Leptin

10 Pages·2001·0.19 MB·English

by  Faggioni R., Feingold K.R., Grunfeld C.

Leptin
Raffaella Faggioni, Kenneth R Feingold and Carl Grunfeld*
MetabolismSection,DepartmentofVeteransAffairsMedicalCenter,DepartmentofMedicine,University
of California, San Francisco, CA 94124, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2001.06007.
SUMMARY db/dbmice,whichhaveamutationinthedbgeneand
displayaphenotypeidenticaltoob/obmice,makethe
Leptinisa16kDaproteinmainlyproducedbyadipose factormissinginob/obmice,butcannotrespondtoit.
tissueindirectproportiontofatdepotmass.Originally Therefore itwas hypothesizedthat the db genewould
thought to be a satiety factor, leptin displays pleio- encode for the ob receptor. In 1994 using positional
tropicactivities.Boththestructureofleptinandthatof cloning technique, Friedman identified the molecular
itsreceptorsuggestthatleptinmightbeclassifiedasa defect responsible for the obesity syndrome in ob/ob
cytokine. The secondary structure of leptin has simil- mice (Zhang et al., 1994). The 16kDa protein
aritiestothelong-chainhelicalcytokinefamily,which encoded by the ob gene was named leptin, from the
includes IL-6, IL-11, CNTF, and LIF, and the leptin Greek leptos which means thin.
receptor is homologous to the gp130 signal-transduc- Leptinisproducedinadiposetissueandcirculating
ing subunit of the IL-6-type cytokine receptors. levelsdirectlycorrelatewithadiposetissuemass.Leptin
Furthermore, leptin levels are acutely increased by reverses the obesity syndrome in ob/ob mice and
inflammatorystimulisuchasLPSandturpentineand causes decreased food intake and increased activity
by cytokines, indicating that leptin induction is part when administered to normal mice (Campfield et al.,
ofthehostresponsetoinflammation.Defectsinleptin 1995; Halaas et al., 1995; Pelleymounter et al., 1995).
production, such as observed in ob/ob mice, or in the The leptin receptor (OB-R) was cloned shortly there-
long isoform of the leptin receptor (db/db mice and afterbyvirtueofitshighaffinitytoleptinthroughan
fa/farats)causeacomplexsyndromecharacterizedby expression cloning strategy (Tartaglia et al., 1995).
severe obesity, infertility, and impaired immune TheOB-Rwasfoundtobetheproductofthedbgene
responses. and db/db mice were shown to be resistant to leptin
(Lee et al., 1996).
BACKGROUND Alternative names
Discovery Authors refer to the product of the ob gene as leptin,
LEP or OB protein.
Forty years ago a genetic defect was identified in
mice, which, if homozygous, causes a severe obese
Structure
phenotype due to overeating and decreased energy
expenditure(Coleman,1978).Thegenewasnamedob
and the obese mice carrying the mutation were called Despite the absence of sequence similarity between
ob/ob mice. Parabiotic animal experiments suggested leptin and other long-chain helical cytokines, there is
that the ob/ob animals were unable to make a satiety astrikingstructuralsimilarityinthetertiarystructure
factor, but could respond to such a factor from a (Zhang et al., 1997). Leptin has a four-helix bundle
parabiotic mate. Similar experiments suggested that similar to that of the long-chain helical cytokine
CytokineReference Copyright#2001AcademicPress
2 Raffaella Faggioni, Kenneth R Feingold and Carl Grunfeld
family, which also includes IL-6, IL-11, IL-12, LIF, similartothecytokineresponsetoinfectionandinjury.
G-CSF, CNTF, and oncostatin M. Furthermore, the Inaddition,boththestructureofleptinandthatofits
leptinreceptorishomologoustothegp130family,the receptor suggest that leptin might be classified as a
signal-transducing subunit of the IL-6-type cytokine cytokine (Baumann et al., 1996; Zhang et al., 1997).
receptors (Baumann et al., 1996). Furthermore, leptin deficiency in ob/ob mice causes
impaired immune responses, with lymphoid atrophy,
reducedTcellfunctionandenhancedsusceptibilityto
Main activities and infections (Chandra, 1980; Faggioni et al., 1999).
Hyperresponsiveness to monocyte/macrophage-acti-
pathophysiological roles
vating stimuli, i.e. LPS or TNF(cid:11), is present in both
genetically leptin-deficient (ob/ob) mice and physiolo-
Leptin and the Control of Food Intake
gically leptin-deficient starved mice (Faggioni et al.,
Leptinwasoriginallyproposedasasatietyfactorpro- 1999,2000b;Takahashietal.,1999).Leptindeficiency
duced by adipose tissue in proportion to fat depot isaccompaniedbyincreasedsusceptibilitytoLPS-and
mass (Campfield et al., 1995; Halaas et al., 1995; TNF-induced lethality and liver injury and decreased
Pelleymounter et al., 1995). Leptin signals the nutri- inductionofanti-inflammatorycytokines(Yangetal.,
tional status from the periphery to the center of the 1997; Faggioni et al., 1999; Takahashi et al., 1999).
brain involved in the homeostasis of energy balance. Humans with genetic leptin deficiency also exhibit
In agreement with the proposed role of leptin as a increasedlethalityfrominfections(Ozataetal.,1999).
satiety factor, the absence of leptin, as observed in Leptin has been shown to have direct effects on T
leptin-deficient, obese ob/ob mice, causes overeating lymphocytes, enhancing the T helper (TH) allopro-
anddecreasedactivity.Leptinreplacementnormalizes liferativeresponse(Lordetal.,1998).Leptinpolarizes
food intake and increases activity, decreasing body TH cells toward a TH1 phenotype by enhancing
weight to normal levels. However, the physiological INF(cid:13) and IL-2 and inhibiting IL-4 production.
role initially proposed for leptin as a satiety signal is Leptin plays an important role in T cell-mediated
not consistent with certain aspects of its physiologic livertoxicityinassociationwitharegulatoryeffecton
regulation. For example, leptin levels acutely change thymus and peripheral blood cellularity as well as on
with feeding or fasting disproportionately to the the production of two proinflammatory cytokines,
changes in fat depot (Ahima et al., 1996). Therefore, TNF(cid:11) and IL-18 (Faggioni et al., 2000a).
leptin cannot just be a read-out of the fat stores. A diminished immune response has long been
Secondly,leptintreatmentatphysiologicallevelsdoes recognized as a consequence of starvation (Chandra,
notcausesatiety, butdecreases food intakein the ob/ 1996). Thymic atrophy and decreased T lymphocyte
ob to normal; higher doses of leptin are required to responses, such as delayed-type hypersensitivity
decrease food intake in normal animals (Campfield (DTH)reaction,areprominentfeaturesofstarvation.
et al., 1995; Halaas et al., 1995; Pelleymounter et al., Increased susceptibility to infection also accompanies
1995).Moreimportant,apleiotropicroleforleptinin malnutrition. Starvation also causes a significant
mammalian physiology is suggested by the complex reduction in circulating leptin levels. This decrease is
syndromeexhibitedbyleptin-deficientob/obmiceand now thought to be responsible for the diminished
leptin receptor-deficient db/db mice. Those mice are immune response during starvation (Ahima et al.,
not only obese, but they have abnormal reproductive 1996). Leptin administration protects mice from the
function, hormonal abnormalities, and impaired lymphoid atrophy associated with starvation and
immune function (Chehab et al., 1996; Flier, 1998; reverses the inhibitory effect of starvation on the
Howard et al., 1999; Faggioni et al., 1999). development of DTH reactions (Lord et al., 1998;
Howard et al., 1999). Leptin administration is also
effective in reversing the increase in LPS sensitivity
Leptin as a Cytokine
caused by starvation (Faggioni et al., 2000b).
