Science - USA (2022-02-11)

11 FEBRUARY 2022 • VOL 375 ISSUE 6581 621

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complex inter-relationship be-

tween metabolic, immune, and

inflammatory pathways ( 6 ).

Adipose tissue–derived factors

are implicated in loss of meta-

bolic integrity and increased

inflammatory tone, including

factors produced by adipocytes,

macrophages, and stromovas-

cular cell types. In mice, CR

substantially lowers adiposity

and influences the abundance

of adipose tissue-derived fac-

tors, including adipokines, lipo-

kines, and circulating lipids ( 7 ).

Reverse translation is an

approach that takes clini-

cal observations and investi-

gates the underlying biology

in laboratory models (animals

and cell culture). Spadaro et

al. took advantage of data

and specimens captured as

part of the CALERIE study

(Comprehensive Assessment of

Long-term Effects of Reducing

Intake of Energy). This clini-

cal trial involved 2 years of di-

etary intervention, and although the target

was 25% CR, the eventual level attained was

closer to 14% ( 8 ). Notably, many of the fea-

tures of CR identified in mouse, rat, and non-

human primate studies were also evident in

humans undergoing CR, including reduced

adiposity, improvements in insulin sensitiv-

ity, and lower risk markers of cardiovascular

disease ( 9 – 11 ). Spadaro et al. showed that in

humans, CR preserves thymic volume, and

that CD4+ and CD8+ T cell production is pre-

served, suggesting that the effects of CR are

protective. The thymus is a key tissue for T

cell maturation, and shinkage of the thymus,

which begins during middle age, blunts im-

mune surveillance. The authors went on to

investigate adipose tissue using gene expres-

sion profiles from abdominal subcutaneous

depots and found evidence for substantial

adipose tissue remodeling with CR, and

changes were identified in pathways of me-

tabolism, innate-immune and antigen pro-

cessing, and inflammation. One gene that

was lower in expression in adipose tissue in

response to CR was PLA2G7.

PLA2G7 is best known for its role in degrad-

ing platelet-activating factor, a phospholipid

mediator of platelet aggregation and potent

activator of inflammation. In clinical studies,

higher circulating amounts of PLA2G7 have

been associated with numerous disorders

that have a basis in metabolic, immune, and

inflammatory dysfunction, including stroke,

chronic obstructive pulmonary disease, au-

toimmune dieases, cardiovascular diseases,

type II diabetes, neuropathy, and some types

of cancer. A causal role for PLA2G7 in disease

onset has not been identified, and it is not

yet clear how increased circulating amounts

could be predisposing for this host of chronic

diseases. Little is known about the biology

of PLA2G7; it is a secreted enzyme that is

physically associated with lipoproteins (par-

ticles that transport triacylglycerides and

cholesterol in the blood) and is particularly

enriched on low-density lipoproteins (LDLs)

( 12 , 13 ), the particles associated with “bad

cholesterol.” PLA2G7 plays a role in degrad-

ing other lipid inflammatory mediators, and

its expression is sensitive to differences in

composition of circulating lipids ( 14 , 15 ). In

this way, PLA2G7 could link lipid metabolism

and lipid signaling to disease vulnerability.

To understand the basis for the lower ex-

pression of PLA2G7 in adipose tissue in peo-

ple undergoing CR, Spadaro et al. deleted the

corresponding gene in mice. This protected

mice from high-fat diet–induced obesity. In

addition to lower adiposity, increased adi-

pose tissue lipolysis, and reduced hepatic ste-

atosis (fatty liver), the authors demonstrate

that mice lacking Pla2g7 had lower circu-

lating concentrations of proinflammatory

cytokines. The absence of PLA2G7 changed

the cellular composition of visceral adipose

tissue toward a more healthy disposition,

lowering the relative numbers of B cells, T

cells, and proinflammatory macrophages.

Furthermore, the ability to induce inflamma-

tion in adipose tissue–derived macrophages

was blunted when PLA2G7 was genetically

disabled. Notably, the connection to lipids was

again observed; macrophages

primed with the proinflamma-

tory molecule lipopolysaccha-

ride (LPS) were protected by

loss of PLA2G7, but only when

a lipid ceramide was used as

the inflammatory trigger. The

loss of PLA2G7 also protected

thymic volume in older mice

and preserved thymocyte abun-

dance, both changes that are

predicted to be beneficial for

immune health. Together, these

findings demonstrate clear

connections between PLA2G7-

directed lipid processing and

inflammation and suggest that

PLA2G7 plays a role in coordi-

nating metabolic, immune, and

inflammatory status (see the

figure).

The study by Spadaro et al.

adds to the evidence linking nu-

trition to metabolism, immune

regulation, and inflammation

and provides further support

for the idea that lipid-derived

molecules are a key mediator in

nutritional modulation of health. The imple-

mentation of reverse translation has clearly

borne fruit in this work. In taking the leap

from observations in humans to experiments

with transgenic mouse models, Spadaro et

al. provide new insight into the biology of

PLA2G7 and its important role in immuno-

metabolic regulation and systemic homeosta-

sis. This work is a nice example of what can

be gained by focusing on the mechanisms un-

derlying the beneficial effects of CR. j

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ACKNOWLEDGMENTS

The authors are supported by National Institutes of Health

grants AG067330, AG057408, AG070686; the Department

for Veterans Affairs BX003846; the Simons Foundation; and

Impetus Grants.

10.1126/science.abn6576

Obesity/high-fat diet Aging Caloric restriction

PLA2G7

Acetylhydrolase

Serum

Platelet activation

Lipoprotein-

associated

Thymus

Cellular

composition

T cell repertoire

?

Adipose tissue

Transcriptome

Cellular composition

Secretome

Macrophages

Polarity

Cytokines

Inflammasome

Cytokines

Inflammasome

Cellular Cellular

Ce

SeS

Celul

compositionp

T cell repertoiree

A regulator of immunometabolism

Obesity and high-fat diet stimulate platelet-activating factor acetylhydrolase

(PLA2G7) expression in mice, whereas caloric restriction in humans attenuates

its expression. Through immunometabolic regulation in various tissues, PLA2G7

influences pathways that contribute to local and systemic metabolic integrity,

immune regulation, and inflammation.