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  3. Partial inhibition of adipose CIDEC improves insulin sensitivity and increases energy expenditure in high-fat diet-fed mice via activating ATGL-PPARα pathway

Partial inhibition of adipose CIDEC improves insulin sensitivity and increases energy expenditure in high-fat diet-fed mice via activating ATGL-PPARα pathway

  • Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Aug;1870(6):159659. doi: 10.1016/j.bbalip.2025.159659.
Qinghua Fu 1,  Peng Wang 1,  Weilin Li 1,  Zhenhua Cai 1,  Shiji Zhao 1,  Weidong Ling 1,  Mingxun Li 2,  Xiaochuan Tang 3,  Ziyi Song 4
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530004, China.
  • 2 Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
  • 3 Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530004, China. Electronic address: tangxiaochuan7@163.com.
  • 4 Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, Guangxi 530004, China. Electronic address: Ziyi.Song@gxu.edu.cn.
PMID: 40633832 DOI: 10.1016/j.bbalip.2025.159659
Abstract

Obesity poses a significant risk for metabolic disorders, such as Insulin resistance and metabolic-associated fatty liver disease (MAFLD), yet effective treatments remain limited. Cell Death-Inducing DNA Fragmentation Factor-α-Like Effector C (CIDEC), a lipid droplet membrane protein, facilitates lipid droplet fusion and is crucial for adipose tissue expansion, making it a key target for obesity and related metabolic diseases. However, previous research revealed that complete genetic deletion of Cidec in adipose tissues, while reducing fat accumulation, induced severe Insulin resistance in high-fat diet (HFD)-fed mice, potentially due to ectopic fat storage in the liver. Given that complete knockout is an extreme approach, partial inhibition holds greater clinical relevance. Therefore, this study aimed to investigate the effects of partial inhibition of CIDEC in adipose tissues on fat accumulation and Insulin sensitivity in mice. Using the Cre-LoxP system, we generated adipose Cidec haploinsufficient mice. Under a standard diet, these mice exhibited normal body weight, fat accumulation, and Insulin sensitivity. Notably, under HFD conditions, mice with partial Cidec deficiency showed reduced fat accumulation in adipose tissues while hepatic fat accumulation remained unchanged, accompanied by improved Insulin sensitivity and increased energy expenditure. Mechanistically, we found partial Cidec deficiency activated thermogenic program in adipocytes in vivo and in vitro through the ATGL-PPARα pathway. In conclusion, adipose CIDEC partial inhibition attenuates HFD-induced obesity and Insulin resistance by enhancing ATGL-PPARα-mediated energy expenditure, establishing this approach as a promising therapeutic strategy for obesity and related metabolic diseases.

Keywords

Brown fat; Cidec; Energy expenditure; Insulin resistance; Obesity; White fat.

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