Leptin levels are acutely increased by inflammatory
stimuli such as LPS and turpentine and by cytokines,
Leptin and the Neuroendocrine Response to
suchasTNF(cid:11)andIL-1,indicatingthatleptininduction
Starvation
ispartofthehostresponsetoinflammation(Grunfeld
etal.,1996b;Sarrafetal.,1997;Faggionietal.,1998). Leptin promptly signals the shift between sufficient
Furthermore,theincreaseinleptinproductionduring and insufficient energy availability (Ahima et al.,
local and systemic inflammation is absent in IL-1(cid:12)- 1996). In fact, leptin levels fall rapidly with the onset
deficient mice (Faggioni et al., 1998). Thus, during ofstarvation,disproportionallytochangesinadipose
inflammationleptinexpressionisregulatedinamanner tissuemass.Thisfallinleptinlevelsis asignal forthe
Leptin 3
braintoinitiatetheadaptativeresponsestostarvation. binding protein (cid:11) (C/EBP(cid:11)) (Miller et al., 1996). In
During the adaptative response to starvation all the contrast, thiazoladinedione agonists for peroxisome
nonvital activities that might increase metabolic proliferator-activated receptor (cid:13) (PPAR(cid:13)) transcrip-
demands are downregulated in order to put all effort tion factor suppress leptin expression in vitro and
into preservation of the energy stores. The endocrine in vivo in rodents, and this may involve, at least in
changes include suppression of reproductive and part, a functional antagonism between C/EBP(cid:11) and
thyroid function and stimulation of the hypothala- PPAR(cid:13) on the leptin promoter (Hollenberg et al.,
mus-pituitary-adrenal (HPA) axis. Preventing the 1997).Theleptinpromoterhasalsobeenshowntobe
starvation-inducedfallinleptinwithexogenousleptin transactivated by adipocyte determination differen-
administration substantially blunts the changes in tiation dependent factor 1 (ADD1)/ sterol regulatory
gonadal, adrenal, and thyroid axes in male mice and element binding protein 1 (SREP1), a transcription
prevents the starvation-induced delay in ovulation in factor responsive to insulin (Kim et al., 1998).
female mice (Ahima et al., 1996). When adequate
caloricintakeandenergystoresarenormal,leptinlevels
returntonormalanditspermissiveroleonbehavioral, Cells and tissues that express the
metabolic, and endocrine function is restored.
gene
Likewise, genetically leptin-deficient mice are not
only obese, but also have some of the hormonal and
White adipose tissue is the major site of leptin gene
metabolic disorders characteristic of early starvation,
expression (Zhang et al., 1994). Constitutive leptin
such as abnormal reproductive function, decreased
mRNA has also been detected in placenta tropho-
thyroid hormones levels, hypercortisolemia, and
blasts and amnion cells and in a cultured human
decreased activity (Chehab et al., 1996; Flier, 1998).
choriocarcinomacellline,BeWocells(Masuzakietal.,
Therefore ob/ob mice seem to exist in a state of
1997). LeptinmRNA is also selectively transcribedin
perceived starvation and as a consequence, they
specific areas of rat brain and pituitary, and in a rat
became obese when given free access to food.
glioblastoma cell line (Morash et al., 1999). Leptin
geneexpressionispresentinanumberoftissuesinthe
GENE AND GENE REGULATION fetal mouse, such as bone and cartilage (Hoggard
et al., 1997). Leptin messenger RNA has been
detected in rat gastric epithelium and in the glands
Accession numbers
of the gastric fundic mucosa (Bado et al., 1998).
GenBank:
Human: U18915
PROTEIN
Mouse: U18812
Accession numbers
Chromosome location
Human: AAA60470
The human leptin gene exists as a single copy gene Mouse: AAA64564
located on chromosome 7g31 (Green et al., 1995).
Sequence
Relevant linkages
See Figure 1.
The human ob gene consists of three exons and two
introns and spans about 18kb, encoding a 3.5kb
cDNA (Gong et al., 1996). Description of protein
Regulatory sites and corresponding The structure reveals a four-helix bundle similar to
that of the long-chain helical cytokine family (Zhang
transcription factors
etal.,1997).TheN-terminalregionofleptinhasbeen
shown to be essential for both its biological and
The ob gene promoter is positively regulated through receptor-binding activities. The amino acid sequence
a functional binding site for CCAAT/enhancer of the C-terminal loop structure is also important for
4 Raffaella Faggioni, Kenneth R Feingold and Carl Grunfeld
Figure 1 Amino acid sequence for human and mouse leptin.
enhancing these actions, whereas the C-terminal chronic HPA axis activation, which is reversed by
disulfide bond is not needed (Imagawa et al., 1998). leptin treatment (Ahima et al., 1998). In addition,
leptin administration substantially prevents the
activation of the HPA axis in response to stress or
CELLULAR SOURCES AND fasting (Ahima et al., 1996; Heiman et al., 1997).
Negativeregulatorsinclude(cid:12)-adrenergicagonistsand
TISSUE EXPRESSION
cAMP (Slieker et al., 1996; Trayhurn et al., 1996).
Interactions exist between leptin and cytokines.
Cellular sources that produce
Proinflammatory cytokines increase leptin levels,
whereas leptin regulates the production of several
Whiteadiposetissueisthemajorsiteofleptinsecretion pro- and anti-inflammatory cytokines. In vivo, leptin
(Zhang et al., 1994). Another source of leptin is levels are acutely increased by TNF(cid:11) and IL-1
placenta. Leptin is produced by primary cultured (Grunfeld et al., 1996b; Sarraf et al., 1997). In vitro,
human amnion cells. Leptin production has been leptin has been shown to modulate cytokine produc-
detected in a cultured human choriocarcinoma cell tion by macrophages and T cells (see Leptin
line,BeWocells(Masuzakietal.,1997).Leptinprotein regulation of cytokine production).
has been shown in specific areas of rat brain and Leptin production and gene expression in BeWo
pituitary, and in a rat glioblastoma cell line (Morash cells,ahumantrophoblasticcellline,areincreasedby
et al., 1999). Cells of the rat gastric epithelium and of treatmentwithphorbolmyristateacetate(PMA).The
the glands of the gastric fundic mucosa are immuno- PMA-induced increase in leptin production is
reactive for leptin (Bado et al., 1998). completely suppressed by H7 and staurosporine,
both of which are inhibitors of protein kinase C
(Yura et al., 1998).
