NEWS AND VIEWS
Are all fats created equal? Kevin G Murphy & Stephen R Bloom
© 2006 Nature Publishing Group http://www.nature.com/naturemedicine
The interplay of factors that impair insulin signaling to cause type 2 diabetes is unclear, but one idea is that visceral fat might produce them. Visfatin, a protein previously known for its effect on immune cells, may be one of these factors. The last decade has revolutionized our view of adipose tissue, transforming it from an inert storage depot into an important dynamic endocrine organ, secreting a number of adipokines—hormones produced by adipose tissue that regulate metabolism and energy homeostasis. More recently, new research has challenged the idea that adipose deposits represent a single aggregate functional entity. In fact, it appears that different adipose depots are discrete hormone factories, regulating various physiological processes to distinct agendas. All adipocytes are not, therefore, created equal. Visceral fat, in particular, keeps its own counsel. Visceral fat is specifically associated with type 2 diabetes and the accompanying metabolic consequences1. The factors responsible for the impairment of insulin signaling that causes type 2 diabetes are still unclear, but a common hypothesis is that such a factor is secreted disproportionately from visceral fat. So, there is great interest in those adipokines that are secreted preferentially by visceral fat. Early last year, Fukuhara et al.2 reported in Science that they had identified one such protein. They named it visfatin. Visfatin was uncovered by differential display of cDNAs from samples of female human subcutaneous and visceral fat, and by northern blotting. The plasma concentrations of the encoded 52 kDa protein correlated strongly with amount of visceral fat in human subjects. Mouse models of obese type 2 diabetes and of diet-induced obesity had higher plasma visfatin levels and increased expression of visfatin in their visceral fat2. Visfatin had been previously discovered as a cytokine-like growth factor expressed in lymphocytes and named pre-B cell colonyenhancing factor (PBEF) for its actions on early B-lineage precursor cells3. Fukuhara and colleagues suggested a new role for PBEF in the regulation of insulin signaling. Rather than impairing insulin signaling, visfatin The authors are in the Department of Metabolic Medicine, Hammersmith Hospital, Imperial College London, London, W12 0NN, UK. E-mail:
[email protected]
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was in fact found to have biological actions similar to insulin itself. So, acute intravenous administration reduced, in a dosedependent manner, levels of plasma glucose in mice. Overexpression of visfatin chronically reduced the concentration of plasma glucose and insulin in mice. Although mice homozygous null for the gene encoding visfatin died during early embryogenesis, heterozygotes had 30% lower concentrations of circulating visfatin, which were associated with higher levels of plasma glucose, suggesting a physiological role for visfatin in the regulation of blood glucose. Visfatin also acted as an insulin mimetic in vitro, stimulating glucose uptake in cultured adipocytes and myocytes, suppressing glucose release from cultured hepatocytes and inducing triglyceride accumulation and synthesis in preadipocytes. This is not merely functional convergence. Further experiments showed that visfatin bound to the insulin receptor with an affinity similar to that of insulin, although it appeared to bind to a different site (Fig. 1). Like insulin, visfatin promoted the phosphorylation of various intracellular signaling proteins both in vitro and in vivo2, including the insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2. There are still several important elements of the visfatin story that require elucidation or verification. The physiological role of visfatin is still unclear. Circulating levels of visfatin are an order of magnitude lower than insulin, and are not changed by fasting or feeding in mice, suggesting that its endocrine role may be physiologically unimportant. Visfatin may have a more important autocrine or paracrine role in adipose tissue, stimulating adipogenesis and lipogenesis2. It is also possible that changes in concentrations of circulating visfatin reflect long-term rather than short-term metabolic changes. Individuals with type 2 diabetes have elevated concentrations of plasma visfatin 4. It is too soon to determine whether this rise represents the response of a feedback loop to impaired visfatin or insulin signaling in these individuals. But if visfatin signaling is not impaired in insulin-resistant states,
Visceral adipocytes
Visfatin
Insulin
Insulin receptor
P
MAPK
P
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PI3K Akt Figure 1 Visfatin is secreted by visceral fat and binds to the insulin receptor at a site different from that of insulin, phosphorylating a number of components of the insulin signaling cascade2.
it may represent an exciting new target for diabetes therapy. Visfatin is expressed in a number of nonadipose human tissues, including bone marrow, liver, muscle and lung, where it may have tissue-specific roles3. It is unclear whether visfatin is released from cells by a regulated secretion pathway. The protein lacks a typical secretory sequence, and it has been suggested that visfatin acts primarily as an intracellular factor and that the source of circulating visfatin is lysis of adipocytes rather than regulated release5. Visfatin acts as an intracellular nicotinamide phosphoribosyltranferase in vitro6. The final important question that needs to be answered is whether and to what degree visfatin is preferentially expressed in visceral fat. Berndt et al.7 recently found in humans that plasma visfatin concentrations do not correlate with visceral fat mass and that expression of the gene encoding
VOLUME 12 | NUMBER 1 | JANUARY 2006 NATURE MEDICINE
NEWS AND VIEWS mimetic role of visfatin has further complicated an already complex story. It is our hope that this year will see the completion of the crucial experiments required to define the physiological role or roles of this interesting molecule. 1. Bosello, O. & Zamboni, M. Obes. Rev. 1, 47–56 (2000).
