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Cell Metabolism

Previews

Treating Obesity Like a Tumor

Randy J. Seeley1,*1University of Cincinnati, Cincinnati, OH 45237, USA*Correspondence: randy.seeley@uc.eduDOI10.1016/j.cmet.2011.12.007

Expanding adipose tissue in obesity requires a great deal of angiogenesis to support increasing volumes of

tissue. A growing body of evidence indicates that inhibiting these blood vessels can result in substantial

weight loss, and now this has been demonstrated in nonhuman primates.

Extremely skeptical. That is the best

description of my response to publica-

tions indicating that either diet-induced

or genetic forms of obesity could be re-

versed by giving inhibitors to blood vessel

formation. The first of these reports camefrom Maria Rupnick and Judah Folkman,

whoused agents that inhibit tumor growth

and found profound weight loss in mice

(Rupnick et al., 2002). The next of these

reports used a more sophisticated ap-

proach in an attempt to direct the inhibi-

tion of the blood vessels specifically to

adipose tissue. In an effort led by Wadih

Arap and Renata Pasqulini, they used

a technology called phage display that

had been designed to identify the signa-

tures of tumor-associated blood vessels

that might be different than other blood

vessels. However, they determined that

many tissues, including adipose tissue,

had unique properties. They were able to

identify short peptide sequences that

would selectively bind to the vasculature

of white adipose tissue, but not other

tissues they examined. As cancer re-

searchers, they took the next logical step.

They used this peptide and attached a

poison pill that would produce apoptosis

in the targeted blood vessels (Kolonin

et al., 2004). This targeted approach also

led to rapid and substantial weight loss

in mice. In their most recent manuscriptpublished in Science Translational Medi-

cine, this group has extended these

results to obese nonhuman primates,

showing substantial weight and body fat

loss after 28 days of treatment with this

peptide (Barnhart et al., 2011).

The reason for my skepticism toward

this approach centered on the assump-

tion that, whether untargeted or targeted,

reducing adipose tissue blood vessels

would impair adipose tissue function.

While obesity is a scourge to be fought

and is the direct result of expanding

adipose tissue, the truth is that healthy

adipose tissue serves an important func-

tion to protect the rest of the body from

nutrients that, when stored in other tis-

sues such as muscle and liver, cause

metabolic dysfunction. The most obviousexample of this comes from humans

or mice who fail to make sufficient

adipocytes. While leaner, such individuals

nevertheless have severe metabolic prob-

lems, including liver steatosis, hyper-

lipidemia, and severe insulin resistance

(Huang-Doran and Savage, 2011). Thus,

it seemed likely that such an approach

that compromised adipose tissue func-

tion could result in leaner individuals

who were more at risk for metabolic

disease.

Ultimately, the data in mice and

nonhuman primates simply do not sup-

port my assumption. In nonhuman pri-

mates, weight loss is accompanied by

reduced insulin resistance (Barnhart et al.,

2011). In mice, our own work has dem-

onstrated that treatment with this pep-

tide results in rapid weight loss that is

primarily due to reduced intake, and it

is accompanied by metabolic improve-

ments (Kim et al., 2010). The important

point here is that the response to tar-

geting the adipose tissue vasculature is

the exact opposite of what is observed

when adipocytes are not present or arepushed into apoptosis. While removal of

adipocytes is associated with increased

intake and decreased insulin sensitivity

(Pajvani et al., 2005), removal of the sup-

porting vasculature results in decreased

intake and increased insulin sensitivity

(Kim et al., 2010). The conclusion to be

drawn is that adipocytes are an important

source of signals to both the brain and

other tissues and that the removal of

those signals is deleterious. Targeting

the adipose tissue vasculature results in

changes in adipocyte communication

that promote weight loss and improved

metabolic regulation.

This work has opened up an entirely

unappreciated aspect of adipose tissue

biology that explores the intimate relation-

ship between adipocytes and their sup-porting vasculature. More importantly,

understanding and manipulating this rela-

tionship has important therapeutic impli-

cations, given the potent effects of this

particular peptide. A crucial question is

whether this approach borrowed from

cancer treatment is going to be suffi-

ciently safe to be used in the growing

number of individuals suffering under

the burden of obesity and its comorbid

conditions. After all, treating cancer is

considerably different from treating a

chronic condition such as obesity. Cancer

patients are often under a short-term

threat, while obesity is a much longer-

term threat to an individuals health. As

a consequence, the risk-benefit analysis

is considerably different. For example,

the specificity of the targeting is less of a

concern in cancer as compared to obesity

treatment. Imagine a peptide with 90%

targeting selectivity to the tumor. Given

that the plan would be to treat the cancer

patient for weeks or months, as long as

the tumor is being undermined faster

than normal tissue, and that normal tissue

can recover once treatment is terminated,it can be a viable therapy. For the obese

patient who is likely to be taking such a

treatment for the better part of his or

her life, would 90% targeting selectivity

be sufficient to avoid adverse effects

on other tissues? Ninety-five percent?

Ninety-nine percent? This is a complex

question that will need to be answered

before we know whether this approach

will become therapy.

The important new insights driven

by the work with these targeted pep-

tides are an important advance in an

Cell Metabolism 15, January 4, 2012 2012 Elsevier Inc. 1

http://-/?-http://-/?-mailto:randy.seeley@uc.eduhttp://dx.doi.org/10.1016/j.cmet.2011.12.007http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.cmet.2011.12.007mailto:randy.seeley@uc.eduhttp://-/?-http://-/?-

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environment where few effective treat-

ment strategies short of bariatric sur-

gery are available to help obese patients.

It is clear that more creative strategies

from a wider range of disciplines areneeded. To that end, further under-

standing of how adipose tissue signal-

ing is altered by various aspects of its

milieu, including the supporting blood

vessels, macrophages, and its extracel-

lular matrix, is necessary if we are to bring

more therapiesto thelargeunmetmedical

need presented by increasing rates of

obesity.

REFERENCES

Barnhart, K.F., Christianson, D.R., Hanley, P.W.,Driessen, W.H., Bernacky, B.J., Baze, W.B., Wen,S., Tian, M., Ma, J., Kolonin, M.G., Saha, P.K.,Do, K.A., Hulvat, J.F., Gelovani, J.G., Chan, L.,

Arap, W., and Pasqualini, R. (2011). Sci. Transl.Med.3, 108ra112.

Huang-Doran, I., and Savage, D.B. (2011). Pediatr.Endocrinol. Rev.8, 190199.

Kim, D.H., Woods, S.C., and Seeley, R.J. (2010).Diabetes 59, 907915.

Kolonin, M.G., Saha, P.K., Chan, L., Pasqualini, R.,and Arap, W. (2004). Nat. Med. 10, 625632.

Pajvani, U.B., Trujillo, M.E., Combs, T.P., Iyengar,P., Jelicks,L., Roth, K.A.,Kitsis,R.N., and Scherer,P.E. (2005). Nat. Med.11, 797803.

Rupnick, M.A., Panigrahy, D., Zhang, C.Y., Dallab-rida, S.M., Lowell, B.B., Langer, R., and Folkman,M.J. (2002). Proc. Natl. Acad. Sci. USA 99,1073010735.

Reactive Oxygen Species Resultingfrom Mitochondrial Mutation DiminishesStem and Progenitor Cell Function

Brian S. Garrison1,2 and Derrick J. Rossi1,2,*1Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA2The Immune Disease Institute and Program in Cellular and Molecular Medicine, Childrens Hospital Boston, Boston, MA 02115, USA*Correspondence: rossi@idi.harvard.eduDOI10.1016/j.cmet.2011.12.008

While age-dependent stem cell decline is widely recognized as being a key component of organismal aging,

the underlying mechanisms remain elusive. In this issue of Cell Metabolism, Suomalainen and colleagues

provide evidence that mitochondrial mutation and associated reactive oxygen species can adversely impact

tissue-specific stem and progenitor cell function.

Physiological aging invariably leads to

a loss in normal tissue maintenance and

reduced regenerative potential. The fact

that these processes are normally under

the functional purview of adult tissue-

specific stem cells implicates age-associ-

ated stem cell decline as a fundamental

contributor to the aging of tissues and

organisms. Indeed, the importance ofthe stem cell compartment in contributing

to age-associated pathophysiology has

been demonstrated in a number of stud-

ies (Rossi et al., 2008). Consistent with

the inherent complexity of physiological

aging, the mechanistic basis for age-

related stem cell decline is similarly

complex, with evidence suggesting the

involvement of cellular, genetic, and epi-

genetic components (Rossi et al., 2008).

However, recent evidence from a number

of papers, including a paper by Suomalai-

nen and colleagues in this issue of Cell

Metabolism, suggests that accumulating

mitochondrial DNA damage may also be

an important contributor to somatic stem

cell decline with age.