Eliciting and inhibitory stimuli,
including exogenous and
endogenous modulators RECEPTOR UTILIZATION
Insulin increases leptin expression and levels (Saladin The leptin receptor (OB-R) is related to class I
et al., 1995; Leroy et al., 1996). Falling insulin levels cytokinereceptors,whichincludegp130,thecommon
may be a key regulatory signal for the suppression of signal transducing component for the IL-6 related
leptin expression with starvation (Schwartz et al., family of cytokines (Baumann et al., 1996). Several
1997). On the other hand, leptin can inhibit insulin alternatively spliced isoforms of OB-R have been
gene expression and production and modulates cloned(Feietal.,1997).Theweight-regulatingeffects
insulin sensitivity (Kulkarni et al., 1997; Zhao et al., ofleptinaremediatedthroughtheOB-Rbforminthe
1998; Shimomura et al., 1999). hypothalamus (Vaisse et al., 1996). The OB-Rb
Glucocorticoids at high doses are positive regula- isoform is also present in the kidney, where mediates
tors of leptin expression and levels (De Vos et al., the clearance of leptin from the circulation. The
1995; Murakami et al., 1995; Slieker et al., 1996). short isoform (OB-Ra) is the predominant OB-R
Interestingly, a regulatory loop exists between the mRNA found in most tissues and cells, including
hypothalamus–pituitary–adrenal (HPA) axis and kidney, lung, liver, spleen, and macrophages
circulating leptin. In mice, adrenalectomy decreases (Tartaglia et al., 1995). Leptin, a relatively large
basal leptin levels and corticosterone replacement protein that would ordinarily be inaccessible to the
therapy restores circulating leptin to physiological brain, is transported through the blood–brain barrier
levels (Spinedi et al., 1998). Furthermore, leptin viaasaturabletransportsystem(Goldenetal.,1997).
deficiency, as observed in ob/ob mice, results in OB-Ra is highly expressed in the choiroid plexus
Leptin 5
where it might function as a transporter across the Proliferative and Anti-apoptotic Activities
blood–brain barrier (Tartaglia et al., 1995). Leptin
Leptinactsonmurinehematopoiesis.Inbonemarrow
circulates both in bound and free form (Sinha et al.,
cells from normal mice, leptin induces granulocyte–
1996). The OB-Re isoform is a soluble receptor (Li
macrophage colony formation in a dose-dependent
et al., 1998).
manner. Similar to IL-6, leptin stimulates the pro-
TheOB-Rbisoformcontainsafull-lengthcytosolic
liferation of murine myelocytic progenitor cells and
domain that includes binding motifs required for the
synergizes with stem cell factor in the proliferation of
activation of the Janus kinase (JAK)/signal transduc-
primitive hematopoietic progenitors (Umemoto et al.,
tion and activators of transcription (STAT) signaling
1997). In transfection experiments, the long form of
pathways and has been shown to have signaling
the OB-R has been shown to be capable of signaling
capabilities of IL-6 type cytokine receptors (Vaisse
for cell survival and proliferation in the murine IL-3-
etal.,1996).Ithasalsobeendemonstratedthatleptin
dependent bone marrow-derived Ba/F3 cell line and
can activate the mitogen-activated protein kinase
forthedifferentiationofleukemicM1cellsintomacro-
(MAP) signal transduction pathway in a variety of
phages (Gainsford et al., 1996). Importantly, leptin
invitrosystems(Takahashietal.,1997;Tanabeetal.,
also increases the proliferation of CD34+ stem cells
1997).LeptininducesexpressionofSOCS(suppressor
from human umbilical cord blood and murine fetal
of cytokine signaling)-3 mRNA in the hypothalamus
liverstemcells(flASKcells),indicatingaroleforleptin
(Bjorbaeketal.,1999).SOCS-3isamemberofanew
as a hematopoietic regulator (Bennett et al., 1996).
family of cytokine-inducible inhibitors of signaling
Dexamethasoneinducesapoptosisofmurinethymo-
that has recently been identified. Members of the
cytes. Leptin protects thymocytes from steroid-
cytokine superfamily including leptin, IL-6, interfer-
induced apoptosis in vitro (Howard et al., 1999).
ons, and LIF, induce transcription of SOCS genes
Leptin has been shown to induce cell proliferation
in vivo and in vitro, and when expressed in cell lines,
of awide spectrumofcell types. It can stimulate pro-
SOCS proteins inhibit signaling and biological activi-
liferation of primary cultures of murine tracheal epi-
ties of cytokines. Therefore, SOCS proteins are
thelialcellsandhumanlungsquamouscellline(SQ5),
thoughttofunctionasinducibleintracellularnegative
as well as mouse embryonic cell line (C3H10T1/2)
regulators of cytokine signal transduction. Accord-
(Takahashi et al., 1997; Tsuchiya et al., 1999). Leptin
ingly, transfection data suggest that SOCS-3 is an
induces proliferation of pancreatic (cid:12) cell line MIN6
inhibitor of leptin signaling (Bjorbaek et al., 1999).
through activation of MAP kinase (Tanabe et al.,
1997).Inaddition,leptinprotectsagainstapoptosisof
(cid:12) cellsinducedbyfattyacidsthroughmaintenanceof
Bcl-2 expression (Shimabukuro et al., 1998).
IN VITRO ACTIVITIES
In vitro findings Effect on Insulin Secretion and Insulin Activities
Leptin has a direct effect on insulin secretion. An
Leptin Regulation of Cytokine Production
inhibitory effect of mouse leptin on insulin secretion
Leptin has been shown to potentiate LPS-stimulated was observed in both human and rat islets (Kulkarni
production of TNF(cid:11), IL-6, and IL-12 in peritoneal et al., 1997). Leptin suppresses insulin release stimu-
macrophages (Loffreda et al., 1998; Santos-Alvarez lated with glucose in mouse ((cid:12)TC6) and rat
et al., 1999). In addition, leptin induces IL-1Ra (RIN5HA and RINm5F) insulinoma cell lines
production and upregulates the IL-1Ra induction by (Kulkarni et al., 1997). In pancreatic (cid:12) cells (rat
LPS in RAW cells (Faggioni et al., 1999). Leptin can pancreatic islet and a (cid:12) cell line, HIT-T15) leptin
enhance phagocytic function of murine peritoneal inhibits glucose- and glucagon-like peptide 1-stimu-
and bone marrow macrophages of both Leishmania lated insulin secretion, via phosphatidylinositol (PI)
and Candida parasilopsis (Gainsford et al., 1996; 3-kinase-dependent activation of cyclic nucleotide
Loffreda et al., 1998). phosphodiesterase 3B (PDE3B) and subsequent
Furthermore, leptin regulates the balance of TH1/ suppression of cAMP levels (Zhao et al., 1998).
