerance and decreases insulin, yet the animals are very obese (8). Interestingly, humans exhibiting a metabolically healthy obese phenotype have levels of adiponectin that are within the range found in individuals with normal BMI (9). These data suggest that the quality of the adipose tissue may be as important as the quantity of adipose tissue in the determination of metabolic abnormalities.

So what determines the quality of adipose tissue? A good deal of attention is now being paid to the inflammation state of fat in metabolic dysfunction, specifically with respect to macrophage phenotypes in fat.Macrophages can be classified on the basis of their activation state. Classically activated macrophages, denoted as M1, exhibit a proinflammatory phenotype, whereas, alternatively activated macrophages (M2) are polarised to produce the anti-inflammatory cytokine IL-10 and downregulated levels of proinflammatory cytokines. Inspection of fat pads from obese and lean animals reveals a higher level of M1 macrophages in obese animals, whereas lean animals present with more M2 macrophages. M1 macrophages are associated with classical inflammatory responses while M2 macrophages are associated with the repair of injured tissue. By extension,M1 macrophages are consistent with insulin resistance while M2 macrophages might be thought of as protective. In line with this is the observation that APN-KO mice show a polarisation toward the M1 phenotype, and APN over-expressing animals show far fewer macrophages in their adipose tissue.

If alternatively activated macrophages (M2) are the key to regulating insulin sensitivity, then what regulates the M2 phenotype? A recent paper by Wu et al provides evidence that eosinophils play a key role in regulating the M1/M2 polarisation (10). The M2 phenotype is driven by IL-4 and IL-13, and cultured adipocytes have the ability to produce these cytokines.Wu and colleagues have demonstrated that eosinophils are the major IL-4 expressing cells in mouse adipose tissue and that this cell type is responsible for maintaining the M2 phenotype. Animals deficient in eosinophils and fed a high fat diet developed increased adiposity, became insulin resistant and were glucose intolerant. In addition, helminth infection of animals, which produces eosinophilia, enhances glucose tolerance. Taken together, the data demonstrate a surprising role for a cell type not thought to be important in metabolic homeostasis.

This rather simplistic discussion is an attempt to lay out, in broad terms, the interplay between metabolism, energy stores and inflammation. Until rather recently, adipose tissue was relegated the role of serving as the primary storage depot for fat; a caloric warehouse that could be called upon to deliver energy when needed. Over the last decade, we have had to revise our view of adipose tissue and view it as a multifaceted organ capable of influencing and being influenced by our adaptive immune system. This new approach is certain to open new avenues to exploit for the development of therapeutics to treat and prevent obesity-related disorders.

References

  1. Mathis D and Shoelson SE, Immunometabolism: an emerging frontier, Nat Rev Immunol 11: p81, 2011
  2.  Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA and Shoelson SE, The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomised trial, Ann Intern Med 152: pp346-357, 2010
  3. Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, Mandrup-Poulsen T and Donath MY, Interleukin-1-receptor antagonist in type 2 diabetes mellitus, N Engl J Med 356: pp1,517-1,526, 2007
  4. Tsubakio-Yamamoto K, Matsuura F, Koseki M, Oku H, Sandoval JC, Inagaki M, Nakatani K, Nakaoka H, Kawase R, Yuasa-Kawase M et al, Adiponectin prevents atherosclerosis by increasing cholesterol efflux from macrophages, Biochem Biophys Res Commun 375: pp390-394, 2008
  5. Ouchi N, Shibata R and Walsh K, Cardioprotection by adiponectin, Trends Cardiovasc Med 16: pp141-146, 2006
  6. Walsh KB, Toledo AH, Rivera-Chavez FA, Lopez-Neblina F and Toledo- Pereyra LH, Inflammatory mediators of liver ischemia-reperfusion injury, Exp Clin Transplant 7: pp78-93, 2009
  7. Wang Y, Lau WB, Gao E, Tao L, Yuan Y, Li R, Wang X, Koch WJ and Ma XL, Cardiomyocyte-derived adiponectin is biologically active in protecting against myocardial ischemia-reperfusion injury, Am J Physiol Endocrinol Metab 298: E663-670, 2010
  8. Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM, Schraw T, Durand JL, Li H, Li G et al, Obesity-associated improvements in metabolic profile through expansion of adipose tissue, J Clin Invest 117: pp2,621-2,637, 2007
  9. Aguilar-Salinas CA, Garcia EG, Robles L, Riano D, Ruiz-Gomez DG, Garcia-Ulloa AC, Melgarejo MA, Zamora M, Guillen-Pineda LE, Mehta R et al, High adiponectin concentrations are associated with the metabolically healthy obese phenotype, J Clin Endocrinol Metab 93: pp4,075-4,079, 2009
  10. Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, Chawla A and Locksley RM, Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis, Science 332: pp243-247, 2011

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Joseph A Cornicelli is the Director of Inflammation and Cardiovascular Pharmacology Services for Charles River Discovery, and has over 22 years of experience in drug discovery and development. Trained at the University of Cincinnati, Joe completed post-doctoral fellowships at the Mayo Clinic Foundation and Columbia University. He joined Warner-Lambert in 1985 where he served as a Research Fellow in the inflammation and cardiovascular therapeutic areas. In 2008, Joe joined Charles River Discovery Services, as Director of Discovery Efforts in the areas of metabolism, cardiovascular and inflammatory diseases, where he leads the Discovery Services Group's work in the assessment of potential preventative and therapeutic therapies in these key areas. Email: joe.cornicelli@crl.com
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