Mitochondria are frequently referred

to as the cells power plants since

they play a fundamental role in the

production of adenosine triphosphate

(ATP) through oxidative phosphorylation(OXPHOS). Most aerobic organisms use

some form of OXPHOS because it is

a highly efficient method for produc-

ing ATP; however, the downside of this

energy-producing pathway is that it also

leads to theproduction of reactive oxygen

species (ROS) that have the potential to

damage cellular macromolecules and, in

such a way, contribute to aging. Mito-

chondrial DNA (mtDNA) is believed to be

highly susceptible to oxidative damage

in part because of itsproximity to theelec-

tron transport chain, but also because

mtDNA lacks protective histones. Accu-

mulation of damage in the mitochondrial

genome has been proposed to lead to

mitochondrial dysfunction and concomi-

tant cellular decline and, in such a way,

contribute to physiological aging (Har-

man, 1972). This long-held theory was

supported experimentally with the gener-

ation of mtDNA mutator mice bearing aproofreading-deficient mtDNA polymer-

ase (POLG) that exhibit a spectrum of

degenerative phenotypes reminiscent of

aging (Kujoth et al., 2005; Trifunovic

et al., 2004). More recently, these mice

have also provided the necessary ex-

perimental tool to address how mtDNA

mutation accumulation impacts stem cell

function and to determine whether it

contributes to age-associated stem cell

decline.

Within mammalian tissues, aging has

been most comprehensively studied in

Cell Metabolism

Previews

2 Cell Metabolism15, January 4, 2012 2012 Elsevier Inc.

http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-mailto:rossi@idi.harvard.eduhttp://dx.doi.org/10.1016/j.cmet.2011.12.008http://dx.doi.org/10.1016/j.cmet.2011.12.008mailto:rossi@idi.harvard.eduhttp://-/?-http://-/?-http://-/?-http://-/?-http://-/?-

5/19/2018 Metabolismo celular

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environment where few effective treat-

ment strategies short of bariatric sur-

gery are available to help obese patients.

It is clear that more creative strategies

from a wider range of disciplines areneeded. To that end, further under-

standing of how adipose tissue signal-

ing is altered by various aspects of its

milieu, including the supporting blood

vessels, macrophages, and its extracel-

lular matrix, is necessary if we are to bring

more therapiesto thelargeunmetmedical

need presented by increasing rates of

obesity.

REFERENCES

Barnhart, K.F., Christianson, D.R., Hanley, P.W.,Driessen, W.H., Bernacky, B.J., Baze, W.B., Wen,S., Tian, M., Ma, J., Kolonin, M.G., Saha, P.K.,Do, K.A., Hulvat, J.F., Gelovani, J.G., Chan, L.,

Arap, W., and Pasqualini, R. (2011). Sci. Transl.Med.3, 108ra112.

Huang-Doran, I., and Savage, D.B. (2011). Pediatr.Endocrinol. Rev.8, 190199.

Kim, D.H., Woods, S.C., and Seeley, R.J. (2010).Diabetes 59, 907915.

Kolonin, M.G., Saha, P.K., Chan, L., Pasqualini, R.,and Arap, W. (2004). Nat. Med. 10, 625632.

Pajvani, U.B., Trujillo, M.E., Combs, T.P., Iyengar,P., Jelicks,L., Roth, K.A.,Kitsis,R.N., and Scherer,P.E. (2005). Nat. Med.11, 797803.

Rupnick, M.A., Panigrahy, D., Zhang, C.Y., Dallab-rida, S.M., Lowell, B.B., Langer, R., and Folkman,M.J. (2002). Proc. Natl. Acad. Sci. USA 99,1073010735.

Reactive Oxygen Species Resultingfrom Mitochondrial Mutation DiminishesStem and Progenitor Cell Function

Brian S. Garrison1,2 and Derrick J. Rossi1,2,*1Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA2The Immune Disease Institute and Program in Cellular and Molecular Medicine, Childrens Hospital Boston, Boston, MA 02115, USA*Correspondence: rossi@idi.harvard.eduDOI10.1016/j.cmet.2011.12.008

While age-dependent stem cell decline is widely recognized as being a key component of organismal aging,

the underlying mechanisms remain elusive. In this issue of Cell Metabolism, Suomalainen and colleagues

provide evidence that mitochondrial mutation and associated reactive oxygen species can adversely impact

tissue-specific stem and progenitor cell function.

Physiological aging invariably leads to

a loss in normal tissue maintenance and

reduced regenerative potential. The fact

that these processes are normally under

the functional purview of adult tissue-

specific stem cells implicates age-associ-

ated stem cell decline as a fundamental

contributor to the aging of tissues and

organisms. Indeed, the importance ofthe stem cell compartment in contributing

to age-associated pathophysiology has

been demonstrated in a number of stud-

ies (Rossi et al., 2008). Consistent with

the inherent complexity of physiological

aging, the mechanistic basis for age-

related stem cell decline is similarly

complex, with evidence suggesting the

involvement of cellular, genetic, and epi-

genetic components (Rossi et al., 2008).

However, recent evidence from a number

of papers, including a paper by Suomalai-

nen and colleagues in this issue of Cell

Metabolism, suggests that accumulating

mitochondrial DNA damage may also be

an important contributor to somatic stem

cell decline with age.

Mitochondria are frequently referred

to as the cells power plants since

they play a fundamental role in the

production of adenosine triphosphate

(ATP) through oxidative phosphorylation(OXPHOS). Most aerobic organisms use

some form of OXPHOS because it is

a highly efficient method for produc-

ing ATP; however, the downside of this

energy-producing pathway is that it also

leads to theproduction of reactive oxygen

species (ROS) that have the potential to

damage cellular macromolecules and, in

such a way, contribute to aging. Mito-

chondrial DNA (mtDNA) is believed to be

highly susceptible to oxidative damage

in part because of itsproximity to theelec-

tron transport chain, but also because

mtDNA lacks protective histones. Accu-

mulation of damage in the mitochondrial

genome has been proposed to lead to

mitochondrial dysfunction and concomi-

tant cellular decline and, in such a way,

contribute to physiological aging (Har-

man, 1972). This long-held theory was

supported experimentally with the gener-

ation of mtDNA mutator mice bearing aproofreading-deficient mtDNA polymer-

ase (POLG) that exhibit a spectrum of

degenerative phenotypes reminiscent of

aging (Kujoth et al., 2005; Trifunovic

et al., 2004). More recently, these mice

have also provided the necessary ex-

perimental tool to address how mtDNA

mutation accumulation impacts stem cell

function and to determine whether it

contributes to age-associated stem cell

decline.

Within mammalian tissues, aging has

been most comprehensively studied in

Cell Metabolism

Previews

2 Cell Metabolism15, January 4, 2012 2012 Elsevier Inc.

http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-mailto:rossi@idi.harvard.eduhttp://dx.doi.org/10.1016/j.cmet.2011.12.008http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.cmet.2011.12.008mailto:rossi@idi.harvard.eduhttp://-/?-http://-/?-http://-/?-http://-/?-http://-/?-

5/19/2018 Metabolismo celular

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the hematopoietic system and, to a lesser

extent, the brain. In the blood, the hema-

topoietic stem cell (HSC) compartment

has been well documented to contribute

to pathophysiological conditions associ-ated with aging, which include reduced

regenerative potential, diminished adap-

tive immune competence, and myeloge-

nous disease predisposition (Rossi et al.,

2008). And while genomic DNA damage

accrual is thought to limit the regenerative

response of HSCs from old mice (Rossi

et al., 2007), the impact of mitochondrial

mutagenesis on hematopoietic aging has

until recently been unexplored. Two

groups have recently shown that the

mtDNA mutator mice exhibited a number

of hematopoietic phenotypes, including

abnormalities in erythroid and lymphocytedevelopment (Chen et al., 2009; Norddahl

et al., 2011). The fact that these hemato-

logic deficiencies could be transplanted

into wild-type recipients indicated that

they were cell-autonomous defects trans-

mitted by HSCs (Chen et al., 2009; Nord-

dahl et al., 2011). However, although

anemia and lymphoid deficiencies are

commonly associated with aging in both

mice and people, Bryder and colleagues

went on to show that the aging of muta-

tor stem cells was molecularly distinct

from normal physiological stem cell aging

(Norddahl et al., 2011). Using a tran-

scriptional profiling strategy to compare

steady-state mutator HSCs against stem

cells purified from old wild-typemice, little

similarity was noted in their respective

profiles, suggesting that, at least at this

resolution, mitochondrial mutation-driven

stem cell decline could be uncoupled

from normal physiological stem cell aging

(Norddahl et al., 2011). Nonetheless, it re-

mains possible that mitochondrial muta-

tion contributes mechanistically to stem

cell aging despite the lack of evidence

at the transcriptional level, perhaps byinfluencing the mobilization of energy

stores that these normally dormant stem

cells must harness when called into

action under conditions of stress or

regeneration.

