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

Abhishek Gupta, Bijinu Balakrishnan, Shakun Karki, Mark Slayton, Sukanta Jash, Sayani Banerjee, Tan Hooi Min Grahn, Srikarthika Jambunathan, Sarah Disney, Hebaallaha Hussein, Dong Kong, Bradford B. Lowell, Purushothaman Natarajan, Umesh K. Reddy, Noyan Gokce, Vishva M. Sharma, Vishwajeet Puri

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 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.

Original languageEnglish (US)
Article number102347
JournalJournal of Biological Chemistry
Volume298
Issue number9
DOIs
StatePublished - Sep 2022
Externally publishedYes

Keywords

  • CGI-58
  • Cidec
  • FSP27
  • diabetes
  • lipid droplets
  • lipids
  • metabolism
  • obesity

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology

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