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Adipocytokines: mediators linking adipose tissue, inflammation and immunity

Key Points

  • Insulin resistance, most commonly in the context of obesity, is the main risk factor for type 2 diabetes mellitus and cardiovascular diseases.

  • Several pro-inflammatory cytokines (such as tumour-necrosis factor and interleukin-6), signalling proteins and endoplasmic-reticulum stress are associated with the development of insulin resistance.

  • Adipose tissue is the largest endocrine organ in humans and releases large amounts of adipocytokines — mediators that are mainly, but not exclusively, synthesized by adipocytes in white adipose tissue. Adiponectin and leptin are the two most abundant adipocytokines.

  • Adipose tissue contributes to the development of insulin resistance, not only by the synthesis of adipocytokines, but also by the production of many other pro-inflammatory mediators.

  • Obesity is associated with increased macrophage infiltration of adipose tissue, and these macrophages might contribute to the chronic inflammatory response that is observed in obesity and insulin resistance.

  • Adiponectin is synthesized mainly by adipocytes. It suppresses macrophage functions and inflammatory processes throughout the body, and decreases insulin resistance.

  • Leptin, an adipocytokine that was identified more than a decade ago, links nutritional status with neuroendocrine and immune functions. In contrast to adiponectin, serum levels of leptin are increased in people who are obese and this adipocytokine has several pro-inflammatory properties.

  • Resistin, another pro-inflammatory adipocytokine, seems to have different functions in mice and humans. It is potentially involved in the regulation of insulin resistance and has many pro-inflammatory functions.

  • Visfatin mimics insulin functions and thereby decreases insulin resistance. Its initial identification as pre-B-cell colony-enhancing factor (PBEF) indicates that it has an important role in inflammatory processes, again supporting the close relationship between inflammation and insulin resistance.

Abstract

There has been much effort recently to define the role of adipocytokines, which are soluble mediators derived mainly from adipocytes (fat cells), in the interaction between adipose tissue, inflammation and immunity. The adipocytokines adiponectin and leptin have emerged as the most abundant adipocyte products, thereby redefining adipose tissue as a key component not only of the endocrine system, but also of the immune system. Indeed, as we discuss here, several adipocytokines have a central role in the regulation of insulin resistance, as well as many aspects of inflammation and immunity. Other adipocytokines, such as visfatin, have only recently been identified. Understanding this rapidly growing family of mainly adipocyte-derived mediators might be of importance in the development of new therapies for obesity-associated diseases.

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Figure 1: Adipose tissue: cellular components and molecules synthesized.
Figure 2: Adiponectin: sources, structure and effects on pro- and anti-inflammatory cytokines.
Figure 3: Effects of various adipocytokines on the monocyte–macrophage system.
Figure 4: Effects of adipocytokines on adaptive immunity.

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Acknowledgements

We gratefully acknowledge A. Kaser for helpful discussions and critical reading of the manuscript. We are supported by grants from the Austrian Science Foundation and the Christian-Doppler Research Society (Austria).

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Glossary

Atherosclerosis

A chronic disorder of the arterial wall characterized by endothelial damage that gradually induces deposits of cholesterol, cellular debris, calcium and other substances. These deposits finally lead to plaque formation and arterial stiffness.

Complement factors

Complement factors are components of the complement system. Activation of these factors, which involves proteolytic cleavage of serum and cell-surface glycoproteins, leads to the formation of a terminal cell-lytic complex inside the cell membrane of a target cell. Complement fragments such as C3a and C5a have important pro-inflammatory properties, such as vasodilation, chemotaxis and opsonization.