An important outstanding question was

whether the hematopoietic phenotypes

exhibited by the mutator mice arose only

after a threshold level of mtDNA mutation

had occurred in the adult animals as they

aged. This is one of several issues ad-

dressed in a new article by Suomalainen

and colleagues featured in this issue(Ahlqvist et al., 2012). To examine the

timing of the mutator hematopoietic de-

fect manifestation, the investigators ex-

amined embryonic hematopoietic devel-

opment at E13.515.5 in the fetal liver of

mutator fetuses and discovered dimin-

ished erythropoiesis and reduced fre-

quencies of erythroid progenitors, likely

representing a precursor phenotype to

the later-observed adult anemia (Chen

et al., 2009; Norddahl et al., 2011). They

also observed a defect in fetal lymphopoi-

esis characterized by elevated B220-

positive B cells. Importantly, they discov-ered that administration of the antioxidant

N-acetylcysteine (NAC) throughout preg-

nancy could normalize fetal hematopoi-

esis to wild-type levels, implicating ROS

as an underlying mediator leading to the

fetal hematopoietic phenotypes observed

in the mutator mice. The researchers also

questioned how other tissue-specific

stem cell populations might be affected

in the mutator mice. In the brain, the

numbers of stem cells in the subventricu-

lar zone (SVZ) are the result of a tightly

controlled balance between the cell fates

of self-renewal, differentiation, and apo-

ptosis. This means that controlling of the

fate of SVZ NSCs, which can be identified

by their nestin positivity, plays a critical

role in determining the number of neu-

rons, astrocytes, and oligodendrocytes

in the brain. The researchers therefore

examined the number of nestin-positive

neural cells in the SVZ of wild-type and

mutator mice and discovered a significant

decrease in this important cell type in the

mutants. Despite the observed decrease

in NSCs, however, a multiparameter his-

tological and biochemical examinationfailed to uncover significant in vivo neuro-

logic phenotypes in aged mutator mice.

However, when the authors examined

the NSCs using an in vitro neurosphere

self-renewal assay, they discovered that

mutator NSCs formed significantly fewer

neurospheres than wild-type cells, indi-

cating that these cells suffer from a defect

in self-renewal that could explain the de-

creased NSC numbers observed in vivo.

Importantly, as the authors had observed

with the hematopoietic defects, the self-

renewal deficits of the mutator NSCscould also be largely ameliorated through

treatment with NAC.

The findings of Suomalainen and col-

leagues at once support a growing body

of evidence showing how critical ROS

management is for proper stem and pro-

genitor cell function (Ito et al., 2006; To-

thova and Gilliland, 2007) and, at the

same time, identify that a consequence

of mutation accrual in the mitochondrial

genome is deregulation of ROS, which

can then work its mischief by impairing

tissue-specific stem and progenitor cells.

However, the connection of mitochondrialgenome maintenance to physiological

stem cell aging remains unclear.

REFERENCES

Ahlqvist,K., Hamalainen, R.H., Yatsuga,S., Uutela,M., Terzioglu, M., Gotz, A., Forsstrom, S., Salven,P., Angers-Loustau, A., Kopra, O.H., et al. (2012).Cell Metab.15, this issue, 100109.

Chen, M.L., Logan, T.D., Hochberg, M.L., Shelat,S.G., Yu, X., Wilding, G.E., Tan, W., Kujoth, G.C.,Prolla, T.A., Selak, M.A., et al. (2009). Blood 114,40454053.

Harman, D. (1972). J. Am. Geriatr. Soc. 20,145147.

Ito, K.,Hirao, A.,Arai, F.,Takubo,K., Matsuoka, S.,Miyamoto, K., Ohmura, M., Naka, K., Hosokawa,K., Ikeda, Y., and Suda, T. (2006). Nat. Med. 12 ,446451.

Kujoth, G.C., Hiona, A., Pugh, T.D., Someya, S.,Panzer, K., Wohlgemuth, S.E., Hofer, T., Seo,

A.Y., Sullivan, R., Jobling, W.A., et al. (2005).Science309, 481484.

Norddahl, G.L., Pronk, C.J., Wahlestedt, M., Sten,G., Nygren, J.M., Ugale, A., Sigvardsson, M., andBryder, D. (2011). Cell Stem Cell 8, 499510.

Rossi, D.J., Bryder, D., Seita, J., Nussenzweig, A.,Hoeijmakers, J., and Weissman, I.L. (2007). Nature

447, 725729.

Rossi, D.J., Jamieson, C.H., and Weissman, I.L.(2008). Cell 132, 681696.

Tothova, Z., and Gilliland, D.G. (2007). Cell StemCell 1, 140152.

Trifunovic, A., Wredenberg, A., Falkenberg, M.,Spelbrink, J.N., Rovio, A.T., Bruder, C.E., Bohlo-oly-Y, M., Gidlof, S., Oldfors, A., Wibom, R., et al.(2004). Nature 429, 417423.

Cell Metabolism 15, January 4, 2012 2012 Elsevier Inc. 3

Cell Metabolism

Previews

http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-

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Power Surge: Supporting CellsFuel Cancer Cell Mitochondria

Ubaldo E. Martinez-Outschoorn,1,2,3,4 Federica Sotgia,1,2,3,5,*and Michael P. Lisanti1,2,3,4,5,*1The Jefferson Stem Cell Biology and Regenerative Medicine Center2Department of Stem Cell Biology and Regenerative Medicine3Department of Cancer Biology4Department of Medical OncologyKimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA5Manchester Breast Centre and Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, School of Cancer,Enabling Sciences and Technology, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, UK*Correspondence: federica.sotgia@jefferson.edu(F.S.), michael.lisanti@kimmelcancercenter.org(M.P.L.)DOI10.1016/j.cmet.2011.12.011

An emerging paradigm in tumor metabolism is that catabolism in host cells fuels the anabolic growth of

cancer cells via energy transfer. A study in Nature Medicine (Nieman et al., 2011) supports this; they

show that triglyceride catabolism in adipocytes drives ovarian cancer metastasis by providing fatty acidsas mitochondrial fuels.

Our understanding of tumor metabolism

is evolving. A new central concept in

cancer metabolism is that tumor cells

function as metabolic parasites to extract

energy from supporting host cells, such

as fibroblasts and adipocytes. It has re-

cently been demonstrated that metabolic

coupling exists in human tumors (Sotgia

et al., 2011). In two-compartment tumor

metabolism, the tumor stroma and adja-

cent host tissues are catabolic and the

cancer cells are anabolic (Figure 1). In

this model, energy is transferred from the

catabolic compartment to the anabolic

compartment via the sharing of nutrients

that promote tumor growth, behaving as

onco-metabolites. Although most studies

on two-compartment tumor metabolism

were first performed on fibroblasts and

breast cancer cells (Martinez-Outschoorn

et al., 2011; Sotgia et al., 2011, 2012;

Whitaker-Menezes et al., 2011), an ele-

gant study in Nature Medicine now

broadens this emerging paradigm to adi-

pocytes and ovarian cancer cells (Niemanet al., 2011).

The tumor cellular microenvironment

contains supporting host cells, including

fibroblasts, adipocytes, smooth muscle

cells, endothelia, and immunecells, which

functionally promote tumor growth. In

two-compartment tumor metabolism, an-

abolic cancer cells extract energy from

the surrounding host cells by inducing

catabolic processes, such as autophagy,

mitophagy, and aerobic glycolysis. These

processesprovide high-energy mitochon-

drial fuels (L-lactate, ketones, and gluta-

mine) forcancer cellsto burn. In response,

cancer cells amplify or hyperactivate

their capacity for oxidative phosphoryla-

tion (OXPHOS) by increasing their mito-

chondrial mass (Sotgia et al., 2012). For

example, cancer-associated fibroblasts

show a shift toward aerobic glycolysis

and secrete L-lactate via MCT4 trans-

porters. L-lactate is taken up by cancer

cells via MCT1 transporters, leading to

thegenerationof ATPvia OXPHOS(Sotgia

et al., 2012). This process can be phe-

nocopied by incubating cancer cellsalone

with high-energy fuels, such as L-lactate.

Tumor cells can also exert metabolic

effects at a distance, which leads to in-

creased fatty acid generation in adipose

tissue and catabolism in muscle (Das

et al., 2011). These key examples show

that energy transfer occurs in human

tumors and that cancer cells can exert

metabolic effects locally, in differenttumor

compartments, and at distant sites.

Over 80% of ovarian cancers are

metastatic to the omental fat. It is notknown why ovarian cancer cells pre-

ferentially seed the omentum as com-

paredto other sites.To address this issue,

the study by Nieman et al. (2011) uses

SKOV3ip1 human ovarian cancer cells

intraperitoneally (i.p.) injected into nude

mice or cocultured with adipocytes. They

describe how omental adipocytes are

metabolically reprogrammed to become

highly catabolic, generating free fatty

acids that are transferred to cancer cells.

Cancer cells then reutilize these fatty

acids to generate ATP via mitochondrial

b-oxidation. Utilization of adipocyte-

derived fatty acids was related to the

production of fatty acid binding protein 4

(FABP4) by adipocytes. Importantly, this

study evaluates tumor metabolism in the

more physiological context of its proper

microenvironment.

Energy production and apoptosis are

important mitochondrial functions that

are biologically linked in normal cells.

For example, the mitochondrial proteins

Bcl-2 and Bcl-xL are antiapoptotic and

favor mitochondrial OXPHOS (Chen and

Pervaiz, 2010; Vander Heiden et al.,

2001). A mitochondrial paradox exists

in cancer research, since it is not under-

stood why cancer cells, which are resis-

tant to apoptosis, would use energetically

inefficient low mitochondrial metabolism

(aerobic glycolysis, also known as the

Warburg effect) (Le et al., 2010; Fogal

et al., 2010). Interestingly, Nieman et al.

