BRIEF REVIEW www.jasn.

org

Mechanisms Linking Obesity, Chronic Kidney Disease,

and Fatty Liver Disease: The Roles of Fetuin-A,
Adiponectin, and AMPK
Joachim H. Ix*† and Kumar Sharma*‡
*Division of Nephrology and Hypertension, Department of Medicine, University of California–San Diego/Veterans Affairs
San Diego Healthcare System; †Division of Preventive Medicine, Department of Family and Preventive Medicine,
University of California–San Diego; and ‡Center for Renal Translational Medicine, University of California–San Diego/
Veterans Affairs San Diego Healthcare System, San Diego, California

ABSTRACT
Obesity is a risk factor for chronic kidney disease (CKD) and nonalcoholic fatty liver risk of ESRD. Those with extreme obesity
disease (NAFLD). Recent studies identify mechanisms common to both diseases are at even higher risk.6
linked through an interorgan communication orchestrated by fetuin-A and adi- The liver also frequently develops
ponectin. In liver and kidney, the energy sensor 5⬘-AMP activated protein kinase obesity-related complications. Nonalco-
(AMPK) is pivotal to directing podocytes and hepatocytes to compensatory and holic fatty liver disease (NAFLD) repre-
potentially deleterious pathways, leading to inflammatory and profibrotic cascades sents the most common hepatic disorder
culminating in end-organ damage. Regulation of these early upstream pathways in western countries8 and is strongly
may provide new therapeutic targets for these increasingly common sequelae of linked with insulin resistance and obe-
obesity. sity.9 –11 Given these are common risk
factors for CKD and NAFLD, it is not
J Am Soc Nephrol 21: 406 –412, 2010. doi: 10.1681/ASN.2009080820
surprising that the two conditions are as-
sociated with one another.12,13 Intrigu-
ingly, mechanisms leading to both dis-
The prevalence of obesity in the United and atherosclerosis. However, obesity eases may be interlinked through
States has increased dramatically from may also directly lead to CKD. Patho- crosstalk between fat, the kidney, and
approximately 12% in 1991 to over 20% logic studies demonstrate that subjects liver through at least two serum pro-
a decade later.1,2 Individuals older than with severe obesity develop proteinuria teins—fetuin-A and adiponectin. In re-
60 years of age have experienced the most with pathologic findings of podocyte hy- sponse, both tissues exhibit similar local
rapid increase in prevalence3; an omi- pertrophy, mesangial expansion, glo- effects mediated through the energy sen-
nous trend because this age group expe- merular enlargement, and focal segmen- sor 5⬘-AMP activated protein kinase
riences the greatest burden of chronic tal glomerular sclerosis in the absence of (AMPK). Here we review the current un-
kidney disease (CKD), cardiovascular diabetes and hypertension.4,5 Epidemio- derstanding of these pathways, highlight-
disease, and malignancy on the basis of logic studies also support a direct effect. ing areas that are common to obesity-
their age alone, each of which may be ex- Hsu and colleagues evaluated over related CKD and obesity-related NAFLD
acerbated by obesity. Understanding the 300,000 Kaiser Permanente healthcare and that could serve as potential targets for
mechanisms linking obesity and CKD is members, among whom nearly 1500 de- intervention.
important not only because of the soci- veloped ESRD over approximately 26
etal health burden of both conditions but years.6,7 There was a graded increase in Published online ahead of print. Publication date
also because novel insights to underlying risk of ESRD for those who were over- available at www.jasn.org.
mechanisms may lead to new strategies weight or obese despite adjustment for Correspondence: Dr. Kumar Sharma, Director,
to treat or prevent CKD and its associ- demographics, smoking, and cardiovas- Center for Renal Translational Medicine, University
ated comorbidities. cular disease. Even when accounting for of California–San Diego/Veterans Affairs San Diego
Healthcare System, La Jolla, CA 92093-0711.
Obesity almost certainly indirectly blood pressure and diabetes at baseline, Phone: 858-822-0860; Fax: 858-822-7483; E-mail:
contributes to CKD because obesity as- the association was only partially attenu- kusharma@ucsd.edu
sociates with many dominant CKD risk ated, and individuals with obesity re- Copyright 䊚 2010 by the American Society of
factors such as diabetes, hypertension, mained at approximately 3-fold greater Nephrology