TH2 cytokines. Leptin enhances the alloproliferative Inhumanhepaticcells(HepG2)leptincausesatten-
response of peripheral blood lymphocytes by provok- uation of several insulin-induced activities, including
ing a strong proliferative response by both na(cid:127)(cid:16)ve and tyrosine phosphorylation of the insulin receptor sub-
memory T cells. Moreover, leptin has been shown to strate 1 (IRS-1), association of the adapter molecule
increase IL-2 and IFN(cid:13) while inhibiting IL-4 growth factor receptor-bound protein 2 with IRS-1,
production by T cells (Lord et al., 1998). and downregulation of gluconeogenesis. In contrast,
6 Raffaella Faggioni, Kenneth R Feingold and Carl Grunfeld
leptinincreasedtheactivityofIRS-1-associatedphos- It is therefore possible that the significant decrease in
phatidylinositol 3-kinase (Cohen et al., 1996). These thenumberoflymphocyteswhichoccursinsepticand
findings raise the possibility that high leptin levels in endotoxicshock,willimpactmultiplefacetsoftheim-
obesity could directly contribute to diabetes and munological response and may lead to uncontrolled
insulin resistance in vivo. To date there are no data inflammatoryresponseanddeath.Theprofoundlym-
demonstrating such activities of leptin in humans. phopeniaofob/obmicemight,therefore,substantially
contributetotheirincreasedsusceptibilitytoinfection
and inflammation.
IN VIVO BIOLOGICAL
ACTIVITIES OF LIGANDS IN
Pharmacological effects
ANIMAL MODELS
Effect of Leptin on Food Intake
Knockout mouse phenotypes
Chronic peripheral administration of leptin to ob/ob
mice has been shown to lower their body weight,
Leptin-deficient ob/ob mice exhibit a complex phe-
percentage body fat, food intake, and serum concen-
notype characterized not only by obesity, but also by
trations of glucose and insulin (Halaas et al., 1995;
multiplehormonalandmetabolicdisorders,including
Pelleymounter et al., 1995). In addition, metabolic
infertility and dysfunctional adrenal and thyroid axes
rate, body temperature, and activity levels were in-
(Coleman,1978).Ob/obmicehaveabnormalimmune
creased by this treatment. None of these parameters
and inflammatory responses (Faggioni et al., 1999;
wasalteredbeyondthelevelobservedinleancontrols,
Howard et al., 1999). In accordance with the pro-
suggestingthatleptinnormalizedthemetabolicstatus
liferative activity of leptin on stem cell populations, a
of the ob/ob mice. Lean animals injected with leptin
deficit in hematopoiesis is observed in ob/ob mice
hadasmallerweightlossthroughoutthe28-daystudy
(Howard et al., 1999). They have lymphoid atrophy
andshowedno changesinanyofthe metabolic para-
accompanied with alterations in the number of
meters. The central route of administration of leptin
circulating lymphocytes and monocytes. The ability
ismoreeffectivethantheperipheralrouteinreducing
of leptin to protect against thymic atrophy probably
food intake and body weight in ob/ob and diet-
involves a direct anti-apoptotic mechanism. Ob/ob
induced obese mice, indicating the brain as the main
miceexhibitdefectivecell-mediatedimmunity,asthey
target for effect of leptin on food intake (Campfield
have an impaired delayed-type hypersensitivity reac-
et al., 1995).
tion (DTH) (Chandra, 1980). Furthermore, ob/ob
mice are protected from liver damage in models of T
The Neuroendocrine Response of Starvation
cell-mediatedhepatitisassociatedwithreducedinduc-
tion of TNF(cid:11) and IL-18 (Faggioni et al., 2000a). Leptin levels fall during starvation disproportionally
Exogenous leptin replacement restored the respon- tothedecreaseinfatdepot.Preventingthestarvation-
siveness of ob/ob mice to ConA and normalized their induced fall in leptin with exogenous leptin substan-
lymphocyteandmonocytepopulations(Faggionietal., tially blunts the changes in gonadal, adrenal, and
2000a; Howard et al., 1999). Therefore, leptin acts as thyroid axes in male mice, and prevents the
a regulator of T cell-mediated inflammation in vivo. starvation-induced delay in ovulation in female
In contrast, increased sensitivity to proinflamma- mice. In contrast, leptin repletion during this period
tory monocyte/macrophage-activating stimuli, parti- of starvation has little or no effect on body weight,
cularly LPS and TNF(cid:11), is observed in ob/ob mice blood glucose, or ketones (Ahima et al., 1996).
(Faggioni et al., 1999; Takahashi et al., 1999). How-
ever, in addition to reduced thymic and circulating
The Immunosuppression of Starvation
lymphocytes,a4-foldincreaseinthenumberofcircu-
lating monocytes is present in ob/ob mice (Faggioni Starvation suppresses immunity, particularly T
etal.,2000a).Therefore,itislikelythattheabsenceof lymphocyte responses, and decreases resistance to
leptin will lead to reduced sensitivity to T cell- infection.Preventionofthefasting-inducedfallinthe
activating stimuli and enhanced responses to mono- level of leptin by administering exogenous recombi-
cyte activators. Interestingly, it has recently been nant leptin reverses the suppressive effects of acute
shown that prevention of lymphocyte apoptosis is starvation on cell-mediated immunity. In addition,
associated with improved survival in a murine model administration of leptin to starved mice protected
of sepsis, suggesting a critical role of the lymphocyte mice from starvation-induced thymic atrophy (Lord
in resolving severe infection (Hotchkiss et al., 1999). etal.,1998).Furthermore,administrationofleptinto
Leptin 7
starved mice markedly reversed their increased Ozata et al., 1999). One of two very obese
susceptibility to both LPS and TNF(cid:11) toxicity consanguineous cousins who have congenital leptin
(Faggioni et al., 2000b). deficiency due to an inactivating mutation of the
leptin gene has recently been treated with leptin.
Correction of the ob Phenotype Administration of leptin to one of these obese
children ameliorates hyperphagia, promoted weight
Chronic leptin treatment of leptin-deficient ob/ob
loss while preserving lean mass, and may have had a
reversestheirneuroendocrineandmetabolicabnorm-
permissiveroleintheonsetofpuberty(Farooqietal.,
alities (Campfield et al., 1995; Halaas et al., 1995;
1999).
Pelleymounter et al., 1995). Noteworthy, leptin
More commonly, obese humans are not leptin
restores the responsiveness of ob/ob mice to T cell-
deficient and plasma leptin levels are elevated in
activatingstimuli,mainlybyincreasingthymiccellular-
most overweight individuals (Maffei et al., 1995).
ity (Howard et al., 1999). The increased susceptibility
The results of the first clinical trial show that
to LPS- and TNF-induced lethality observed in
some study participants given leptin lost more weight
ob/ob mice is also reversed by leptin treatment
than controls (Heymsfield et al., 1999). The differ-
(Faggioni et al., 1999; Takahashi et al., 1999).
ences were statistically significant, however, only in
obese subjects given the two highest leptin doses.