(2011) demonstrate that ovarian cancer

cells have high mitochondrial metabolic

activity, specifically fatty acidb-oxidation,when cocultured with adipocytes. This

type of mitochondrial metabolism was

not observed when ovarian cancer cells

were cultured alone, highlighting the im-

portance of catabolite transfer to cancer

cells. As such, high-energy nutrients pro-

vided by host cells may bolster mitochon-

drial metabolism in cancer cells, protect-

ing them against apoptosis. The answer

to the mitochondrial paradox may lie

in the metabolic reprogramming of can-

cer cells toward anabolic metabolism in

the presence of catabolic host cells,

4 Cell Metabolism15, January 4, 2012 2012 Elsevier Inc.

Cell Metabolism

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leading to mitochondrial biogenesis

and OXPHOS in tumor cells, driv-

ing chemoresistance and distant

metastasis.

Thus, the authors demonstratethat it is crucial to include the

supporting microenvironment when

studying cancer cell metabolism

and that simply examining primary

cancer cells alone may not be

adequate. Unfortunately, most tradi-

tional cancer metabolism studies

have been carried out using tumor

cells alone, or using whole tumors,

without modeling the host microen-

vironment. As such, one might gain

incomplete or inaccurate informa-

tion by studying primary cancer cells

or cancer cell lines in the absence ofsupporting host cells.

Studies describing the compart-

mentalization of tumor metabolism

and energy transfer may pave the

way toward the development of re-

lated predictive biomarkers and

targeted personalized therapies. It

will be important to investigate

whether metabolically uncoupling

cancer cells from catabolic host cells

can be used as a new effective anticancer

strategy. Earlier studies have suggested

that the detection of host-tumor meta-

bolic coupling may be useful for identi-

fying high-risk patients at diagnosis in

human breast cancers. For example,

loss of expression of the caveolin-1 pro-

tein in cancer-associated fibroblasts is

a marker for tumor-stroma metabolic

coupling (Sotgia et al., 2011) and is tightly

correlated with recurrence, metastasis,

and tamoxifen resistance as well as

poor clinical outcome. Metabolic coupling

between host cells and breast cancer

cells also results in the generation of reac-

tive oxygen species and inflammatory

cytokine production, such as IL-6 and

IL-8 (Sotgiaet al., 2012). Most importantly,

FDA-approved drugs that inhibit mito-

chondrial metabolism (metformin, arsenic

trioxide) or strong antioxidants (catalase)

can uncouple two-compartment tumor

metabolism and induce apoptosis in

cancer cells (Martinez-Outschoorn et al.,

2011; Sotgia et al., 2012)(Figure 1).

In conclusion, the importance of the

host microenvironment and energy trans-

fer in cancer metabolism is highlighted by

Nieman et al.(2011). More studies on two-

compartment tumor metabolism will be

necessary to understand and thera-

peutically exploit the metabolic coupling

between parasitic tumor cells and their

hosts. Uncoupling parasitic cancer

cellsshould allow us to starvecancer cells

and effectively treat advanced

and metastatic cancers. New imag-

ing techniques to visualize two-

compartment tumor metabolism in

real time will allow us to measurethe effectiveness of anticancer ther-

apies and facilitate more personal-

ized cancer treatments.

REFERENCES

Chen, Z.X., and Pervaiz, S. (2010). CellDeath Differ. 17, 408420.

Das,S.K., Eder,S., Schauer, S., Diwoky, C.,Temmel, H., Guertl, B., Gorkiewicz, G.,Tamilarasan, K.P., Kumari, P., Trauner, M.,et al. (2011). Science 333, 233238.

Fogal, V., Richardson, A.D., Karmali, P.P.,Scheffler, I.E., Smith, J.W., and Ruoslahti,E. (2010). Mol. Cell. Biol. 30, 13031318.

Le, A., Cooper, C.R., Gouw, A.M., Dinavahi,R., Maitra, A., Deck, L.M., Royer, R.E., Van-der Jagt, D.L., Semenza, G.L., and Dang,C.V. (2010). Proc. Natl. Acad. Sci. USA107, 20372042.

Martinez-Outschoorn, U.E., Goldberg, A.,Lin, Z., Ko, Y.H., Flomenberg, N., Wang,C., Pavlides, S., Pestell, R.G., Howell, A.,Sotgia, F., and Lisanti, M.P. (2011). CancerBiol. Ther. 12, 924938.

Nieman, K.M., Kenny, H.A., Penicka, C.V.,Ladanyi, A., Buell-Gutbrod, R., Zillhardt, M.R.,Romero, I.L., Carey, M.S., Mills, G.B., Hotamisligil,G.S., et al. (2011). Nat. Med. 17, 14981503.

Sotgia, F., Martinez-Outschoorn, U.E., Pavlides,S., Howell, A., Pestell, R.G., and Lisanti, M.P.(2011). Breast Cancer Res. 13, 213.

Sotgia, F., Martinez-Outschoorn, U.E., Howell, A.,Pestell, R.G., Pavlides, S., and Lisanti, M.P.(2012). Annu. Rev. Pathol. 7, 423467. Publishedonline November 7, 2011. 10.1146/annurev-pathol-011811-120856.

Vander Heiden, M.G., Li, X.X., Gottleib, E., Hill,R.B., Thompson, C.B., and Colombini, M. (2001).J. Biol. Chem. 276, 1941419419.

Whitaker-Menezes, D., Martinez-Outschoorn,U.E., Flomenberg, N., Birbe, R.C., Witkiewicz,

A.K., Howell, A., Pavlides, S., Tsirigos, A., Ertel,A., Pestell, R.G., et al. (2011). Cell Cycle 10,

40474064.

Two-Compartment Tumor Metabolism

Supporting Host Cell Cancer Cell

Catabolism Anabolic Growth

Nutrients

-Autophagy-Mitophagy

-Glycolysis-Lipolysis

-L-lactate-Ketones-Glutamine

-Fatty Acids

MitochondrialMetabolism

-OXPHOS-Beta-OX

Energy

Therapy

Figure 1. Two-Compartment Tumor Metabolism:Catabolic Host Cells Fuel Anabolic Cancer CellGrowth and Metastasis via Mitochondrial Metabolism

Catabolic host cells that make up the microenvironment (e.g.,

fibroblasts and adipocytes) generate and transfer high-energy

metabolites (L-lactate, ketones, glutamine, and free fattyacids) to epithelial cancer cells, energetically promoting tumor

growth and metastasis. Cancer cells increase their mitochon-

drial massand activity (OXPHOS andb-oxidation) to efficiently

burn these energy-rich mitochondrial fuels. Targeted thera-

pies that metabolically uncouple parasitic cancer cells

from catabolic host cells (such as mitochondrial inhibitors

[metformin and arsenic trioxide], as well as powerful anti-

oxidants) will starve tumor cells. Effective therapies would

block energy transfer, cutting off the fuel supply to cancer

cells.

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Transgenerational Inheritance of Longevity:Epigenetic Mysteries Abound

Shelley L. Berger1,2,3,*1Department of Cell and Developmental Biology2Department of Biology3Department of Genetics1057 BRB, 421 Curie Boulevard, University of Pennsylvania, Philadelphia, PA 19104, USA*Correspondence: bergers@upenn.eduDOI10.1016/j.cmet.2011.12.012

Transgenerational inheritance of epigenetic characteristics in plants has been reported, whereas nongenetic

persistence of complex phenotypes in animals is controversial. A recent report by Anne Brunet and

colleagues describes a fascinating example of persistence across generations of extended life span in

worm and explores whether epigenetic mechanisms account for the longevity.

Major questions in the field of epigenetics

are whether chromatin states persist

through, first, mitotic cell division and,

second, meiotic germ cell generation, in

both cases to provide memory of the epi-

genome. The mitotic memory issue is

relevant to cell type differentiation during

development of multicellular organisms

and to loss of differentiation in human

disease states such as cancer, as well

as to tissue regenerative medicine and

the difficulties inherent in erasing or pro-

foundly altering cell identity. The second

question, of meiotic memory through

germ cells to embryos, while similar in

principle, is more provocative, since this

could perpetuate nongenetic inheritance

across generations. A recent report in

Nature by Anne Brunet and colleagues

unveils a fascinating example of transge-

nerational inheritance, extending life

span in the worm C. elegans and poten-

tially regulated by an epigenetic state

(Greer et al., 2011).

As background, it is important to under-

stand certain theoretical and practical

considerations regarding epigeneticmemory. The key theoretical issue is the

mechanism(s) underlying cell recollection

of identity through cell division, as well

as through gametogenesis and early

embryogenesis, i.e., whether the mole-

cules that transmit memory consist of

DNA-bound transcription factors, long

noncoding RNAs, bona fide chromatin-

regulatory enzymes, specialized histones,

or some combination thereof (Berger

et al., 2009). The practical consideration

is that many epigenetic regulators are

enzymes, enabling discovery of small

molecule modulators; such therapeutics

are already in the clinic or in aggressive

pharmaceutical development and thus

have huge potential impact on human

health (Rodrguez-Paredes and Esteller,

2011).