Type 2 diabetes mellitus

A disorder of glucose homeostasis that is characterized by inappropriately increased blood-glucose levels and resistance of tissues to the action of insulin. Recent studies indicate that inflammation in adipose tissue, liver and muscle contributes to the insulin-resistant state that is characteristic of type 2 diabetes mellitus, and that the anti-diabetic actions of peroxisome-proliferator-activated receptor-γ (PPARγ) agonists result, in part, from their anti-inflammatory effects in these tissues.

ob/ob mice

Mice with a spontaneous mutation in the gene encoding leptin (chromosome 6) that leads to decreased leptin production. These mice are severely obese and develop noninsulin-dependent diabetes mellitus.

Endoplasmic-reticulum stress

(ER stress). A response by the ER that results in the disruption of protein folding and in the accumulation of unfolded proteins in the ER.

Collagen-like region

The amino-terminal domain of adiponectin contains a signal sequence that is followed by a stretch of 22 collagen-like repeats, consisting of 7 perfect Gly-X-Pro repeats and 15 'imperfect' Gly-X-Y repeats (where X and Y are different amino acids), which — similar to procollagen — allows the assembly of three full-length adiponectin molecules to an adiponectin trimer.

C1q-like globular domain

The carboxy-terminal globular domain of adiponectin, which has marked homology to several other proteins, including subunits of the complement factor C1q.

Visceral obesity

Accumulation of adipose tissue inside the abdominal cavity, in particular at omental and mesenteric regions, which are drained by the portal vein and therefore have direct access to the liver.

T-cadherin

A member of the cadherin family of transmembrane glycoproteins that mediate cell-adhesive interactions.

Peroxisome-proliferator-activated receptor-γ

(PPARγ). A nuclear receptor that is a master transcriptional regulator of metabolism and fat-cell formation. The activity of PPARγ can be modulated by the direct binding of small molecules — thiazolidinediones. PPARγ has anti-inflammatory properties by limiting the availability of limited cofactors or blocking promoters of pro-inflammatory genes.

IL-1 receptor antagonist

(IL-1RA). A secreted protein that binds to IL-1R, thereby blocking IL-1R downstream signalling. IL-1RA inhibits the pro-inflammatory properties of IL-1α/β.

Carbon-tetrachloride liver-fibrosis model

Intraperitoneal or oral administration of hepatotoxic carbon tetrachloride (CCl4) to mice is a commonly used model of both acute and chronic liver injury. CCl4 causes hepatocyte injury that is characterized by centrilobular necrosis followed by hepatic fibrosis.

KK-Ay obese mice

The spontaneous Ay mutation (agouti signal protein; yellow) was introduced onto the KK strain background. KK-Ay heterozygous mice have yellow hair pigment and black eyes and develop hyperglycaemia, hyperinsulinaemia, glucose intolerance and obesity by 8 weeks of age.

Lipodystrophic transgenic mice

Transgenic mice that express a truncated, constitutively active form of the sterol-regulatory-element-binding protein 1C (SREBP1C) transcription factor under the control of the adipose-specific aP2 promoter. Lipodystrophic mice have low plasma leptin levels, hyperphagia, hyperglycaemia and hyperinsulinaemia.

Body-mass index

(BMI). This is the most frequently used method to gauge an individual's deviation from 'normal' body weight. The BMI is the quotient of body weight (in kg) through the square of height (m2). Underweight: <20; ideal: 20–25; overweight: >25; obese: >30.

Mixed lymphocyte reaction

A tissue-culture technique that is used for the in vitro testing of the proliferative response of T cells from one individual to lymphocytes from another individual.

TNF-mediated toxicity

The injection of tumour-necrosis factor (TNF) into animals, which results in acute anorexia, weight loss, shock and even death.

Experimental autoimmune encephalomyelitis

(EAE). An experimental model of multiple sclerosis that is induced by immunization of susceptible animals with myelin-derived antigens, such as myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein.

Atherosclerotic aneurysm

A localized dilation of a blood vessel by more than 50% of its diameter owing to atherosclerotic structural damage of the vessel wall.

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Tilg, H., Moschen, A. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6, 772–783 (2006). https://doi.org/10.1038/nri1937

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