Interactions with cytokine network Weight loss was small and did not result in loss of
obesity.
The induction of leptin during the host response to
infection and inflammation is mediated by release of
the cytokines IL-1 and TNF(cid:11). During local and Infectious and Inflammatory Diseases
systemic inflammation caused by injection of turpen-
Acute illness: Leptin levels are elevated in
tineorLPSinmice,IL-1(cid:12) hasbeenshowntoplayan
patients with sepsis (Torpy et al., 1998).
essentialroleintheinductionofleptin(Faggionietal.,
Interestingly, there is a positive correlation between
1998). Leptin levels are increased in mice during
leptin levels and survival (Bornstein et al., 1998;
bacterialperitonitis,andblockingtheTNF(cid:11)response
Arnalich et al., 1999). In addition, in humans
blunts the increase (Moshyedi et al., 1998).
genetic leptin deficiency is associated with high mor-
Conversely, leptin upregulates LPS-induced pha-
tality due to infections; 7 out of 11 obese members of
gocytosis and proinflammatory cytokine expression
the family with consanguineous homozygous leptin
(TNF(cid:11),IL-6,IL-12)inexvivomacrophagesfrommice
deficiencydiedofinfectioninchildhood(Ozataetal.,
(Loffreda et al., 1998; Santos-Alvarez et al., 1999).
1999).
LeptinactionsinthebrainappeartodependonIL-
The following results have been noted in animal
1(cid:12). Luheshi and coworkers showed that leptin
models:
increases levels of IL-1(cid:12) in the hypothalamus of
normal rats. The effect of leptin on fever and food
intake is abolished by IL-1 receptor antagonist (IL- (cid:15) Leptin levels are transiently induced by LPS in
1Ra) and is absent in mice lacking the main IL-1 rodents with endotoxic shock (Grunfeld et al.,
receptor (80kDa, R1) responsible for IL-1 actions 1996b).
(Luheshi et al., 1999). (cid:15) Polymycrobic sepsis (cecal ligation and puncture,
CLP): leptin levels are elevated (Moshyedi et al.,
1998).
PATHOPHYSIOLOGICAL ROLES
(cid:15) Sterile abscess: turpentine injection increases leptin
IN NORMAL HUMANS AND expression and secretion (Faggioni et al., 1998).
(cid:15) Leptin deficiency is associated with increased
DISEASE STATES AND
susceptibility to endotoxic shock (Faggioni et al.,
DIAGNOSTIC UTILITY
1999).
Role in experiments of nature and
Chronicillness:Leptinlevelsaresignificantlylower
disease states
in patients with AIDS compared with normal
subjects, related to body mass index (Grunfeld et al.,
Obesity
1996a). Leptin concentrations are similar in the
Leptin deficiency as a cause of human obesity inflammatory bowel disease and control groups
appears to be extremely rare (Montague et al., 1997; (Ballinger et al., 1998).
8 Raffaella Faggioni, Kenneth R Feingold and Carl Grunfeld
IN THERAPY were statistically significant, however, only in obese
subjects given the two highest leptin doses.
Preclinical – How does it affect
disease models in animals? References
Obesity
Ahima,R.S.,Prabakaran,D.,Mantzoros,C.,Qu,D.,Lowell,B.,
Leptin administration is effective in normalizing the Maratos-Flier,E.,andFlier,J.S. (1996).Roleofleptininthe
neuroendocrineresponsetofasting.Nature382,250–252.
metabolic, endocrine, reproductive, and immune
Ahima, R. S., Prabakaran, D., and Flier, J. S. (1998). Postnatal
abnormalities of ob/ob mice (Campfield et al., 1995;
leptin surge and regulation of circadian rhythm of leptin by
Halaas et al., 1995; Pelleymounter et al., 1995). In feeding.Implicationsforenergyhomeostasisandneuroendocrine
mice, diet-induced obesity produces resistance to function.J.Clin.Invest.101,1020–1027.
peripheral leptin treatment. Interestingly, those mice Arnalich, F., Lopez, J., Codoceo, R., Jim nez, M., Madero, R.,
andMontiel,C.(1999).Relationshipofplasmaleptintoplasma
retained sensitivity to centrally administered leptin
cytokines and human survival in sepsis and septic shock.
(Van Heek et al., 1997).
J.Infect.Dis.180,908–911.
Bado, A., Levasseur, S., Attoub, S., Kermorgant, S.,
Inflammation Laigneau, J. P., Bortoluzzi, M. N., Moizo, L., Lehy, T.,
Guerre-Millo,M.,LeMarchand-Brustel,Y.,andLewin,M.J.
Leptin deficiency is associated with enhanced (1998).Thestomachisasourceofleptin.Nature394,790–793.
susceptibility to LPS, as assessed by increased liver Ballinger,A.,Kelly,P.,Hallyburton,E.,Besser,R.,andFarthing,
M.(1998).Plasmaleptininchronicinflammatoryboweldisease
injuryandlethality(Yangetal.,1997;Faggionietal.,
and HIV: implications for the pathogenesis of anorexia and
1999). Leptin administration reverses the increased
weightloss.Clin.Sci.(Colch.)94,479–483.
sensitivity to LPS lethality observed in ob/ob mice Baumann, H., Morella, K. K., White, D. W., Dembski, M.,
(Faggioni et al., 1999). Bailon, P. S., Kim, H., Lai, C. F., and Tartaglia, L. A.
(1996).Thefull-lengthleptinreceptorhassignalingcapabilities
of interleukin 6-type cytokine receptors. Proc. Natl Acad. Sci.
Starvation
USA93,8374–8378.
Bennett,B.D.,Solar,G.P.,Yuan,J.Q.,Mathias,J.,Thomas,G.R.,
Leptin levels drop dramatically with the onset of
andMatthews,W.(1996).Aroleforleptinanditscognaterecep-
starvation.Leptinadministrationduringtheperiodof
torinhematopoiesis.Curr.Biol.6,1170–1180.
starvation effectively prevents the neuroendocrine Bjorbaek, C., El-Haschimi, K., Frantz, J. D., and Flier, J. S.
response to starvation (Ahima et al., 1996). The (1999).TheroleofSOCS-3inleptinsignalingandleptinresis-
adaptative response to starvation includes changes in tance.J.Biol.Chem.274,30059–30065.
Bornstein, S. R., Licinio, J., Tauchnitz, R., Engelmann, L.,
gonadal, adrenal, and thyroid axes in male mice and
Negrao, A. B., Gold, P., and Chrousos, G. P. (1998). Plasma
delay in ovulation in female mice, all of which are
leptinlevelsareincreasedinsurvivorsofacutesepsis:associated
affected by leptin treatment. In addition, leptin lossofdiurnalrhythm,incortisolandleptinsecretion.J.Clin.
administration during fasting protects mice from the Endocr.Metab.83,280–283.
lymphoidatrophyandreversestheinhibitoryeffectof Campfield,L.A.,Smith,F.J.,Guisez,Y.,Devos,R.,andBurn,P.