406 ISSN : 1046-6673/2103-406 J Am Soc Nephrol 21: 406–412, 2010

 www.jasn.org BRIEF REVIEW

FETUIN-A INDUCES INSULIN
RESISTANCE AND REGULATES
ADIPONECTIN
In the renal field, fetuin-A has principally
been studied as an inhibitor of ectopic
calcium deposition,14 –16 yet fetuin-A is
also an important promoter of insulin
resistance. Different from adipocyto-
kines, which are derived from fat cells,
fetuin-A is a 64-kDa glycoprotein pro-
duced exclusively by the liver and se-
creted into serum17 where it is found in
relatively high concentrations in hu-
mans.18 Fetuin-A binds and inhibits the
insulin receptor tyrosine kinase in skele-
tal muscle and hepatocytes, inhibiting
insulin signal transduction and resulting
in insulin resistance in these target tis-
sues.19 –21 Consistent with these in vitro
observations, the fetuin-A null mouse is
insulin sensitive, has increased skeletal
muscle glycogen content, and is resistant
to weight gain when challenged with a
high-fat diet.22,23 Conversely, treatment
of wild-type mice with fetuin-A induces
insulin resistance.24 In humans, higher
fetuin-A levels associate with obesity and
insulin resistance in the general popula-
tion25–27 and in patients with CKD and
ESRD28,29 and associates with future risk
of diabetes.30,31 Higher fetuin-A levels
also associate with NAFLD, and short-
term diet and exercise interventions re-
sult in declines in serum fetuin-A levels
3.50
Natural Log Adiponectin (mg/L)
commensurate with improvement in
NAFLD and decline in body weight.27,32
However, as fetuin-A is a liver-secreted
protein and also induces insulin resis-
tance, it is uncertain whether fetuin-A
directly contributes to development of
NAFLD, whether elevated serum levels
reflect the presence or severity of
NAFLD, or whether other unidentified
factors simultaneously influence both.
Fetuin-A and adiponectin may work
in concert to regulate insulin resistance.
Genes for both proteins are located at
3q27 in the human genome; a diabetes
and metabolic syndrome susceptibility
locus.33,34 Serum levels of both proteins
are consistently associated with key com-
ponents of the metabolic syndrome, but
in opposite directions. For example,
higher fetuin-A levels associate with
greater body mass index and hypertri-
glyceridemia,25 whereas lower adiponec-
tin levels associate with the same out-
comes.35,36 Treatment with pioglitazone
results in a decline in fetuin-A levels37
and an increase in adiponectin levels.38,39
In a cohort of 963 individuals, we found
that serum fetuin-A and adiponectin lev-
els were inversely correlated with one an-
other (Figure 1), thus confirming similar
findings in a smaller sample by others.24
However, although these correlations are
intriguing, evidence for overlapping bi-
ology remained uncertain until recently
when Hennige and colleagues24 demon-
Adjusted* P value for trend < 0.001
strated that fetuin-A suppresses mRNA
encoding adiponectin in cultured hu-
man adipocytes, and treatment of wild-
type mice with fetuin-A lowered serum
adiponectin levels. The effect of fetuin-A
on adiponectin is specific because fe-
tuin-A treatment did not affect levels of
mRNA encoding leptin and resistin or
serum levels. Collectively, these studies
suggest the liver-secreted protein fe-
tuin-A inhibits generation of adiponec-
tin in adipose tissue. Higher fetuin-A and
lower adiponectin may contribute to obe-
sity-induced insulin resistance and devel-
opment of diabetes. In turn, adiponectin is
a key regulator of end-organ damage in
obesity-related CKD and NAFLD (as de-
scribed in the following section).
ADIPONECTIN MEDIATES
CROSSTALK BETWEEN ADIPOSE,
KIDNEY, AND LIVER
Adiponectin is a 30-kDa protein secreted
from adipose tissue and circulates in mul-
timers ranging from trimers to 12- to 18-
mers.40 Adiponectin improves insulin sen-
sitivity and decreases the adverse effects of
inflammatory mediators in vascular cells,
and the high-molecular-weight multimers
may be more potent.40,41 Despite its source
from adipose tissue, individuals with obe-
sity consistently have lower serum adi-
ponectin levels.35,36,42 The mechanisms for
this paradox are uncertain but may reflect
inhibition of gene expression and secre-

