Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis
Elevated eripheral serotonin reduces brown adipose tissue thermogenesis and promotes obesity and metabolic dysfunction. Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue 1 , 2 , but its thermogenic po...
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Published in | Nature medicine Vol. 21; no. 2; pp. 166 - 172 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.02.2015
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Elevated eripheral serotonin reduces brown adipose tissue thermogenesis and promotes obesity and metabolic dysfunction.
Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue
1
,
2
, but its thermogenic potential is reduced with obesity and type 2 diabetes
3
,
4
,
5
for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively
6
,
7
,
8
. Recent findings suggest that increased peripheral serotonin
9
and polymorphisms in
TPH1
are associated with obesity
10
; however, whether this is directly related to reduced BAT thermogenesis and obesity is not known. We find that
Tph1
-deficient mice fed a high-fat diet (HFD) are protected from obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD) while exhibiting greater energy expenditure by BAT. Small-molecule chemical inhibition of Tph1 in HFD-fed mice mimics the benefits ascribed to
Tph1
genetic deletion, effects that depend on UCP1-mediated thermogenesis. The inhibitory effects of serotonin on energy expenditure are cell autonomous, as serotonin blunts β-adrenergic induction of the thermogenic program in brown and beige adipocytes
in vitro
. As obesity increases peripheral serotonin, the inhibition of serotonin signaling or its synthesis in adipose tissue may be an effective treatment for obesity and its comorbidities. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. |
ISSN: | 1078-8956 1546-170X |
DOI: | 10.1038/nm.3766 |