Adcy8 deficiency contributes to impaired lipolysis and an increased prevalence of obesity in mice

Mengxue Han; Qing Shu; Ruili Yu; Shaohong Wu; Handan Deng; Yang Liu; Quan Yu; Wei Li; Luyang Gao; Yawen Zhao; Geyang Xu

doi:10.1016/j.bbalip.2025.159648

Adcy8 deficiency contributes to impaired lipolysis and an increased prevalence of obesity in mice

Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jun 16;1870(6):159648. doi: 10.1016/j.bbalip.2025.159648. Online ahead of print.

Authors

Mengxue Han¹, Qing Shu¹, Ruili Yu², Shaohong Wu¹, Handan Deng¹, Yang Liu¹, Quan Yu³, Wei Li⁴, Luyang Gao¹, Yawen Zhao¹, Geyang Xu⁵

Affiliations

¹ Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou 510632, Guangdong, China.
² Department of Pathology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou 450001, Henan, China.
³ Medical Experimental Center, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou 510632, Guangdong, China.
⁴ Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China.
⁵ Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou 510632, Guangdong, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, Guangdong, China. Electronic address: xugeyangliang@163.com.

PMID: 40527393
DOI: 10.1016/j.bbalip.2025.159648

Abstract

Obesity is a global chronic disease characterized by an imbalance in energy homeostasis. Dysfunction of adipocytes and adipose tissue are fundamental defects that contribute to the development of obesity. Adenylate cyclase 8 (ADCY8) serves as a key downstream signaling factor of G protein-coupled receptors, catalyzing the conversion of ATP to cyclic AMP (cAMP), which is essential for maintaining energy balance. Although ADCY8 is expressed in adipose tissue, its specific role in adipose energy homeostasis remains unclear and warrants further investigation. Our findings demonstrate that compared to individuals with a normal body mass index (BMI), obese individuals exhibit increased visceral adipose tissue (VAT) accumulation, significantly enlarged adipocytes, reduced ADCY8 expression in VAT, decreased cAMP levels, and diminished phosphorylation of key lipolytic enzymes. In Adcy8 knockout (Adcy8^-/-) mice, more severe lipid accumulation was observed under both normal and high-fat diet (HFD) conditions, accompanied by reduced activity of the adipose tissue cAMP-PKA signaling pathway. Notably, forskolin enhanced lipolysis and reduced adipocyte size in diet-induced obese wild-type mice, an effect abrogated in Adcy8^-/- mice. Collectively, these results indicate that adipose tissue ADCY8 regulates phosphorylation of lipolysis-related proteins via the cAMP-PKA signaling pathway, thereby influencing adipose tissue lipid accumulation. These findings establish ADCY8 as a novel molecular target and provide a theoretical foundation for obesity therapy.

Keywords: ADCY8; Adipose tissue; HSL; PKA; PLIN1; cAMP.