Hepatic overexpression of steroid sulfatase ameliorates mouse models of obesity and type 2 diabetes through sex-specific mechanisms.
The steroid sulfatase (STS)-mediated desulfation is a critical metabolic mechanism that regulates the chemical and functional homeostasis of endogenous and exogenous molecules. In this report, we first showed that the liver expression of Sts was induced in both the high fat diet (HFD) and ob/ob models of obesity and type 2 diabetes and during the fed to fasting transition. In defining the functional relevance of STS induction in metabolic disease, we showed that overexpression of STS in the liver of transgenic mice alleviated HFD and ob/ob models of obesity and type 2 diabetes, including reduced body weight, improved insulin sensitivity, and decreased hepatic steatosis and inflammation. Interestingly, STS exerted its metabolic benefit through sex-specific mechanisms. In female mice, STS may have increased hepatic estrogen activity by converting biologically inactive estrogen sulfates to active estrogens and consequently improved the metabolic functions, whereas ovariectomy abolished this protective effect. In contrast, the metabolic benefit of STS in males may have been accounted for by the male-specific decrease of inflammation in white adipose tissue and skeletal muscle as well as a pattern of skeletal muscle gene expression that favors energy expenditure. The metabolic benefit in male STS transgenic mice was retained after castration. Treatment with the STS substrate estrone sulfate also improved metabolic functions in both the HFD and ob/ob models. Our results have uncovered a novel function of STS in energy metabolism and type 2 diabetes. Liver-specific STS induction or estrogen/estrogen sulfate delivery may represent a novel approach to manage metabolic syndrome.
From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania 15261.
Mengxi
M
Jiang
Jinhan
J
He
Heidi
H
Kucera
Nilesh W
NW
Gaikwad
Bin
B
Zhang
Meishu
M
Xu
Robert M
RM
O'Doherty
Kyle W
KW
Selcer
Wen
W
Xie
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004734:Energy Metabolism; D004967:Estrogens / Q000378:metabolism; D005234:Fatty Liver / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005260:Female; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D043266:Steryl-Sulfatase / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D004967:Estrogens; D043266:Steryl-Sulfatase
Diabetes; Energy Metabolism; Estrogen; Obesity; Steroid Hormone; Transgenic Mice