Human CIDEC transgene improves lipid metabolism and protects against high-fat diet–induced glucose intolerance in mice
(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.
(Less)
- author
- organization
- publishing date
- 2022-09
- 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
-
- scopus:85137639450
- pmid:35963433
- 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
- 2024-11-28 14:07:45
@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}}, }