Science - USA (2022-04-15)

sphingosine-1-phosphate released under cellu-
lar stress conditions ( 31 ).
The lack of Nod2 in inhibitory neurons had
particularly strong effects on appetite in fe-
males over 6 months of age. A variety of brain-
and metabolism-related diseases have shown
sex- and age-dependent phenotypes ( 32 – 35 ).
Thus, understanding the mechanisms behind
such biases may lead to more specific and ef-
ficient therapeutic approaches. To explore the

mechanisms behind such sex- and age-based

specificity, we evaluated different parameters:

(i) Nod2 expression by hypothalamic nuclei,

(ii) brain neuronal responses to MDP, and (iii)

PG pharmacokinetics. Among these factors,

only the increased accumulation of muropep-

tides in the female brain (relative to males)

correlates with sex-specific hypothalamic neu-

ronal activation in response to MDP. Previous

studieshavealsodescribedageandsexbiasesin

the context of gut-brain communication ( 29 , 36 ).

For example, microglial responses to bacterial

metabolites are stronger in males during the

embryonic phase, whereas female microglia

are more responsive in adulthood ( 36 ). More-

over, the absence of Pglyrp2 influences brain

development and behavior, leading eventually

to sex- and age-dependent alterations ( 9 , 29 ).

Many additional factors that show age and

sex differences—such as hormonal status and

Gabanyiet al.,Science 376 , eabj3986 (2022) 15 April 2022 5 of 12

A

CTR MDP CTR MDP

Raw data Heatmaps P-values map

younger females

older females

older males

CTR

CTR

CTR

MDP

MDP

MDP

B

-4 -2 0 2 4

2

1.5

1

0.5

0

2.5

FL

FC POS

GRN

Gpe

mcp

HPFMG

older males

ARC

PSTNMS

NLL

SOCLGd

IOLDPGRN

GPi

older females

2

1.5

1

0.5

0

2.5

-4 -2 0 2 4

Up

Downn.s.

Fos expression changes in brain nuclei - MDPctr vs MDP

younger females

-log10(

pValue)

2

1.5

1

0.5

0

2.5

log2(fold change)

-4 -2 0 2 4

Up

Downn.s.

UpDown

n.s.

DMH

ARC

LH

DMH

ARC

LH

DMH

ARC

LH

lower or higher in MDP

30

20

10

0

Fig. 3. MDP affects neuronal activation in a sex- and age-dependent manner.
(AandB) Analysis of brain neuron Fos expression in wild-type mice 3 hours after
MDP or MDPctr gavage of younger females (2 to 3 months), older females (7 to
8 months), and older males (7 to 8 months) (n= 4 per group). (A) Volcano plots
from the automated analysis of Fos+cells distribution in the brain. (B) Raw data
and heatmaps indicating the number of Fos+cells, andP-value maps of Fos expression
in the hypothalamus, highlighting DMH, ARC, and LH. Shown are regions with
higher (magenta) or lower (green) numbers of Fos+neurons in the MDP group as
compared to the MDPctr group; scale bars, 200mm. *P≤0.05 (unpairedttest).

Abbreviations: ARC, arcuate hypothalamic nucleus; DMH, dorsomedial nucleus of

the hypothalamus; LGd, dorsal part of the lateral geniculate complex; FC, fasciola

cinereal; FL, flocculus; GRN, gigantocellular reticular nucleus; Gpe, globus pallidus

external segment; GPi, globus pallidus internal segment; HPF, hippocampal formation;

IO, inferior olivary complex; LD, lateral dorsal nucleus of thalamus; LH, lateral

hypothalamic area; MG, medial geniculate complex; MS, medial septal nucleus; mcp,

middle cerebellar peduncle; NLL, nucleus of the lateral lemniscus; PGRN, para-

gigantocellular reticular nucleus; PSTN, parasubthalamic nucleus; POS, postsubic-

ulum; SOC, superior olivary complex; CTR, MDPctr.

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