(1995).RecombinantmouseOBprotein:evidenceforaperiph-
starvation on the development of a delayed-type
eral signal linking adiposity and central neural networks.
hypersensitivity reaction (Lord et al., 1998; Howard
Science269,546–549.
et al., 1999). Furthermore, leptin administration Chandra, R. K. (1980). Cell-mediated immunity in genetically
markedly reversed the increased sensitivity to LPS obeseC57BL/6Job/obmice.Am.J.Clin.Nutr.33,13–16.
caused by starvation (Faggioni et al., 2000b). Chandra, R. K. (1996). Nutrition, immunity and infection: from
basicknowledge ofdietary manipulation ofimmune responses
topracticalapplicationofamelioratingsufferingandimproving
Toxicity survival.Proc.NatlAcad.Sci.USA93,14304–14307.
Chehab,F.F.,Lim,M.E.,andLu,R.(1996).Correctionofthe
sterility defect in homozygous obese female mice by treatment
Leptin can cause redness and swelling at the site of withthehumanrecombinantleptin.NatureGenet.12,318–320.
injection,severeenoughtocausesubjectstodropout Cohen,B.,Novick,D.,andRubinstein,M.(1996).Modulationof
insulinactivitiesbyleptin.Science.274,1185–1188.
of the study early (Heymsfield et al., 1999).
Coleman,D.L.(1978).Obeseanddiabetes:twomutantgenescausing
diabetes-obesitysyndromesinmice.Diabetologia14,141–148.
De Vos, P., Saladin, R., Auwerx, J., and Staels, B. (1995).
Clinical results
Inductionofobgeneexpressionbycorticosteroidsisaccompa-
nied by body weight loss and reduced food intake. J. Biol.
Chem.270,15958–15961.
The results of the first clinical trial show that some
Faggioni,R.,Fantuzzi,G.,Fuller,J.,Dinarello,C.A.,Feingold,
study participants given leptin lost more weight than
K.R.,andGrunfeld,C.(1998).IL-1betamediatesleptininduc-
controls (Heymsfield et al., 1999). The differences tionduringinflammation.Am.J.Physiol.274,R204–R208.
Leptin 9
Faggioni,R.,Fantuzzi,G.,Gabay,C.,Moser,A.,Dinarello,C.A., Hollenberg, A. N., Susulic, V. S., Madura, J. P., Zhang, B.,
Feingold, K. R., and Grunfeld, C. (1999). Leptin deficiency Moller, D. E., Tontonoz, P., Sarraf, P., Spiegelman, B. M.,
enhances sensitivity to endotoxin-induced lethality. Am. J. and Lowell, B. B. (1997). Functional antagonism between
Physiol.276,R136–R142. CCAAT/Enhancer bindingprotein-alpha andperoxisome pro-
Faggioni, R., Jones-Carson, J., Reed, D. A., Dinarello, C. A., liferator-activated receptor-gamma on the leptin promoter. J.
Feingold, K. R., Grunfeld, C., and Fantuzzi, G. (2000a). Biol.Chem.272,5283–5290.
Leptin-deficient(ob/ob)miceareprotectedfromTcell-mediated Hotchkiss, R. S., Tinsley, K. W., Swanson, P. E., Chang, K. C.,
hepathotoxicity:roleoftumornecrosisfactorandIL-18.Proc. Cobb,J.P.,Buchman,T.G.,Korsmeyer,S.J.,andKarl,I.E.
NatlAcad.Sci.USA97,2367–2372. (1999). Prevention of lymphocyte cell death in sepsis
Faggioni,R.,Feingold,K.R.,andGrunfeld,C.(2000b).Reduced improves survival in mice. Proc. Natl Acad. Sci. USA 96,
leptin levels in starvation increase susceptibility to endotoxic 14541–14546.
shock.Am.J.Phatol.156,1781–1787. Howard, J. K., Lord, G. M., Matarese, G., Vendetti, S.,
Farooqi, I. S., Jebb, S. A., Langmack, G., Lawrence, E., Ghatei,M.A.,Ritter,M.A.,Lechler,R.I.,andBloom,S.R.
Cheetham, C. H., Prentice, A. M., Hughes, I. A., (1999).Leptinprotectsmicefromstarvation-inducedlymphoid
McCamish,M.A.,andO’Rahilly,S.(1999).Effectsofrecom- atrophyandincreasesthymiccellularityinob/obmice.J.Clin.
binantleptintherapyinachildwithcongenitalleptindeficiency. Invest.104,1051–1059.
N.Engl.J.Med.341,879–884. Imagawa,K.,Numata,Y.,Katsuura,G.,Sakaguchi,I.,Morita,A.,
Fei,H., Okano,H. J., Li,C., Lee,G.H., Zhao,C., Darnell, R., Kikuoka,S.,Matumoto,Y.,Tsuji,T.,Tamaki,M.,Sasakura,K.,
and Friedman, J.M. (1997). Anatomic localization of alterna- Teraoka, H., Hosoda, K., Ogawa, Y., and Nakao, K. (1998).
tivelysplicedleptinreceptors(Ob-R)inmousebrainandother Structure-functionstudiesofhumanleptin.J.Biol.Chem.273,
tissues.Proc.NatlAcad.Sci.USA94,7001–7005. 35245–35249.
Flier,J.S.(1998).Clinicalreview94:What’sinaname?Insearchof Kim, J. B., Sarraf, P., Wright, M., Yao, K. M., Mueller, E.,
leptin’sphysiologicrole.J.Clin.Endocr.Metab.83,1407–1413. Solanes, G., Lowell, B. B., and Spiegelman, B. M. (1998).
Gainsford, T., Willson, T. A., Metcalf, D., Handman, E., Nutritional and insulin regulation of fatty acid synthetase and
McFarlane, C., Ng, A., Nicola, N. A., Alexander, W. S., and leptingeneexpressionthroughADD1/SREBP1.J.Clin.Invest.
Hilton, D. J. (1996). Leptin can induce proliferation, differen- 101,1–9.
tiation, and functional activation of hemopoietic cells. Proc. Kulkarni, R. N., Wang, Z. L., Wang, R. M., Hurley, J. D.,
NatlAcad.Sci.USA93,14564–14568. Smith, D. M., Ghatei, M. A., Withers, D. J., Gardiner, J. V.,
Golden, P. L., Maccagnan, T. J., and Pardridge, W. M. (1997). Bailey,C.J.,andBloom,S.R.(1997).Leptinrapidlysuppresses
Humanblood–brainbarrierleptinreceptor.Bindingandendo- insulinreleasefrominsulinomacells,ratandhumanisletsand,
cytosisinisolatedhumanbrainmicrovessels.J.Clin.Invest.99, invivo,inmice.J.Clin.Invest.100,2729–2736.
14–18. Lee, G. H., Proenca, R., Montez, J. M., Carroll, K. M.,
Gong,D.W.,Bi,S.,Pratley,R.E.,andWeintraub,B.D.(1996). Darvishzadeh, J. G., Lee, J. I., and Friedman, J. M. (1996).