tion.43 Adiponectin null mice have in-

3.25
creased susceptibility to insulin resistance
with high-fat feeding,44 and treatment with
adiponectin conversely improves insulin
3.00 sensitivity.
The best-characterized receptors for
2.70
adiponectin are the AdipoR1 and AdipoR2
receptors; the former is ubiquitously ex-
pressed, whereas the latter is found primar-
2.50
I II III IV
ily in hepatocytes.45 Both contain seven
(<0.56) (<0.56–0.63) (<0.64–0.73) (>0.73) transmembrane domains but are structur-
Serum Fetuin-A Quartiles (mg/L) ally and functionally distinct from G-pro-
tein-coupled receptors. Unlike G-protein-
Figure 1. There is an inverse correlation between serum fetuin-A levels and adiponectin
in patients with stable cardiovascular disease. The association was adjusted for age, sex, coupled receptors, the amino (N)-termini
race, body mass index, and estimated GFR among a population of 963 outpatients (n ⫽ of both receptors are intracellular and the
242 or 243 per quartile). Mean estimated GFR ⫽ 71 ml/min/1.73 m2 (29% with esti- C-terminal end is extracellular and binds
mated GFR ⬍ 60, none with ESRD). The unadjusted Spearmen correlation (r ⫽ ⫺0.27; adiponectin.46 Although the intracellular
P ⬍ 0.001). Error bars reflect 95% confidence intervals. signaling cascade is not known,47 the func-