2. Fukuhara, A. et al. Science 307, 426–430 (2005). 3. Samal, B. et al. Mol. Cell Biol. 14, 1431–1437 (1994). 4. Chen, M.P. et al. J. Clin. Endocrinol. Metab (doi: 10.1210/jc.2005-1475). 5. Hug, C. & Lodish, H. F. Science 307, 366–367 (2005). 6. Rongvaux, A. et al. Eur. J. Immunol. 32, 3225–3234 (2002). 7. Berndt, J. et al. Diabetes 54, 2911–2916 (2005). 8. Kloting, N. & Kloting, I. Biochem. Biophys. Res. Commun. 332, 1070–1072 (2005).
The tangled path to glucose production Michihiro Matsumoto & Domenico Accili Liver glucose production is crucial to survival during fast and is abnormally elevated in diabetes. Studies of the transcriptional coactivator Torc2 redefine the mechanism by which cAMP signaling affects fasting-induced glucogenesis. During fast, the liver is the main provider of glucose to the brain and contributes to maintaining constant levels of plasma glucose. Hepatic production of glucose arises from two sources: breakdown of glycogen (glycogenolysis) and gluconeogenesis from lactate, pyruvate, glycerol and amino acids. Fasting promotes glucose production through cAMP-dependent mechanisms. Feeding inhibits glucose production through insulin. The cAMP response is dependent on phosphorylation of the cAMP response element binding (CREB) protein and recruitment of the coactivators Cbp/p300 to promoters of gluconeogenic genes. In Nature, Koo and colleagues report that the mechanism of cAMP-induced glucose production is in fact much more complex, and identify the CREB coactivator Torc2 as the main mediator of the fasting response1. Hepatic glucose production is the result of a concerted process that integrates metabolite fluxes to and from the liver, hormonal cues and neurotransmitter release. The classic work of Exton and colleagues in perfused livers showed that glucagon mediates glucose production through cAMP2. This effect does not require new protein synthesis and occurs within seconds. Insulin’s inhibitory effect is equally rapid and results in the suppression of phosphoenolpyruvate carboxykinase (encoded by Pck1)3 and glucose-6-phosphatase (encoded by G6pc) expression. The identification of hormone-regulated transcription factors that mediate gluconeogenesis has proven exceedingly difficult. The The authors are in the Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA. E-mail:
[email protected]
cAMP response has classically been viewed as the result of CREB phosphorylation, leading to its recruitment, along with the coactivators p300/Cbp, to the Pck1 and G6pc promoters (Fig. 1)4. The opening salvo of the Koo et al. report is in this respect rather startling. They show that phosphorylation of CREB is induced equally by cAMP and insulin, indicating that phosphorylation is permissive, but not sufficient, to explain the induction of gluconeogenic genes by fasting. However, a different CREB coactivator—Torc2—is specifically dephosphorylated in response to cAMP and translocates to the nucleus to activate CREBdependent transcription of Pck1 and G6pc. Moreover, the authors show that Torc2 acts upstream of Pgc1α, a known coactivator of fasting-induced glucose production (Fig. 1)5. After activation of gene expression, the plot thickens, as Torc2 is rapidly inactivated through phosphorylation by the salt-inducible kinase Sik1. This is consistent with the finding that the glucogenetic response is self-limiting and declines upon prolonged exposure to cAMP6. Sik1, in turn, is activated by AMP-dependent protein kinase (AMPK), but not by insulin, ruling out its participation in insulin inhibition of gluconeogenesis (Fig. 1). AMPK is also activated in response to feeding and promotes utilization of nutrients. Thus, the Sik1-Torc2 pathway may explain the suppression of gluconeogenesis by AMPK agonists, such as the drug metformin. It remains to be seen whether fasting-induced changes in AMPK activity are of sufficient magnitude to account for dephosphorylation of Torc2, and to identify the relevant phosphatases. Several transcription factors and coactivators have a role in glucose production. In addition to the PKA-CREB cascade, another important
NATURE MEDICINE VOLUME 12 | NUMBER 1 | JANUARY 2006
AMPK
Sik1
Akt
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Pgc1α Foxo1 Simon Fenwick
© 2006 Nature Publishing Group http://www.nature.com/naturemedicine
visfatin is similar in visceral and subcutaneous adipose tissue. Similar results have also been obtained in two different strains of rat8. Further studies are required before the matter is settled conclusively, but it does seem possible that visfatin may yet receive a third name, one more indicative of its true physiological actions. Thus far, the insulin-
Foxa2 C/ebpα
Figure 1 Pathways of gluconeogenesis. The involvement of several transcription factors and coactivators has been suggested in the nutritional and hormonal control of gluconeogenesis and are listed above the DNA double strand. Green symbols represent mediators of the cAMP (fasting) response, red symbols represent mediators of the insulin response and brown symbols represent mediators of the AMPK (feeding) response. Akt inhibits glucose production by phosphorylation of Foxo1 and Cbp. Sik inhibits glucose production through phosphorylation of Torc2. Foxa2 is also involved in glucose production during fasting, but its post-translational regulation is disputed. C/ebpα is the main promoter of gluconeogenesis in the early postnatal phase, but does not appear to be hormonally regulated.
pathway depends on the forkhead protein Foxo1, acting in concert with the coactivator Pgc1α5. Foxo1 is required for induction of G6pc in response to cAMP and for the insulinmediated inhibition of this process (Fig. 1)7. It is unclear how Foxo1 and CREB signaling interact; one possibility is that they compete for a limited pool of Pgc1α8. Unlike other actors on this crowded stage, Foxo1 is exclusively regulated by insulin through phosphorylation and does not require synthesis of new protein, providing a rapid-response mechanism to mediate hormone-dependent changes.
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