Genomic structure and promoter analysis of the human obese Abnormal splicing of the leptin receptor in diabetic mice.
gene.J.Biol.Chem.271,3971–3974. Nature379,632–635.
Green,E.D.,Maffei,M.,Braden,V.V.,Proenca,R.,DeSilva,U., Leroy, P., Dessolin, S., Villageois, P., Moon, B. C.,
Zhang,Y.,Chua,S.C.Jr.,Leibel,R.L.,Weissenbach,J.,and Friedman, J. M., Ailhaud, G., and Dani, C. (1996).
Friedman, J. M. (1995). The human obese (OB) gene: RNA Expression of ob gene in adipose cells. Regulation by insulin.
expression pattern and mapping on the physical, cytogenetic, J.Biol.Chem.271,2365–2368.
andgeneticmapsofchromosome7.GenomeRes.5,5–12. Li,C.,Ioffe,E.,Fidahusein,N.,Connolly,E.,andFriedman,J.M.
Grunfeld,C.,Pang,M.,Shigenaga,J.K.,Jensen,P.,Lallone,R., (1998). Absence of soluble leptin receptor in plasma from
Friedman,J.,andFeingold,K.R.(1996a).Serumleptinlevels dbPas/dbPas and other db/db mice. J. Biol. Chem. 273,
in the acquired immunodeficiency syndrome. J. Clin. 10078–10082.
Endocrinol.Metab.81,4342–4346. Loffreda,S.,Yang,S.Q.,Lin,H.Z.,Karp,C.L.,Brengman,M.L.,
Grunfeld, C., Zhao, C., Fuller, J., Pollack, A., Moser, A., Wang,D.J.,Klein,A.S.,Bulkley,G.B.,Bao,C.,Noble,P.W.,
Friedman,J.,andFeingold,K.R.(1996b).Endotoxinandcyto- Lane,M.D.,andDiehl,A.M.(1998).Leptinregulatesproin-
kinesinduceexpressionofleptin,theobgeneproduct,inham- flammatoryimmuneresponses.FASEBJ.12,57–65.
sters.J.Clin.Invest.97,2152–2157. Lord, G. M., Matarese, G., Howard, J. K., Baker, R. J.,
Halaas,J.L.,Gajiwala,K.S.,Maffei,M.,Cohen,S.L.,Chait,B.T., Bloom, S. R., and Lechler, R. I. (1998). Leptin modulates the
Rabinowitz,D.,Lallone,R.L.,Burley,S.K.,andFriedman,J.M. T-cell immune response and reverses starvation-induced
(1995).Weight-reducingeffectsoftheplasmaproteinencodedby immunosuppression.Nature394,897–901.
theobesegene.Science269,543–546. Luheshi,G.N.,Gardner,J.D.,Rushforth,D.A.,Loudon,A.S.,
Heiman, M. L., Ahima, R. S., Craft, L. S., Schoner, B., andRothwell,N.J.(1999).Leptinactionsonfoodintakeand
Stephens, T. W., and Flier, J. S. (1997). Leptin inhibition of body temperature are mediated by IL-1. Proc. Natl Acad. Sci.
the hypothalamic-pituitary-adrenal axis in response to stress. USA96,7047–7052.
Endocrinology138,3859–3863. Maffei, M., Halaas, J., Ravussin, E., Pratley, R. E., Lee, G. H.,
Heymsfield, S. B., Greenberg, A. S., Fujioka, K., Dixon, R. M., Zhang,Y.,Fei,H.,Kim,S.,Lallone,R.,andRanganathan,S.
Kushner, R., Hunt, T., Lubina, J. A., Patane, J., Self, B., (1995). Leptin levels in human and rodent: measurement of
Hunt, P., and McCamish, M. (1999). Recombinant leptin for plasma leptin and ob RNA in obese and weight-reduced sub-
weightlossinobeseandleanadults:arandomized,controlled, jects.NatureMed.1,1155–1161.
dose-escalationtrial.J.Am.Med.Assoc.282,1568–1575. Masuzaki, H., Ogawa, Y., Sagawa, N., Hosoda, K.,
Hoggard, N., Hunter, L., Duncan, J. S., Williams, L. M., Matsumoto, T., Mise, H., Nishimura, H., Yoshimasa, Y.,
Trayhurn,P.,andMercer,J.G.(1997).Leptinandleptinrecep- Tanaka,I.,Mori,T.,andNakao,K.(1997).Nonadiposetissue
tormRNAandproteinexpressioninthemurinefetusandpla- production of leptin: leptin as a novel placenta-derived hor-
centa.Proc.NatlAcad.Sci.USA94,11073–11078. moneinhumans.NatureMed.3,1029–1033.
10 Raffaella Faggioni, Kenneth R Feingold and Carl Grunfeld
Miller,S.G.,DeVos,P.,Guerre-Millo,M.,Wong,K.,Hermann,T., Spinedi,E.,andGaillard,R.C.(1998).Aregulatoryloopbetween
Staels,B.,Briggs,M.R.,andAuwerx,J.(1996).Theadipocyte the hypothalamo-pituitary-adrenal (HPA) axis and circulating
specific transcription factor C/EBPalpha modulates human ob leptin:aphysiologicalroleofACTH.Endocrinology139,4016–
geneexpression.Proc.NatlAcad.Sci.USA93,5507–5511. 4020.
Montague, C. T., Farooqi, I. S., Whitehead, J. P., Soos, M. A., Takahashi,N.,Waelput,W.,andGuisez,Y.(1999).Leptinisan
Rau, H., Wareham, N. J., Sewter, C. P., Digby, J. E., endogenous protective protein against the toxicity exerted by
Mohammed, S. N., Hurst, J. A., Cheetham, C. H., Earley, tumornecrosisfactor.J.Exp.Med.189,207–212.
A. R., Barnett, A. H., Prins, J. B., and O’Rahilly, S. (1997). Takahashi, Y., Okimura, Y., Mizuno, I., Iida, K.,
Congenitalleptindeficiencyisassociatedwithsevereearly-onset Takahashi, T., Kaji, H., Abe, H., and Chihara, K. (1997).
obesityinhumans.Nature387,903–908. Leptin induces mitogen-activated protein kinase-dependent
Morash, B., Li, A., Murphy, P. R., Wilkinson, M., and Ur, E. proliferation of C3H10T1/2 cells. J. Biol. Chem. 272, 12897–
(1999).Leptingeneexpressioninthebrainandpituitarygland. 12900.
Endocrinology140,5995–5998. Tanabe,K.,Okuya,S.,Tanizawa,Y.,Matsutani,A.,andOka,Y.
Moshyedi,A.K.,Josephs,M.D.,Abdalla,E.K.,Mackay,S.L., (1997).Leptininduces proliferationofpancreatic betacellline
Edwards,C.K.3rd,Copeland,E.M.3rd,andMoldawer,L.L. MIN6 through activation of mitogen-activated protein kinase.