There is little doubt that epigenetic

memory exists through mitosis; this

phenomenon was initially recognized

through genetic analysis of development

in complex model organisms (Ringrose

and Paro, 2004). However, the question

of transgenerational memory via chro-

matin epigenetic statesis farmore contro-

versial, since it challenges conventional

dogma about genetic inheritance. Indeed,

previous observations of transgenera-

tional inheritance in animals have been

largely anecdotal or epidemiological (Dax-

inger and Whitelaw, 2010); the evolution of

this emerging field requires both molec-

ular experimentation and manipulation.

A number of recent studies have found

a chromatin basis for setting life span,

including chromatin posttranslational

modifications such as reversible histone

acetylation. Sirtuins have long beenknown to have a role in longevity, and al-

though these enzymes have many cellular

substrates, histones indeed appear to be

key age-relevant acetylated substrates

in yeastS. cerevisiaeand in mouse, func-

tioning at telomeres (Dang et al., 2009;

Michishita et al., 2008). Further, histone

methylation also contributes to setting

life span, as shown in C. elegans, in that

deletion of the Set2 methylase enzyme

or other protein components of the H3

Lys4 (H3 K4) methylase complex extends

life span (Greer et al., 2010) (Figure 1A).

Thus, there appears to be chromatin

regulation of aging through organismal

life span involving relaxation of chromatin,

which may be deleterious to genomic

integrity and lead to aberrant gene ex-

pression. Hence, life span is extended

by reduction of certain histone modifica-

tions (Dang et al., 2009; Greer et al.,

2010) or via increased expression of

histones themselves (Feser et al., 2010).

Interestingly, Brunet and colleagues

now show that deletion of the same

worm histone H3 K4 methylase Set2

leads to transgenerational inheritance of

life span extension in wild-type offspring

(Greer et al., 2011). The authors designed

an experimental protocol to avoid ma-

ternal effects that might be transmitted

to offspringoften a question in transge-

nerational inheritance studies (Daxinger

and Whitelaw, 2010)by testing offspring

from the F3 to F5 generations (Figure 1B).

In brief, set-2-deficient mutants with

extended life span were mated to SET-2

wild-type worms to yield a heterozygous

F1 generation, which was then mated to

produce either genetically wild-type orgenetically mutant offspring. The authors

showed that, remarkably, wild-type off-

spring in generations F3 and F4 showed

the same extended life span as the

set2/ offspring (Figure 1B), thereby

demonstrating transgenerational inheri-

tance of extended life span in worms.

Although this is a fascinating observa-

tion, whether the explanation is truly

due to altered chromatin remains to be

investigated, since the study does not

demonstrate a persistent chromatin

effect. That is, an obvious mechanism

6 Cell Metabolism15, January 4, 2012 2012 Elsevier Inc.

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would be reduced H3 K4 methyla-

tion in the F3 and F4 generations in

spite of wild-type SET-2; however,

the authors tested genome-wide

methylation in the long-lived butwild-type offspring, but found no

lowering of H3 K4 methylation by

global western analysis. This does

not rule out possible localized re-

duction in methylation, for example,

at specific genes that might regulate

longevity. To indirectly test this

hypothesis, the authors performed

genome-wide RNA expression mi-

croarray analysis. Although the

authors detected certain restricted

gene expression similarities of the

F3 and F4 transgenerational off-

spring to the actual mutant, theoverall transcriptional picture unex-

pectedly showed expression clus-

tering more similar to the actual

wild-type expression spectrum

than to theactual mutant expression

spectrum. The authors also pointed

out that certain specific GO cate-

gories that regulate metabolism are

altered like the actual mutant; thus,

modest changes at a few genes

may lead to persistent longevity in

the F3 and F4 generations. To

address whether this is a direct or indirect

effect, it will be important to explore

whether H3 K4 methylation is reduced at

these genes in the wild-type offspring.

Another intriguing observation is that

the extended life span abruptly returns

to normal length in the F5 generation

(Figure 1B) without passing through any

intermediate longevity state. The authors

show an F5 RNA expression microarray

with levels similar to the trueSET-2wild-

type, but since theF3 andF4 transcription

results are not clearly like set-2 mutant,

the interpretation of these findings re-

mains ambiguous. Moreover, since noaltered chromatin state was detected in

the F3 and F4 wild-type-but-extended

offspring, at present the chromatin state

in the F5 generation has yet to be deter-

mined. One possibility is that, since there

is no transitional partial state, a threshold

effect may exist, which would support

the idea that there are only a few genes

critical to life span extension, and, once

the methylation level increasesto a certain

level in the F5, the life span is no longer

extended.

The study also reports that several

other longevity genes, including deletion

of a few chromatin modulators of tran-

scription that extend life span (e.g., the

H3 K9 methylase and H3 K27 demethy-

lases) (Greer et al., 2010; Carone et al.,

2010), fail to show a transgenerationallongevity effect. Thus, it is tempting to

speculate that K4 methylation plays a

key role in transgenerational longevity or

that other epigenetic mediators of trans-

generational longevity exist and

have not yet been tested.

Thus, this report establishes a

precedent that longevity can be

maintained transgenerationally;however, major challenges remain

to show a direct epigenetic basis

for the transgenerational inheritance.

Taken together with other emerging

examples in animals of trans-

generational inheritance of complex

phenotypes with possibleunderlying

epigenetic mechanisms (Carone

et al., 2010), we can anticipate

many new studies exploring this

fascinating question in the near

future.

REFERENCES

Berger,S.L., Kouzarides, T., Shiekhattar,R.,and Shilatifard, A. (2009). Genes Dev. 23,781783.

Carone, B.R., Fauquier, L., Habib, N., Shea,J.M., Hart, C.E., Li, R., Bock, C., Li, C., Gu,H., Zamore, P.D., et al. (2010). Cell 143,10841096.

Dang, W., Steffen, K.K., Perry, R., Dorsey,J.A., Johnson, F.B., Shilatifard, A., Kaeber-lein, M., Kennedy, B.K., and Berger, S.L.(2009). Nature459, 802807.

Daxinger, L., and Whitelaw, E. (2010). GenomeRes. 20, 16231628.

Feser, J., Truong, D., Das, C., Carson, J.J., Kieft,J., Harkness, T., and Tyler, J.K. (2010). Mol. Cell39, 724735.

Greer, E.L., Maures, T.J., Hauswirth, A.G., Green,E.M., Leeman, D.S., Maro, G.S., Han, S., Banko,M.R., Gozani, O., and Brunet, A. (2010). Nature

466, 383387.

Greer, E.L., Maures, T.J., Ucar, D., Hauswirth,A.G., Mancini, E., Lim, J.P., Benayoun, B.A., Shi,Y., and Brunet, A. (2011). Nature 479, 365371.

Michishita, E., McCord, R.A., Berber, E., Kioi, M.,Padilla-Nash, H., Damian, M., Cheung, P., Kusu-moto, R., Kawahara, T.L., Barrett, J.C., et al.(2008). Nature452, 492496.

Ringrose, L., and Paro, R. (2004). Annu. Rev.Genet. 38, 413443.

Rodrguez-Paredes, M., and Esteller, M. (2011).Nat. Med.17, 330339.

A

B

SET-2

H3K4me

gene

Parents set-2-/- X WT

F1 (set-2+/-)

F2

F3,F4

F5H3K4me

gene

Longer LS Shorter LS

longer

LS

shorter

LS

SET-2+/+

Aging

Figure 1. Transgenerational Inheritance of Longevity(A) Aging may lead to decompaction of chromatin, resulting in

inappropriate gene expression. In the wormC. elegans, dele-

tion of the H3 K4 methylase, SET-2, extends life span.

(B) Transgenerational inheritance of extended life span (LS) in

the worm C. elegans results from parental deletion ofSET-2

(set2/) and transmittal to wild-type F3 and F4 generations.

Shorter life span is resumed in the wild-type F5 generation.

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IL-6 Muscles In on the Gut and Pancreasto Enhance Insulin Secretion

Tamara L. Allen,1 Martin Whitham,1 and Mark A. Febbraio1,*1Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne 3008, Victoria, Australia*Correspondence: mark.febbraio@bakeridi.edu.auDOI10.1016/j.cmet.2011.12.004

The role of the cytokine interleukin-6 (IL-6) in metabolic homeostasis is the subject of conjecture. Recent

work in Nature Medicine (Ellingsgaard et al., 2011) demonstrates that IL-6 released from skeletal muscle

during exercise mediates crosstalk between insulin-sensitive tissues, intestinal L cells, and pancreatic islets

to adapt to changes in insulin demand.

The debate regarding the pathological

versus beneficial nature of IL-6 in metab-

olism remains unclear and the subjectof continuing debate(Mooney, 2007; Ped-

ersen and Febbraio, 2007). On one hand,

increased IL-6 in obesity is associated

with the physiopathology of type 2 dia-

betes (Klover et al., 2003), while on the

other, muscle-derived IL-6 appears to

contribute to improved glycemia following

exercise (Pedersen and Febbraio, 2008).

