4
Adipocytokines: leptin—the classical, resistin—the controversical, adiponectin—the promising, and more to come

https://doi.org/10.1016/j.beem.2005.07.008Get rights and content

With the growing prevalence of obesity, scientific interest in the biology of adipose tissue has been extended to the secretory products of adipocytes, since they are increasingly shown to affect several aspects in the pathogenesis of obesity-related diseases. The cloning of the ob gene is consistent with this concept and suggests that body fat content in adult rodents is regulated by a negative feedback loop centred in the hypothalamus. In recent years, a number of additional signalling molecules secreted by adipose tissue have been discovered, commonly referred to as ‘adipocytokines’. Among these, adiponectin is perhaps the most interesting and promising compound for the clinician since it has profound protective actions in the pathogenesis of diabetes and cardiovascular disease. Adiponectin is low in obese subjects and, in particular, insulin-resistant patients. In contrast, resistin seems to be of greater relevance in relation to the immune stress response than in the regulation of glucose homeostasis. However, inflammatory processes have recently been connected with the development of atherosclerosis. Finally, little is known regarding the clinical relevance of visfatin. Recent research has revealed many functions of adipocytokines extending far beyond metabolism, such as immunity, cancer and bone formation. This report aims to review some of the recent topics of adipocytokine research that may be of particular importance.

Section snippets

Leptin—the pleiotropic factor

The cloning of the ob gene has furthered our understanding of the mechanisms underlying adiposity, eating disorders and reproduction.

Resistin—the controversial factor

The discovery of resistin as a novel factor secreted by adipocytes with an impact on insulin sensitivity was proposed as a new mechanism to explain the pathogenic sequence of adipocyte-obesity-insulin resistance.56 To date, many aspects of the biology of resistin in terms of its biological effects and regulation remain controversial, and its role as a mediator of insulin resistance, at least in humans, is questionable. However, studies have provided evidence of a role of resistin in

Adiponectin—the protective adipocytokine

The discovery of adiponectin occurred at about the same time as the discovery of leptin (1995/1996), but it did not receive major attention in the scientific community for the next few years until its markedly protective role in the pathogenesis of obesity-related disorders was acknowledged. Compared with the aforementioned factors, adiponectin differs in almost all biological properties and effects. Nevertheless, to date, it is the most promising adipocytokine with a sincere potential for

Visfatin

A ‘new’ adipocytokine was isolated by Fukuhara et al in 2004.160 This adipocytokine, named ‘visfatin’, was found to be highly enriched in the visceral adipose tissue of both humans and rodents. Visfatin was found to be identical to the previously known pre-B cell colony enhancing factor, a cytokine expressed by lymphocytes. Visfatin has a molecular weight of 52 kDa. The coding region of the gene encodes for 491 amino acids. When given to mice, visfatin lowers blood glucose,160 resembling the

Summary and new adipocytokines of interest

In summary, it has been shown that leptin, the initial and classical adipocytokine, is increased in obesity and exerts pleiotropic actions on glucose metabolism, may promote atherosclerosis and proliferation of cancer cells, and stimulates bone formation. Resistin, the controversial factor, has relevance for humans in stimulating the inflammatory cascade leading to atherosclerosis. Contrary to leptin and resistin, adiponectin, the protective factor, is decreased in obesity and has protective

Acknowledgements

This work was supported by grants the Interdisciplinary Center for Clinical Research at the University of Leipzig to A.K. and J.K. (projects B21 and B15).

References (176)

  • C. Bjorbaek et al.

    Identification of SOCS-3 as a potential mediator of central leptin resistance

    Mol Cell

    (1998)
  • C. Bjorbaek

    El Haschimi K

    Frantz JD.The role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem

    (1999)
  • A. Cheng et al.

    Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B

    Dev Cell

    (2002)
  • J.M. Zabolotny et al.

    PTP1B regulates leptin signal transduction in vivo

    Dev Cell

    (2002)
  • R. Wolk et al.

    Plasma leptin and prognosis in patients with established coronary atherosclerosis

    J Am Coll Cardiol

    (2004)
  • P. Somasundar et al.

    Prostate cancer cell proliferation is influenced by leptin

    J Surg Res

    (2004)
  • P. Somasundar et al.

    Leptin is a growth factor in cancer

    J Surg Res

    (2004)
  • P. Ducy et al.

    Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass

    Cell

    (2000)
  • S. Takeda et al.

    Leptin regulates bone formation via the sympathetic nervous system

    Cell

    (2002)
  • S. Takeda

    Central control of bone remodeling

    Biochem Biophys Res Commun

    (2005)
  • K.H. Kim et al.

    cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation

    J Biol Chem

    (2001)
  • P. Raghu et al.

    Dimerization of human recombinant resistin involves covalent and noncovalent interactions

    Biochem Biophys Res Commun

    (2004)
  • J.N. Fain et al.

    Resistin release by human adipose tissue explants in primary culture

    Biochem Biophys Res Commun

    (2003)
  • L. Patel et al.

    Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators

    Biochem Biophys Res Commun

    (2003)
  • A.H. Minn et al.

    Resistin is expressed in pancreatic islets

    Biochem Biophys Res Commun

    (2003)
  • J.M. Way et al.

    Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists

    J Biol Chem

    (2001)
  • C.C. Juan et al.

    Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids

    Biochem Biophys Res Commun

    (2001)
  • A. Fujinami et al.

    Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes

    Clin Chim Acta

    (2004)
  • H. Osawa et al.

    genotype of a resistin single-nucleotide polymorphism at -420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3

    Am J Hum Genet

    (2004)
  • H.S. Jung et al.

    The effects of rosiglitazone and metformin on the plasma concentrations of resistin in patients with type 2 diabetes mellitus

    Metabolism

    (2005)
  • L. Brunetti et al.

    Resistin, but not adiponectin, inhibits dopamine and norepinephrine release in the hypothalamus

    Eur J Pharmacol

    (2004)
  • Y. Zhang et al.

    Positional cloning of the mouse obese gene and its human homologue

    Nature

    (1994)
  • E.E. Kershaw et al.

    Adipose tissue as an endocrine organ

    J Clin Endocrinol Metab

    (2004)
  • G.H. Lee et al.

    Abnormal splicing of the leptin receptor in diabetic mice

    Nature

    (1996)
  • N. Ghilardi et al.

    signaling by the leptin receptor in diabetic mice

    Proc Natl Acad Sci USA

    (1996)
  • G. Fruhbeck

    A heliocentric view of leptin

    Proc Nutr Soc

    (2001)
  • M. Maamra et al.

    Generation of human soluble leptin receptor by proteolytic cleavage of membrane-anchored receptors

    Endocrinology

    (2001)
  • C. Liu et al.

    Expression and characterization of a putative high affinity human soluble leptin receptor

    Endocrinology

    (1997)
  • M.K. Sinha et al.

    Evidence of free and bound leptin in human circulation

    Studies in lean and obese subjects and during short-term fasting. J Clin Invest

    (1996)
  • J. Kratzsch et al.

    Circulating soluble leptin receptor and free leptin index during childhood, puberty, and adolescence

    J Clin Endocrinol Metab

    (2002)
  • G. Yang et al.

    Modulation of direct leptin signaling by soluble leptin receptor

    Mol Endocrinol

    (2004)
  • O. Zastrow et al.

    The soluble leptin receptor is crucial for leptin action: evidence from clinical and experimental data

    Int J Obes Relat Metab Disord

    (2003)
  • Dal Farra C, Zsurger N, Vincent JP et al. Binding of a pure 125I-monoiodoleptin analog to mouse tissues: a...
  • Bjorbaek C & Kahn BB. Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res 2004; 59:...
  • S. Margetic et al.

    Leptin: a review of its peripheral actions and interactions

    Int J Obes Relat Metab Disord

    (2002)
  • S.B. Heymsfield et al.

    Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial

    JAMA

    (1999)
  • R.C. Frederich et al.

    Expression of ob mRNA and its encoded protein in rodents

    Impact of nutrition and obesity. J Clin Invest

    (1995)
  • R.V. Considine et al.

    Serum immunoreactive-leptin concentrations in normal-weight and obese humans

    N Engl J Med

    (1996)
  • P.J. Havel et al.

    Gender differences in plasma leptin concentrations

    Nat Med

    (1996)
  • R. Heptulla et al.

    Temporal patterns of circulating leptin levels in lean and obese adolescents: relationships to insulin, growth hormone, and free fatty acids rhythmicity

    J Clin Endocrinol Metab

    (2001)
  • Cited by (0)

    View full text