J Am Soc Nephrol 21: 406 –412, 2010 Obesity and Chronic Kidney Disease 407
 BRIEF REVIEW www.jasn.org
tion of these receptors was recently eluci-
dated through genetic manipulations in
mice. Overexpression of both receptors in
liver of db/db mice improves insulin sensi-
tivity.46 AdipoR1 overexpression decreases
hepatic enzymes involved in gluconeogen-
esis,46 whereas AdipoR2 overexpression
increases glucose uptake by stimulating
glucokinase and peroxisome proliferator-
activated receptor-␣ (PPAR␣). Genes
downstream of PPAR␣ such as acyl-CoA
oxidase 1 and uncoupling protein 2 are also
stimulated by AdipoR2 overexpression.46
Studies of specific deletions in AdipoR1 or
AdipoR2 demonstrate that AdipoR1 pre-
dominantly mediates stimulation of
AMPK, whereas AdipoR2 mediates stimu-
lation of PPAR␣.
The potential link between adiponec-
tin and albuminuria was initially raised
in a clinical study of men with essential
hypertension in which serum adiponec-
tin and albuminuria levels were inversely
correlated.48 Because adiponectin levels
are secreted from adipocytes and related
inversely to the amount of adiposity,
these data identify adiponectin as a can-
didate mediator of adipose and kidney
crosstalk. Others observed similar in-
verse correlations in cross-sectional
studies49,50; however, the association be-
tween adiponectin levels and kidney dis-
ease is complex. There is a direct correla-
tion between adiponectin levels and
overt proteinuria,51–53 and studies report
conflicting data between adiponectin
levels and mortality in patients with
CKD or coronary artery disease.36,54 –56
Nonetheless, the inverse correlation be-
tween adiponectin and low-grade albu-
minuria prompted us to investigate
whether a relative adiponectin deficiency
has a causative role in abnormal glomer-
ular function.49
The C57BL/6 adiponectin null mouse
exhibits albuminuria, and pathologic
evaluation demonstrates foot process ef-
facement of podocytes under baseline
conditions.49 Podocytes express the Adi-
poR1 receptor, and treatment with adi-
ponectin normalizes albuminuria and
restores foot process architecture. We
hypothesize the renal pathology in these
animals may result from oxidative stress
because they also have higher urine hy-
408 Journal of the American Society of Nephrology
drogen peroxide levels than control
mice. When the null mice are treated
with exogenous adiponectin, albumin-
uria decreases to levels similar to wild-
type controls. This effect is mediated
through adiponectin stimulation of the
AMPK pathway, a key regulator of intra-
cellular energy status with potent anti-
proliferative effects. AMPK suppression
of an isoform of NADPH oxidase (Nox4)
may account for the improvement in
podocyte cytostructure in adiponectin-
treated animals. Additional support for
the renal protective effects of adiponec-
tin are provided by a recent study using
the 5/6 nephrectomy model,57 in which
adiponectin also inhibited albuminuria
and fibrosis. Collectively, these data
suggest adiponectin protects against al-
buminuria through an AdipoR1 recep-
tor pathway by stimulating AMPK and
inhibiting reactive oxygen species.
Whether additional renal effects are
mediated through AdipoR2 is cur-
rently unknown.
NAFLD strongly associates with insulin
resistance and obesity9 –11 and represents a
spectrum of liver pathology ranging from
hepatic steatosis to inflammation and fi-
brosis characteristic of nonalcoholic ste-
atohepatitis and cirrhosis. Although he-
patic steatosis may be benign, factors
triggering fibrosis and steatohepatitis may
also be the consequence of reactive oxygen
species by driving peroxidation of hepatic
lipids and inducing mitochondrial dam-
age.58 – 60 Similar to its effect on podocytes,
recent studies suggest that adiponectin in-
hibits this critical transition.
Individuals with NAFLD have lower
serum adiponectin levels than healthy
subjects,10,61,62 and among individuals
with NAFLD adiponectin levels are in-
versely correlated with the severity of he-
patic fibrosis and inflammation.61,63,64
Adachi and colleagues65 evaluated the in-
fluence of adiponectin on hepatic stellate
cells, a key cell-type promoting liver fi-
brosis. Adiponectin treatment sup-
pressed the proliferation of hepatic stel-
late cells in a dose-dependent fashion in
vitro. As with podocytes, this effect is me-
diated through activation of AMPK. In-
hibiting AMPK restores proliferation
and results in downregulation of the an-
tioxidant enzymes superoxide dismutase
2 and catalase. In independent studies,
NAFLD also associates with an increase
in NADPH oxidase activity,66 although
the specific subtype, Nox2, is not critical
to mediating onset of disease.39 To our
knowledge, Nox4 has not been evaluated
in NAFLD; however, it is stimulated by
transforming growth factor-␤ in hepato-
cytes,67 thus Nox4 may contribute to the
transition from steatohepatitis to fibrosis
and inflammation. Therefore, current
evidence suggests the fat-derived hor-
mone adiponectin inhibits the transition
from hepatic steatosis to fibrosis through
an AMPK-dependent pathway, accom-
panied by suppression of reactive oxygen
species, similar to the effect of adiponec-
tin on podocytes.
INHIBITION OF AMPK TRIGGERS
THE ONSET OF OBESITY-RELATED
END-ORGAN DISEASE
From a teleological prospective, why ex-
cess fat would lead to albuminuria and
NAFLD is unclear. One explanation may
be provided through AMPK. This pro-
tein is a serine/threonine kinase that
plays a critical role in sensing energy
availability at the cellular level. Upon ex-
posure to low glucose or decreased en-
ergy stores, AMPK inhibits mRNA trans-
lation and protein synthesis of pathways
that are nonessential in the short term. In
turn, during times when food is plentiful,
AMPK activity is inhibited, mRNA
translation is up-regulated, and the cells
and organism can grow in size. Because
most animals do not have continuous ac-
cess to calories, this function may be crit-
ical to evolutionary success. However,
what would be the response in the mod-
ern situation wherein there is a constant
and abundant access to calories? This
scenario might result in chronic deacti-
vation of AMPK and promote cellular
protein synthesis. The pathways in-
volved in mRNA translation and protein
synthesis leading to kidney disease have
recently been elegantly reviewed.68,69
Insights into the role of AMPK on
kidney function are in their infancy.
However, recent studies suggest AMPK
J Am Soc Nephrol 21: 406 –412, 2010

