PBEF/Visfatin: A role in metabolic syndrome

It is well-established that the health risks of obesity, often referred to as the metabolic syndrome (Box 1), depend not only on the amount of adipose tissue, but also on its location.1 Those who tend toward a pear shape are actually at less risk than those with body types shaped more like an apple. Adipose tissue expression of secretory proteins (adipokines) is quite high: 20% of all expressed proteins for subcutaneous fat (predominant for “pears”) versus 30% for visceral fat (increased in “apples”).1 Some adipokines, such as TNF-alpha, serpin E1, and HB-EGF, are not specific to adipose tissue, but do contribute to its detrimental effects. Others appear to be adipose-specific: leptin, which is appetite-controlling but also proinflammatory, and adiponectin, which enhances insulin action but is downregulated in obesity.2 An additional potential adipokine was recently identified in a search for differential expression between subcutaneous and visceral fat. The protein, previously known as pre-B cell enhancing factor (PBEF) was given a new name, visfatin, to designate its preferential expression in visceral fat.3,4 This unusual protein has been the subject of intense research.

Box 1
Visceral fat accumulation is associated with:
  • Glucose intolerance
  • Insulin resistance / hyperinsulinemia
  • Chronic inflammatory response
  • High triglycerides / low HDL
  • Hypertension
  • Coronary artery disease
  • Cardiac left ventricular dysfunction
  • Sleep apnea syndrome

PBEF/visfatin is expressed fairly widely, but is usually intracellular.5,6 Within the cell, PBEF/visfatin functions as a nicotinamide phosphoribosyltransferase, catalyzing the rate-limiting step in the biosynthesis of NAD+.5 As such, it has been shown to be anti-apoptotic and to regulate energy metabolism during stress responses and immune activation.4-6 Crystal structure in complex with ligands has supported this role, but has not yet given clues to how PBEF/visfatin functions extracellularly.6 In fact, PBEF/visfatin lacks a signal sequence and its mode of secretion is not clear.

A seminal paper by Fukuhara et al. identified PBEF/visfatin as an adipokine that lowers plasma glucose due to its ability to bind and stimulate the insulin receptor.3 As a non-competitive insulin mimetic, PBEF/visfatin has the potential to partially overcome insulin resistance, although it circulates in much lower quantities than insulin.1,2 Plasma PBEF/visfatin can be increased in response to a sustained (90-240 minute) blood glucose elevation.7 The vasculature of visceral fat, is unique in that it drains into the hepatic portal vein. Consequently, PBEF/visfatin and other adipokines from this source have a more direct opportunity to affect responses in the liver.8 Clinical studies are mixed, however, regarding the association of increased circulating PBEF/visfatin with diabetes mellitus.1 Long-standing disease and progressive deterioration of beta cells appear to be associated with more pronounced PBEF/visfatin increases.9,10

The finding that PBEF/visfatin is preferentially expressed and secreted by visceral adipose in obese individuals has mainly, though not universally, been upheld in other studies. Why should differences in PBEF/visfatin levels be more pronounced in obese humans or mice? One hypothesis is that the hypoxia that occurs as fat cells and fatty tissues increase in size can induce PBEF/visfatin expression via the transcription factor HIF-1.11,12 Another hypothesis notes that macrophages are more prevalent in obese adipose tissue, especially surrounding apoptotic adipocytes. Not only do the macrophages secrete the inflammatory mediators characteristic of metabolic syndrome, they also join adipocytes in producing PBEF/visfatin.13 Regardless of how a PBEF/visfatin differential is created, once it exists it has the potential to magnify the differential expression of other adipokines and lipolytic pathway molecules due to its ability to promote adipogenesis.1,3,8

What is the relationship between PBEF/visfatin and metabolic syndrome? Is it part of the cause, a compensatory response, or simply an intriguing marker? The studies published in the past year have yielded much new information but definitive answers to these questions remain to be determined.


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  2. Tilg, H. & A.R. Moschen (2006) Nat. Rev. Immunol. 6:772.
  3. Fukuhara, A. et al. (2005) Science 307:426.
  4. Samal, B. et al. (1994) Mol. Cell. Biol. 14:1431.
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  6. Kim, M.-K. et al. (2006) J. Mol. Biol. 326:66.
  7. Haider, D.G. et al. (2006) Diabetologia 49:1909.
  8. Arner, P. (2006) J. Clin. Endocrinol. Metab. 91:28.
  9. Chen, M.-P. et al. (2006) J. Clin. Endocrinol. Metab. 91:295.
  10. Lopez-Bermejo, A. et al. (2006) Diabetes 55:2871.
  11. Segawa, K. et al. (2006) Biochem. Biophys. Res. Comm. 349:875.
  12. Bae, S.-K. et al. (2006) FEBS Lett. 580:4105.
  13. Curat, C.A. et al. (2006) Diabetologia 49:744.