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Human CIDEC transgene improves lipid metabolism and protects against high-fat diet–induced glucose intolerance in mice

Gupta, Abhishek ; Balakrishnan, Bijinu ; Karki, Shakun ; Slayton, Mark ; Jash, Sukanta ; Banerjee, Sayani ; Grahn, Tan Hooi Min LU orcid ; Jambunathan, Srikarthika ; Disney, Sarah and Hussein, Hebaallaha , et al. (2022) In Journal of Biological Chemistry 298(9).
Abstract

Cell death–inducing DNA fragmentation factor-like effector C (CIDEC) expression in adipose tissue positively correlates with insulin sensitivity in obese humans. Further, E186X, a single-nucleotide CIDEC variant is associated with lipodystrophy, hypertriglyceridemia, and insulin resistance. To establish the unknown mechanistic link between CIDEC and maintenance of systemic glucose homeostasis, we generated transgenic mouse models expressing CIDEC (Ad-CIDECtg) and CIDEC E186X variant (Ad-CIDECmut) transgene specifically in the adipose tissue. We found that Ad-CIDECtg but not Ad-CIDECmut mice were protected against high-fat diet-induced glucose intolerance. Furthermore, we revealed the role of CIDEC in lipid metabolism using... (More)

Cell death–inducing DNA fragmentation factor-like effector C (CIDEC) expression in adipose tissue positively correlates with insulin sensitivity in obese humans. Further, E186X, a single-nucleotide CIDEC variant is associated with lipodystrophy, hypertriglyceridemia, and insulin resistance. To establish the unknown mechanistic link between CIDEC and maintenance of systemic glucose homeostasis, we generated transgenic mouse models expressing CIDEC (Ad-CIDECtg) and CIDEC E186X variant (Ad-CIDECmut) transgene specifically in the adipose tissue. We found that Ad-CIDECtg but not Ad-CIDECmut mice were protected against high-fat diet-induced glucose intolerance. Furthermore, we revealed the role of CIDEC in lipid metabolism using transcriptomics and lipidomics. Serum triglycerides, cholesterol, and low-density lipoproteins were lower in high-fat diet-fed Ad-CIDECtg mice compared to their littermate controls. Mechanistically, we demonstrated that CIDEC regulates the enzymatic activity of adipose triglyceride lipase via interacting with its activator, CGI-58, to reduce free fatty acid release and lipotoxicity. In addition, we confirmed that CIDEC is indeed a vital regulator of lipolysis in adipose tissue of obese humans, and treatment with recombinant CIDEC decreased triglyceride breakdown in visceral human adipose tissue. Our study unravels a central pathway whereby adipocyte-specific CIDEC plays a pivotal role in regulating adipose lipid metabolism and whole-body glucose homeostasis. In summary, our findings identify human CIDEC as a potential ‘drug’ or a ‘druggable’ target to reverse obesity-induced lipotoxicity and glucose intolerance.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CGI-58, Cidec, diabetes, FSP27, lipid droplets, lipids, metabolism, obesity
in
Journal of Biological Chemistry
volume
298
issue
9
article number
102347
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • pmid:35963433
  • scopus:85137639450
ISSN
0021-9258
DOI
10.1016/j.jbc.2022.102347
language
English
LU publication?
yes
id
4b440844-6cc2-4891-8a28-333a8bd1193a
date added to LUP
2022-11-30 09:57:44
date last changed
2024-11-13 12:19:47
@article{4b440844-6cc2-4891-8a28-333a8bd1193a,
  abstract     = {{<p>Cell death–inducing DNA fragmentation factor-like effector C (CIDEC) expression in adipose tissue positively correlates with insulin sensitivity in obese humans. Further, E186X, a single-nucleotide CIDEC variant is associated with lipodystrophy, hypertriglyceridemia, and insulin resistance. To establish the unknown mechanistic link between CIDEC and maintenance of systemic glucose homeostasis, we generated transgenic mouse models expressing CIDEC (Ad-CIDECtg) and CIDEC E186X variant (Ad-CIDECmut) transgene specifically in the adipose tissue. We found that Ad-CIDECtg but not Ad-CIDECmut mice were protected against high-fat diet-induced glucose intolerance. Furthermore, we revealed the role of CIDEC in lipid metabolism using transcriptomics and lipidomics. Serum triglycerides, cholesterol, and low-density lipoproteins were lower in high-fat diet-fed Ad-CIDECtg mice compared to their littermate controls. Mechanistically, we demonstrated that CIDEC regulates the enzymatic activity of adipose triglyceride lipase via interacting with its activator, CGI-58, to reduce free fatty acid release and lipotoxicity. In addition, we confirmed that CIDEC is indeed a vital regulator of lipolysis in adipose tissue of obese humans, and treatment with recombinant CIDEC decreased triglyceride breakdown in visceral human adipose tissue. Our study unravels a central pathway whereby adipocyte-specific CIDEC plays a pivotal role in regulating adipose lipid metabolism and whole-body glucose homeostasis. In summary, our findings identify human CIDEC as a potential ‘drug’ or a ‘druggable’ target to reverse obesity-induced lipotoxicity and glucose intolerance.</p>}},
  author       = {{Gupta, Abhishek and Balakrishnan, Bijinu and Karki, Shakun and Slayton, Mark and Jash, Sukanta and Banerjee, Sayani and Grahn, Tan Hooi Min and Jambunathan, Srikarthika and Disney, Sarah and Hussein, Hebaallaha and Kong, Dong and Lowell, Bradford B. and Natarajan, Purushothaman and Reddy, Umesh K. and Gokce, Noyan and Sharma, Vishva M. and Puri, Vishwajeet}},
  issn         = {{0021-9258}},
  keywords     = {{CGI-58; Cidec; diabetes; FSP27; lipid droplets; lipids; metabolism; obesity}},
  language     = {{eng}},
  number       = {{9}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Biological Chemistry}},
  title        = {{Human CIDEC transgene improves lipid metabolism and protects against high-fat diet–induced glucose intolerance in mice}},
  url          = {{http://dx.doi.org/10.1016/j.jbc.2022.102347}},
  doi          = {{10.1016/j.jbc.2022.102347}},
  volume       = {{298}},
  year         = {{2022}},
}