TY - JOUR
T1 - Adipose tissue-specific ablation of Ces1d causes metabolic dysregulation in mice
AU - Li, Gang
AU - Li, Xin
AU - Yang, Li
AU - Wang, Shuyue
AU - Dai, Yulin
AU - Fekry, Baharan
AU - Veillon, Lucas
AU - Tan, Lin
AU - Berdeaux, Rebecca
AU - Eckel-Mahan, Kristin
AU - Lorenzi, Philip L.
AU - Zhao, Zhongming
AU - Lehner, Richard
AU - Sun, Kai
N1 - Funding Information:
The authors would like to thank their colleagues in the Center of Metabolism and Degenerative Diseases for technical support and critical discussions. We thank Dr. Frances M Sladek at the University of California, Riverside, for the ApoB-Luc reporter construct. We also thank Dr. Zhengmei Mao in the microscopy core of the Institute of Molecular Medicine for assistance on imaging and tissue processing. The Ces1d floxed mice were made by Dr. Grant A Mitchell from the Division of Medical Genetics, Ste-Justine Hospital in Montreal, Canada. This study was supported by the National Institute of Health (NIH) grants R01DK109001, R56DK124419 (to K Sun), R01DK092590 (to R Berdeaux), R01DK 125922 (to K Eckel-Mahan); Canadian Institutes of Health Research grant PS 156314 (to R Lehner) and grants S10OD012304-01, P30CA016672 (to PL Lorenzi). This work is supported in part by the Clinical and Translational Proteomics Service Center at the University of Texas Health Science Center. The RNA sequencing and analyses were performed by Cancer Genomics Core supported by the UTHealth Cancer Prevention and Research Institute of Texas (CPRIT RP180734).
Publisher Copyright:
© 2022 Li et al.
PY - 2022/8
Y1 - 2022/8
N2 - Carboxylesterase 1d (Ces1d) is a crucial enzyme with a wide range of activities in multiple tissues. It has been reported to localize predominantly in ER. Here, we found that Ces1d levels are significantly increased in obese patients with type 2 diabetes. Intriguingly, a high level of Ces1d translocates onto lipid droplets where it digests the lipids to produce a unique set of fatty acids. We further revealed that adipose tissue-specific Ces1d knock-out (FKO) mice gained more body weight with increased fat mass during a high fat-diet challenge. The FKO mice exhibited impaired glucose and lipid metabolism and developed exacerbated liver steatosis. Mechanistically, deficiency of Ces1d induced abnormally large lipid droplet deposition in the adipocytes, causing ectopic accumulation of triglycerides in other peripheral tissues. Furthermore, loss of Ces1d diminished the circulating free fatty acids serving as signaling molecules to trigger the epigenetic regulations of energy metabolism via lipid-sensing transcriptional factors, such as HNF4α. The metabolic disorders induced an unhealthy microenvironment in the metabolically active tissues, ultimately leading to systemic insulin resistance.
AB - Carboxylesterase 1d (Ces1d) is a crucial enzyme with a wide range of activities in multiple tissues. It has been reported to localize predominantly in ER. Here, we found that Ces1d levels are significantly increased in obese patients with type 2 diabetes. Intriguingly, a high level of Ces1d translocates onto lipid droplets where it digests the lipids to produce a unique set of fatty acids. We further revealed that adipose tissue-specific Ces1d knock-out (FKO) mice gained more body weight with increased fat mass during a high fat-diet challenge. The FKO mice exhibited impaired glucose and lipid metabolism and developed exacerbated liver steatosis. Mechanistically, deficiency of Ces1d induced abnormally large lipid droplet deposition in the adipocytes, causing ectopic accumulation of triglycerides in other peripheral tissues. Furthermore, loss of Ces1d diminished the circulating free fatty acids serving as signaling molecules to trigger the epigenetic regulations of energy metabolism via lipid-sensing transcriptional factors, such as HNF4α. The metabolic disorders induced an unhealthy microenvironment in the metabolically active tissues, ultimately leading to systemic insulin resistance.
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U2 - 10.26508/lsa.202101209
DO - 10.26508/lsa.202101209
M3 - Article
C2 - 35459739
AN - SCOPUS:85128802505
SN - 2575-1077
VL - 5
JO - Life science alliance
JF - Life science alliance
IS - 8
M1 - e202101209
ER -