A recent study published in Nature Medi-

cine (Ellingsgaard et al., 2011) makes

a telling contribution to our understanding

of this apparent paradox. The authors

found that IL-6, released from either con-

tracting skeletal muscle or white adipose

tissue, stimulated glucagon-likepeptide-1

(GLP-1) from the gut and the pancreas.

As GLP-1 is a hormone that induces

insulin secretion, this complex organ-

to-organ crosstalk provides strong evi-

dence that IL-6 is a cytokine that has

positive effects on maintaining glucose

homeostasis.

Thebasic concept that IL-6 is an inflam-

matorycytokine that leads to insulin resis-

tance was first challenged with the finding

that skeletal muscle releases IL-6 during

contraction (Steensberg et al., 2000) toact in an endocrine-like manner (Febbraio

et al., 2004). Since this discovery, IL-6 has

been found to increase glucose uptake

and fat oxidation in skeletal muscle and

improve glucose tolerance and insulin

sensitivity (Carey et al., 2006; van Hall

et al., 2003), effects that oppose those

seen in the development of metabolic

syndrome. The recent paper by Donath

and colleagues (Ellingsgaard et al., 2011)

neatly demonstrates that IL-6 mediated

increases in GLP-1 secretion from L cells

in the intestine andacells in the pancreas

that led to improvedb cell function, insulin

secretion, and glycemic control. This

study is the first to provide evidence ofa previously unknown link between IL-6

secretion from insulin-sensitive tissues

and the beneficial effects of GLP-1 on

insulin action. By using IL-6 knockout

mice and coadministration of an IL-6 anti-

body, this recent paper (Ellingsgaard

et al., 2011) demonstrated that the exer-

cise-induced increase in GLP-1 was IL-6

dependent. Furthermore, IL-6 was unable

to improve glucose tolerance in mice

lacking the GLP-1 receptor or mice

treated with the GLP-1 receptor antago-

nist, exendin (9-39). Interestingly, in addi-

tion to acute administration of IL-6, the

authors were also able to demonstrate

improved glycemia and glucose tolerance

following twice daily injections of IL-6 for

7 days. These effects were associated

with increases in synthesis and expres-

sion of circulating GLP-1. Significantly,

pancreatic GLP-1, insulin, and glucagon

content were also increased with IL-6

administration, along with insulin secre-

tion from the islets of treated mice.

It is well known that exercise improves

insulin action in the immediate postexer-

cise period (Wojtaszewski et al., 2000),but until now the mechanism has been

unclear. Two important experiments in

the current study (Ellingsgaard et al.,

2011) provide new and important informa-

tion on the phenomenon of enhanced

postexercise insulin action. First, IL-6-

deficient mice displayed no improvement

in glucose tolerance postexercise, and

second, the improvement was seen only

when the glucose tolerance test was

administered orally, not intraperitoneally,

indicative of the dependence on GLP-1.

This study supports the notion that

skeletal muscle is an endocrine organ,

capable of secreting metabolically active

proteins termed myokines (Pedersenand Febbraio, 2008).

As the role of IL-6 in obesity and

metabolic disease is controversial, the

authors sought to investigate whether

additional administration of IL-6 could im-

prove b cell function in overfed, insulin-

resistant, and diabetic animals. Exoge-

nous IL-6 improved glucose tolerance

and insulin secretion in high-fat-fed

ob/obanddb/dbmice. By way of support

for the proposed IL-6/GLP-1 b cell mech-

anism, high-fat-fed mice whose b cells

were destroyed with streptozotocin failed

to improve insulin secretion with adminis-

tration of IL-6. Additionally, endogenous

IL-6 in db/db mice was blocked with

an IL-6 antibody treatment. Increased

fasting glucose levels and decreased glu-

cose tolerance were reported in animals

treated with the IL-6 antibody, as well as

lowered glucagon levels and undetect-

able GLP-1 levels. GLP-1 content in the

pancreas of treated animals was also

lower than in control mice. Importantly,

analysis of high-fat-fed mice found that

IL-6 was required for the high-fat-diet-

induced expansion of a cell mass andincreases in pancreatic GLP-1 content

and subsequent insulin secretion.

This paper highlights the importance of

organ crosstalk and may offer an addi-

tional therapeutic target for the modula-

tion of glucose metabolism in obesity

and diabetes. However, these findings

still need to be interpreted with caution.

There are still many instances in the litera-

ture that suggest that IL-6 may be detri-

mental to maintaining metabolic homeo-

stasis in obesity. While the study by

Ellingsgaard et al. (2011)adds weight to

8 Cell Metabolism15, January 4, 2012 2012 Elsevier Inc.

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theargumentthat IL-6 maybe

elevated in obesity in order to

counteract other more del-

eterious factors associated

with obesity, the pleiotropicnature of IL-6 makes thera-

peutic strategies difficult.

In summary, the work by

Donath and colleagues has

provided crucial data that

adipose tissue-derived IL-6

in obesity and diabetes as

well as skeletal muscle IL-6

during exercise mediate the

production and secretion of

GLP-1 from the intestine and

pancreas, leading to an en-

hanced insulin response and

improved glycemia (see Fig-ure 1). This study provides

further evidence of the impor-

tance of IL-6 in glucose

metabolism and uncovers its

previously unknown role in

linking adipose tissue, skel-

etal muscle, intestines, and

pancreas through GLP-1.

Moreover, the study strengthens the

concept that the skeletal muscle is an

endocrine organ, capable of secreting

factors that can affect not only the

adipose tissue and the liver, but also the

gut, pancreas, and perhaps many other

organs. The work opens the door to the

identification of other skeletal muscle

secretory factors that may modulate

metabolic processes.

ACKNOWLEDGMENTS

M.A.F. is a Senior Principal Research Fellow of the

National Health and Medical Research Council of

Australia.

REFERENCES

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O., Hohnen-Behrens, C., Watt, M.J.,James, D.E., et al. (2006). Diabetes55, 26882697.

Ellingsgaard, H., Hauselmann, I.,Schuler, B., Habib, A.M., Baggio,L.L.,Meier,D.T., Eppler,E., Bouzakri,K., Wueest, S., Muller, Y.D., et al.(2011). Nat. Med.17, 14811489.

Febbraio, M.A., Hiscock, N., Sac-chetti, M., Fischer, C.P., and Peder-sen,B.K. (2004). Diabetes 53, 16431648.

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Klarlund Pedersen, B. (2000). J. Physiol. 529,237242.

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Figure 1. The Pleiotropic Metabolic Effects of the Cytokine IL-6IL-6 is released from contracting skeletal muscle and adipose tissue to trigger

GLP-1 release from the gut and the pancreas to improve glucose tolerance.

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Cell Metabolism

Review

The Inflammasome Puts Obesity in the Danger Zone

Rinke Stienstra,1,2,3 Cees J. Tack,1 Thirumala-Devi Kanneganti,4 Leo A.B. Joosten,1,2 and Mihai G. Netea1,2,*1Department of Medicine2Nijmegen Institute for Infection, Inflammation and Immunity (N4I)Radboud University Nijmegen Medical Centre, Nijmegen 6525 GA, The Netherlands3Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen 6703 HD, The Netherlands4Department of Immunology, St. Jude Childrens Research Hospital, Memphis, TN 38105, USA*Correspondence:m.netea@aig.umcn.nlDOI10.1016/j.cmet.2011.10.011

Obesity-induced inflammation is an important contributor to the induction of insulin resistance. Recently, the

cytokine interleukin-1b (IL-1b) has emerged as a prominent instigator of the proinflammatory response in

obesity. Several studies over the last year have subsequently deciphered the molecular mechanisms respon-

sible for IL-1bactivation in adipose tissue, liver, and macrophages and demonstrated a central role of the

processing enzyme caspase-1 and of the protein complex leading to its activation called the inflammasome.

These data suggest that activation of the inflammasome represents a crucial step in the road from obesity to

insulin resistance and type 2 diabetes.

Introduction

Accumulating evidence links inflammation to metabolic changes

associated with obesity and type 2 diabetes (Donath and Shoe-

lson, 2011). While several studies suggest that expanding

adipose tissue is an important first step in driving the enhanced

state of inflammation, the underlying molecular mechanisms

modulating this process are less clear. A wide variety of immune

cells, including macrophages, monocytes, T cells, and b cells,

have been shown to infiltrate the adipose tissue and affect its

homeostasis by releasing inflammatory cytokines (Anderson

et al., 2010). Adipocytes themselves are also capable of

releasing inflammatory mediators and contribute to the inflam-

matory response (McGillicuddy et al., 2011; Stienstra et al.,

2010; Meijeret al., 2011). In addition to adipose tissue, inflamma-

tion in liver and pancreatic islets is also evident in obese individ-

uals andparticipates in thepathogenesis of type 2 diabetes (Gre-

gor and Hotamisligil, 2011). One of the proinflammatory

cytokines mediating obesity-induced inflammation is interleukin

(IL)-1b, which is processed by caspase-1, a cysteine protease

regulated by a protein complex called the inflammasome.