(1998). Increased leptin expression in mice with bacterial Biochem.Biophys.Res.Commun.241,765–768.
peritonitis is partially regulated by tumor necrosis factor Tartaglia,L.A.,Dembski,M.,Weng,X.,Deng,N.,Culpepper,J.,
alpha.Infect.Immun.66,1800–1802. Devos,R.,Richards,G.J.,Campfield,L.A.,Clark,F.T.,and
Murakami, T., Iida, M., and Shima, K. (1995). Dexamethasone Deeds,J.etal.(1995).Identificationandexpressioncloningofa
regulates obese expression in isolated rat adipocytes. Biochem. leptinreceptor,OB-R.Cell83,1263–1271.
Biophys.Res.Commun.214,1260–1267. Torpy,D.J.,Bornstein,S.R.,andChrousos,G.P.(1998).Leptin
Ozata, M., Ozdemir, I. C., and Licinio, J. (1999). Human leptin andinterleukin-6insepsis.Horm.Metab.Res.30,726–729.
deficiency caused by a missense mutation: multiple endocrine Trayhurn, P., Duncan, J. S., Rayner, D. V., and Hardie, L. J.
defects, decreased sympathetic tone, and immune system dys- (1996). Rapid inhibition of ob gene expression and circulating
function indicate new targets for leptin action, greater central leptin levels in lean mice by the beta 3-adrenoceptor agonists
than peripheral resistance to the effects of leptin,, and sponta- BRL 35135A and ZD2079. Biochem. Biophys. Res. Commun.
neous correction of leptin-mediated defects. J. Clin. Endocr. 228,605–610.
Metab.84,3686–3695. Tsuchiya, T., Shimizu, H., Horie, T., and Mori, M. (1999).
Pelleymounter, M. A., Cullen, M. J., Baker, M. B., Hecht, R., Expressionofleptinreceptorinlung:leptinasagrowthfactor.
Winters, D., Boone, T., and Collins, F. (1995). Effects of the Eur.J.Pharmacol.365,273–279.
obese gene product on body weight regulation in ob/ob mice. Umemoto, Y., Tsuji, K., Yang, F. C., Ebihara, Y., Kaneko, A.,
Science269,540–543. Furukawa, S., and Nakahata, T. (1997). Leptin stimulates the
Saladin, R., De Vos, P., Guerre-Millo, M., Leturque, A., proliferationofmurinemyelocyticandprimitivehematopoietic
Girard,J.,Staels,B.,andAuwerx,J.(1995).Transientincrease progenitorcells.Blood90,3438–3543.
in obese gene expression after food intake or insulin adminis- Vaisse, C., Halaas, J. L., Horvath, C. M., Darnell, J.E. Jr.,
tration.Nature377,527–529. Stoffel, M., and Friedman, J. M. (1996). Leptin activation of
Santos-Alvarez, J., Goberna, R., and Sanchez-Margalet, V. Stat3inthehypothalamusofwild-typeandob/obmicebutnot
(1999). Human leptin stimulates proliferation and activation db/dbmice.NatureGenet.14,95–97.
ofhumancirculatingmonocytes.Cell.Immunol.194,6–11. Van Heek, M., Compton, D. S., France, C. F., Tedesco, R. P.,
Sarraf, P., Frederich, R. C., Turner, E. M., Ma, G., Fawzi, A. B., Graziano, M. P., Sybertz, E. J., Strader, C. D.,
Jaskowiak, N. T., Rivet, D. J. 3rd, Flier, J. S., Lowell, B. B., and Davis, H.R. Jr. (1997). Diet-induced obese mice develop
Fraker,D.L.,andAlexander,H.R.(1997).Multiplecytokines peripheral, but not central, resistance to leptin. J. Clin. Invest.
andacuteinflammationraisemouseleptinlevels:potentialrole 99,385–390.
ininflammatoryanorexia.J.Exp.Med.185,171–175. Yang, S. Q., Lin, H. Z., Lane, M. D., Clemens, M., and
Schwartz,M.W.,andSeeley,R.J.(1997).Seminarsinmedicineof Diehl, A. M. (1997). Obesity increases sensitivity toendotoxin
the Beth Israel Deaconess Medical Center. Neuroendocrine liverinjury:implicationsforthepathogenesisofsteatohepatitis.
responses to starvation and weight loss. N. Engl. J. Med. 336, Proc.NatlAcad.Sci.USA94,2557–2562.
1802–1811. Yura, S., Sagawa, N., Ogawa, Y., Masuzaki, H., Mise, H.,
Shimabukuro, M., Wang, M. Y., Zhou, Y. T., Newgard, C. B., Matsumoto, T., Ebihara, K., Fujii, S., and Nakao, K. (1998).
and Unger, R. H. (1998). Protection against lipoapoptosis of Augmentationofleptinsynthesisandsecretionthroughactiva-
beta cells through leptin-dependent maintenance of Bcl-2 tionofproteinkinasesA,andCinculturedhumantrophoblas-
expression.Proc.NatlAcad.Sci.USA95,9558–9561. ticcells.J.Clin.Endocr.Metab.83,3609–3614.
Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S., and Zhang,Y.,Proenca,R.,Maffei,M.,Barone,M.,Leopold,L.,and
Goldstein, J. L. (1999). Leptin reverses insulin resistance and Friedman,J.M.(1994).Positionalcloningofthemouseobese
diabetesmellitusinmicewithcongenitallipodystrophy.Nature gene and its human homologue [published erratum appears in
401,73–76. Nature1995:374(6521):479].Nature372,425–432.
Sinha,M.K.,Opentanova,I.,Ohannesian,J.P.,Kolaczynski,J.W., Zhang, F., Basinski, M. B., Beals, J. M., Briggs, S. L.,
Heiman, M. L., Hale, J., Becker, G. W., Bowsher, R. R., Churgay, L. M., Clawson, D. K., DiMarchi, R. D., Furman,
Stephens, T. W., and Caro, J. F. (1996). Evidence of free and T.C.,Hale,J.E.,Hsiung,H.M.,Schoner,B.E.,Smith,D.P.,
boundleptininhumancirculation.Studiesinleanandobesesub- Zhang,X.Y.,Wery,J.P.,andSchevitz,R.W.(1997).Crystal
jectsandduringshort-termfasting.J.Clin.Invest.98,1277–1282. structureoftheobeseproteinleptin-E100.Nature387,206–209.
Slieker, L. J., Sloop, K. W., Surface, P. L., Kriauciunas, A., Zhao, A. Z., Bornfeldt, K. E., and Beavo, J. A. (1998). Leptin
LaQuier,F.,Manetta,J.,Bue-Valleskey,J.,andStephens,T.W. inhibitsinsulinsecretionbyactivationofphosphodiesterase3B.
(1996). Regulation of expression of ob mRNA and protein by J.Clin.Invest.102,869–873.
glucocorticoidsandcAMP.J.Biol.Chem.271,5301–5304.