suppression leads to cellular hypertro-
phy, accumulation of matrix molecules,
and mesangial expansion that are hall-
marks of obesity-related CKD. Activated
AMPK is predominant in podocytes un-
der basal conditions in wild-type mice.
With adiponectin depletion, AMPK is
inactivated in podocytes and associated
with foot process effacement.49 Using
conditionally differentiated podocytes,
inhibition of AMPK dramatically alters
podocyte morphology.49 Activation of
AMPK with its analogue aminoimida-
zole carboxamide ribonucleotide re-
stores podocyte morphology in vitro and
normalizes albuminuria in vivo in the
adiponectin null mouse.
In contrast to its emerging role in
kidney disease, the role of AMPK in
NAFLD is better studied. AMPK acti-
vation plays a major role in mediating
the effects of adiponectin in blocking
accumulation of liver fat.70,71 Rats fed
high sucrose develop NAFLD in associ-
ation with reduced AMPK.72 Activa-
tion of AMPK in the liver leads to fatty
acid oxidation, inhibition of glucose
production, and inhibition of lipogen-
esis and protein synthesis. Mice with
genetically engineered chronic liver
disease and AMPK activation are resis-
tant to weight gain and accumulation
of liver fat when fed high-fat diets.73
Intriguingly, therapeutic maneuvers
with potential beneficial effects on obe-
sity, the kidney, and liver are related to
decreasing fetuin-A levels, increasing
adiponectin, and AMPK stimulation.
Caloric restriction,74,75 exercise,75 and
insulin-sensitizing medications such as
pioglitazone76,77 are each associated with
declines in levels of serum fetuin-A, in-
creases in adiponectin levels, and stimu-
lation of AMPK. Angiotensin II infusion
lowers adiponectin levels, and angioten-
sin converting enzyme inhibitors and
angiotensin receptor blockers raise
adiponectin levels,78,79 perhaps by af-
fecting visceral adipose tissue. The sir-
tuin activator resveratrol also improves
organ function of the heart, kidney,
and liver80 – 82 despite high-fat feeding,
which may in part be due to stimula-
tion of AMPK.82 Future studies should
evaluate whether direct administration
J Am Soc Nephrol 21: 406 –412, 2010
www.jasn.org BRIEF REVIEW
Caloric
excess Greater
adiposity
AMPK
Liver fat Liver
accumulation
?
Higher
Fetuin-A
Low
adiponectin
AMPK
Steatohepatitis Albuminuria and
and cirrhosis decreased GFR
Figure 2. With caloric excess, there is fatty acid excess and insulin resistance fueling
hepatic triacylglycerol synthesis and steatosis. Caloric excess and/or a fatty liver may
lead to greater serum fetuin-A levels. Higher fetuin-A levels lead to suppression of
adiponectin transcription in adipocytes through direct mechanisms and potentially
indirectly through an expansion of adipose tissue. Excess caloric intake and lower
adiponectin reduces AMPK activation, promoting hepatic stellate cell proliferation and
generation of reactive oxygen species in the liver, leading to conversion from hepatic
steatosis to steatohepatitis and ultimately cirrhosis. Through similar pathways, lower
adiponectin levels reduce AMPK in podocytes to promote podocyte foot process
effacement and albuminuria.
of adiponectin or novel agents such as endothelial dysfunction,91,92 and other
the sirtuin activators have therapeutic factors90 also play important roles in
potential in patients with obesity and the development of both diseases. Al-
evidence of kidney and liver disease. though it may prove challenging to un-
In conclusion, excessive caloric in- derstand this complex biology, analy-
take contributes to adiposity and ini- ses from multiorgan integrative studies
tiates a cascade that ultimately leads to will provide the insights needed to
end-organ dysfunction including obe- counter the increasingly prevalent and
sity-related CKD and NAFLD. Recent devastating effects of obesity.
studies demonstrate that fetuin-A and
adiponectin are key proteins orches-
trating organ crosstalk between liver DISCLOSURES
and fat cells and between fat cells and The authors thank Dr. Mary Whooley and the
the kidney and liver, respectively. Adi- Heart and Soul Study for providing the clinical
ponectin influences changes in end-or- adiponectin data for this manuscript. These
gan targets, at least in part through studies were conducted with grants from the
AMPK in early stages of disease. These American Diabetes Association (1-08-IG-01),
discoveries demonstrate that obesity- American Heart Association (0575021N), and
related CKD and NAFLD share several the National Institutes of Health (R01
HL096851) to Dr. Ix and grants from the Na-
similar biologic mechanisms (Figure
tional Institutes of Health (R01 DK 053867 and
2); however, the understanding of
U01 DK 060995) to Dr. Sharma.
these overlapping pathways are pres-
ently incomplete. Additional studies
elucidating regulatory mechanisms of
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