Although growing evidence points to a crucial role for IL-1b in

mediating the development of insulin resistance, it should be

stressed that the inflammatory response driving the develop-

ment of insulin resistance probably is comprised of a combina-

tion of proinflammatory cytokines that jointly effectuate type 2diabetes progression. For example, involvement of TNFa in

obesity-associated insulin resistance has been frequently re-

ported. Since biological processes are often multifactorial,

involvement of other cytokines like TNFais plausible.

Although detrimental effects of IL-1b on b cell function have

been well documented, the proinflammatory effects of IL-1bthat

mediate the development of tissue dysfunction and peripheral

insulin resistance have only recently received more interest. While

several lines of evidence have shown involvement of IL-1bin the

developmentof obesity-associatedinsulin resistance peripherally,

the quantitative contribution remains to be defined in more detail.

In the present review we will discuss recently identified meta-

bolic triggers that may function as potential danger signals,

promoting activation of inflammasome-dependent caspase-1,

and highlight new findings regarding the mechanisms involved

in the processing of IL-1b during the progression of obesity

and insulin resistance. In light of the growing interest to block

low-grade inflammation in obese and insulin-resistant subjects,

this reviewwill particularly focus on thepotential of theinflamma-

some as a therapeutic target in the treatment of obesity-induced

insulin resistance.

Pathogenic Role of IL-1b in the Development of Obesity,

Insulin Resistance, and Diabetes

IL-1b elicits potent proinflammatory actions through its binding

to the IL-1 receptor that in turn recruits the IL-1 receptor acces-

sory protein. This receptor complex signals through the myeloid

differentiation factor 88 (MyD88) adaptor protein that spurs on

IL-1 receptor-activated kinases (IRAK1 to 4). This leads to activa-

tion of several protein kinases, including mitogen-activated

protein kinase 8 (JNK), mitogen-activated protein kinase 1

(ERK), p38 MAPK, and inhibitor of kappaB kinase (IKK), that

initiate the transcription factors nuclear factor kB (NF-kB) and

activator protein 1 (AP1) to stimulate inflammatory gene expres-

sion(Dinarello, 2011) (see Figure 1). The proinflammatory actions

of IL-1bare recognized as an important contributor to the devel-

opment of both type 1 and type 2 diabetes (Donath and Shoe-

lson, 2011; Mandrup-Poulsen et al., 2010). While IL-1bhas toxiceffects on pancreatic b cells in the process of autoimmune dia-

betes (Mandrup-Poulsen et al., 1986), the cytokine also appears

to be involved in b cell deterioration related to glucotoxicity in

type 2 diabetes (Donath et al., 2003), with both processes

leading to defective insulin production. By activation of Fas-trig-

gered apoptosis, which involves the transcription factor NF-kB,

IL-1b mediates b cell dysfunction. More peripherally, IL-1b

directly inhibits insulin signaling pathways by reducing tyrosine

phosphorylation of insulin receptor substrate 1 (IRS1) and nega-

tive regulation of IRS1 gene expression levels, thus inducing

a state of insulin resistance (Jager et al., 2007). In animal studies,

the lackof IL-1b or its receptor protects against the development

of adipose tissue inflammation and insulin resistance upon

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high-fat diet feeding (Wen et al., 2011; McGillicuddy et al., 2011).

This protective effect may partially be mediated by the absence

of IL-1b-controlled chemokine synthesis (Dinarello, 2011), which

governs the influx of various immune cells into adipose tissue,

thus promoting inflammation.

In line with the proposed pathogenic role of IL-1b, increased

circulating levels of this cytokine accompanied by elevated

levels of IL-6 positively correlate with the development of type2 diabetes in humans (Spranger et al., 2003). Conversely,

blockade of excessive IL-1 signaling in subjects with type 2 dia-

betes improves glycemic control and b cell function while

reducing markers of systemic inflammation (Larsen et al.,

2007). Although clinical studies have revealed that inhibition of

IL-1 signaling improves glucose tolerance, data pointing to an

improvement of insulin sensitivity upon anti-IL-1 treatment are

scarce. However, clinical studies using salsalate, an unspecific

anti-inflammatory agent, have demonstrated a significant

improvement in insulin sensitivity (Goldfine et al., 2008). It should

be noted that highly targeted anticytokine treatment ap-

proaches, such as treatment with the anti-TNF antibody (inflixi-

mab), have been found to be successful in improving insulin

sensitivity in patients diagnosed with rheumatoid arthritis (Gon-

zalez-Gay et al., 2010; Huvers et al., 2007).

Until recently, the triggers and molecular switches controlling

IL-1bproduction during the development of obesity and insulin

resistance have remained largely unknown. In as much as

IL-1b elicits a vigorous inflammatory response, activation must

be tightly controlled and requires processing from an inactive

procytokine into the biologically active form by proteolyticenzymes. Processing of cytokines of the IL-1 family, such as

IL-1b and IL-18, is mainly mediated by the cysteine protease

caspase-1, which in turn is activated by a protein platform

termed the inflammasome.

The Inflammasome

The inflammasome is an important part of our innate immune

system that responds to danger signals that are sensed by

a number of different intracellular NOD-like receptors (NLRs).

Different inflammasomes have been identified, including NLR

family pyrin domain-containing 1 (NLRP1), NLR family pyrin

domain-containing 3 (NLRP3), NLR family pyrin domain-con-

taining 6 (NLRP6), AIM2 (absent in melanoma 2), and IPAF

Figure 1. IL-1bSignaling Pathway: Overview of the Intracellular Signaling Pathways Activated by Binding of IL-1bto the IL-1 ReceptorUpon activation of the IL-1 receptor complex, IL-1b induces recruitment of the myeloid differentiation primary response gene88 (MyD88), whichin turn promotesactivation of the interleukin-1 receptor kinase (IRAK) cascade. Via tumor necrosis factor-associated factor 6 (TRAF6) and the c-Jun N terminus (JNK), p38mitogen-activated protein (p38 MAPK), and the inhibitor of nuclear factor b (IKK) kinases, theIkB cofactor is degraded, whichsubsequently promotes the nucleartranslocation of NF-kB and AP-1. Both transcription factors have the capacity to induce proinflammatory gene expression of various cytokines and chemokinesthat modulate the inflammatory response.

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(IL-1b-converting enzyme protease-activating factor), which

each have the ability to respond to a wide variety of microbial

products or endogenous danger signals (Dunne, 2011). Hitherto,

NLRP3 is the most extensively studied inflammasome that, upon

its activation, forms a complex with its adaptor molecule PYDand CARD domain containing protein (ASC) and thereby facili-

tates caspase-1-dependent processing of pro-IL-1b into its

active form. Normally, this proinflammatory response provides

protection for the host by inducing an acute phase response

(Dinarello, 2011).

Recentstudies have identified theinflammasomeas an impor-

tant contributor to the development of insulin resistance by

mediation of processing and release of IL-1b in various tissues

and cell types during the development of obesity. In addition to

IL-1b, caspase-1 is also able to process and activate IL-18 and

IL-33 (Arend et al., 2008). In contrast to IL-1b, IL-18 ameliorates

development of obesity and insulin resistance (Netea et al.,

2006). Interestingly, caspase-1 deficient mice lacking both

IL-1band IL-18 are characterized by an improvement in insulinresistance (Stienstra et al., 2010), suggesting that the insulin-

desensitizing effects of IL-1b override IL-18 action. The fact

that expression and circulating levels of IL-18 are easily detect-

able in healthy subjects, as compared to IL-1b, suggests that this

cytokine executes different functions, among which are the

opposing effects on insulin resistance.

NLRP3-Mediated Caspase-1 Activity in the Drivers Seat

Several lines of evidence suggest that activation of inflamma-

some-mediated caspase-1 is one of the culprits behind the

enhanced inflammatory state characteristic of obesity and has

center stage in the pathogenesis of type 2 diabetes by acting

at two different levels.

First, caspase-1 appears to instigate defective insulin secre-

tion by promoting pancreatic dysfunction. Pancreatic b cells it-

self are capable of producing IL-1b (Boni-Schnetzler et al.,

2008; Maedler et al., 2002) through mechanisms involving the

NLRP3 inflammasome (Zhou et al., 2010). Additionally,

enhanced macrophages infiltration of the pancreas observed

in human type 2 diabetic patients and high-fat diet (HFD)-fed

mice(Ehses et al., 2007) may further potentiate IL-1b production.

The IL-1b-driven inflammation of the islets is proposed as the

central mediator of glucose-, lipid-, and amyloid-induced b cell

failure leading to defective insulin secretion (Masters et al.,

2011; Mandrup-Poulsen, 2010) and ultimately b cell death, two

processes distinctive for the pathogenesis of type 2 diabetes.

Second, activation of caspase-1 can alter the function ofperipheral tissues, including adipose tissue and liver, both criti-

cally involved in maintaining glucose homeostasis. Adipose

tissue of animals fed a high-fat diet to induce obesity and insulin

resistance is characterized by enhanced gene expression and

increased protein levels of caspase-1 (Stienstraet al., 2010; Van-

danmagsar et al., 2011). Similarly, feeding mice a methionine-

choline-deficient diet, which promotes the development of

nonalcoholic steatohepatitis (NASH), has been shown to

promote NLRP3-dependent caspase-1 activation within hepato-

cytes (Csak et al., 2011). The elevated activity of caspase-1 leads

to increased processing of IL-1band promotes a proinflamma-

tory environment that drives tissue dysfunction. Indeed, the

absence of caspase-1 provides protection for the host against

the deleterious effects of high-fat diet feeding. For example,

caspase-1/ mice have a decreased influx of macrophages

into adipose tissue upon high-fat diet feeding (Stienstra

et al., 2011). Similarly, ASC/ (Stienstra et al., 2011) and

NLRP3

/

animals (Vandanmagsar et al., 2011) were protectedagainst the development of hepatosteatosis instigated by high-

fat diet feeding. Importantly, HFD-fed mice lacking caspase-1

were characterized by a robust improvement in insulin sensitivity

andwere rescued from thedevelopment of obesity as compared

to wild-type mice (Stienstra et al., 2011). Notably, part of the

protective effects of the absence of caspase-1 may be accom-

plished by the reduction in weight gain as compared to the

wild-type animals fed the high-fat diet. A similar protection

against insulin resistance was observed in HFD-fed animals

lacking ASC or NLRP3 (Wen et al., 2011). However, different

phenotypical responses were observed between the various in-

flammasome knockout models upon high-fat diet feeding.

Whereas the absence of NLRP3 only provided protection against

high-fat diet-induced insulin resistance and fatty liver diseaseafter prolonged exposure to the diet for up to 9 months in one

model (Vandanmagsar et al., 2011), shorter periods of high-fat

diet feeding also appear to activate NLRP3 (Wen et al., 2011).

The absence of caspase-1 and ASC conferred protection

against the development of insulin resistance after 12 or

16 weeks of diet intervention. These results imply that NLRP3

activation may require secondary danger signals that are only

apparent after prolonged high-fat diet feeding and may include

lipotoxic metabolites like sphingolipids. Hypothetically, differ-

ences in the composition of the diets that were used to induce

obesity may have altered the supply of NLRP3 danger signals.

Alternatively, other inflammasomes next to NLRP3 may also be

involved in the development of obesity-induced insulin resis-

tance. Furthermore, differences in expression levels between

distinct adipose tissue cell populations may explain any pheno-

typical variance. While caspase-1 is highly expressed in both

adipocytes and nonadipoycte cells, the inflammasome

members NLRP3 and ASC are predominantly expressed in non-

adipocyte cells that are part of the adipose tissue. Although the

lower expression levels do not rule out any function of ASC and

NLRP3 in adipocytes, it appears that crosstalk between both cell

types determines the secretion levels of IL-1bby adipose tissue.

However, it should be emphasized that isolated adipocytes do

have the potential to produce IL-1b (Koenen et al., 2011b).

Hence, caspase-1 activation in adipocytes may rely on non-

NLRP3 inflammasome members or is controlled independently

of the inflammasome.Additionally, important tissue-specific effects of various in-

flammasomes have recently been described, such as theregula-

tion of IL-18 production in intestinal epithelial cells by the NLRP6

inflammasome (Elinav et al., 2011). This opens up the intriguing

and yet unexplored possibility of specific inflammasome compo-

nents present in adipocytes, hepatocytes, macrophages, or

pancreaticb cells that may differentially affect the development

of insulin resistance. Alternatively, differential regulation of

similar inflammasome subtypes may also occur and mediate

tissue-specific effects.

There is supportive evidence for the involvement of the in-

flammasome in obesity-induced inflammation in humans. For

example, caspase-1 activity levels are more pronounced in the

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visceral fat depot, which is a strong determinant of insulin resis-

tance, as compared to subcutaneous adipose tissue of mildly

obese subjects (Koenen et al., 2011b). In liver, expression levels

of NLRP3, caspase-1, and ASC areelevated in patients suffering

from NASH compared to healthy controls (Csak et al., 2011).Conversely, substantial weight loss in obese subjects with type

2 diabetes was shown to reduce expression levels of IL-1band

NLRP3 in adipose tissue and positively correlated with changes

in fasting plasma glucose levels (Vandanmagsar et al., 2011).

Overall, these results argue that activation of IL-1bby the in-

flammasome plays a central role in the pathogenesis of

obesity-induced insulin resistance. Since activation of cas-

pase-1 leading to the cleavage and secretion of IL-1b is under

tight control of the inflammasome, specific danger signals

should exist that arise during the development of obesity and

that are sensed by intracellular NLRs. Indeed, several studies

have identified metabolic danger signals that can efficiently acti-

vatethe inflammasome, leading to caspase-1-driven cleavageof

IL-1b in a variety of cell types,both from nonmyeloid andmyeloidorigin (Vandanmagsar et al., 2011; Wen et al., 2011; Csak et al.,

2011; Zhou et al., 2010; Masters et al., 2010).

Potential Metabolic Danger Signals that Activate IL-1b

Recent studies have revealed that activation of IL-1b requires

two signals (Gong et al., 2010; Joosten et al., 2010; Hornung

et al., 2009). Whereas the first signal primes the cell and acts

as an inducer of IL-1band NLR mRNA transcription, the second

signal induces conformational changes in the inflammasome

that instigates caspase-1 activation. Classically, the first signal

is provided by invading pathogens driving IL-1b mRNA transcrip-

tion through pattern recognition receptors such as toll-like

receptors (TLRs) (Lamkanfi et al., 2008). The second signal is

of a more heterogeneous nature, as it can be represented by

microbial components such as microbial DNA (Muruve et al.,

2008), cell-wall components, and toxins (Ali et al., 2011), but

also by endogenous ligands such as adenosine triphosphate

(ATP) or uric acid (Mariathasan et al., 2006). The precise unifying

mechanism through which all these ligands induce caspase-1

activation is not known, although a rapid K+ efflux from cells

seems to be a common denominator that triggers activation of

the inflammasome (Lamkanfi et al., 2008). Notably, not all cell

types need sequential hits to induce IL-1b production. For

example, monocytes only require the first signal to induce in-

flammasome-dependent IL-1b release, due to the constitutive

activation of caspase-1 in this cell type (Netea et al., 2009).

Moreover, IL-1bcan also be processed by caspase-1-indepen-dent cleavage through neutrophil-derived serine proteases

(Joosten et al., 2009), yet no information is available concerning

the mechanism that controls this process.

Very recently, fatty acids, glucose, uric acid, and islet amyloid

polypeptide (IAPP) have been put forward as metabolic danger

signals that possess the capacity to activate the inflammasome

and stimulate IL-1bproduction (Figure 2). Below we will discuss

where exactly these signals might act to promote IL-1brelease.

Fatty Acids

Elevated circulating levels of free fatty acids are one of the hall-

marks of type 2 diabetes (Krebs and Roden, 2005). Interestingly,

it has been suggested that saturated fatty acids bind and acti-

vate members of the TLR-family in vitro (Lee et al., 2001). For

example, palmitate acts as a ligand for TLR4 and induces IL-6

mRNA expression through activation of the transcription factor

NF-kB (Shi et al., 2006). Moreover, treatment of human THP-1

cells with palmitate has been shown to induce IL-1b mRNA

expression (Haversen et al., 2009) although some doubt hasbeen cast on whether saturated fatty acids can induce TLR

signaling (Erridge and Samani, 2009). However, elevated levels

of palmitatemay provide thefirst signalneeded forIL-1b produc-

tion though induction of IL-1b gene transcription, although it

has to be kept in mind that levels of all fatty acids are elevated

in type 2 diabetes and may alter the effect of palmitate on

IL-1bproduction.

In addition, recent work demonstrates that palmitate also has

the potential to directly activate the NLRP3-inflammasome in

macrophages and thus provide the second signal needed for

IL-1b release (Wen et al., 2011). Via detailed mechanistic

in vitro studies, it was shown that palmitate negatively affects

the activation of AMP-activated protein kinase (AMPK), an

energy-sensing kinase that regulates multiple biochemical path-ways in all eukaryotes, including lipid and glucose metabolism

and apoptosis (Steinberg and Kemp, 2009). The reduction in

AMPK phosphorylation leads to defective autophagy, a process

known to regulate the clearance of dysfunctional mitochondria.

The authors propose that the subsequent intracellular accumula-

tion of mitochondrial-derived reactive oxygen species (ROS)

represents the trigger activating the inflammasome. Indeed,

ROS have long been proposed to activate the inflammasome,

although some controversy exists. For example, cells isolated

from patients diagnosed with chronic granulomatous disease

(CGD) have defective NADPH activity and thus cannot generate

NADPH-dependent ROS (vande Veerdonk et al., 2010; Meissner

et al., 2010). Upon stimulation, monocytes from CGD patients

produced similar or even increased amounts of IL-1b as

compared to cells from unaffected subjects, indicating

NADPH-independent activation of the inflammasome. In this

respect, enhanced production of ROS by mitochondria, a hall-

mark of insufficient mitochondrial function that is strongly asso-

ciated with type 2 diabetes (Jin and Patti, 2009), may be an alter-

native source driving NLRP3 inflammasome activation

(Tschopp, 2011).

Other pathways that mediate palmitate-induced inflamma-

some activation can also be envisaged. Exposure of cells to

palmitate induces intracellular accumulation of ceramide, which

is produced by a ubiquitous bi