Interplay of FXN expression and lipolysis in white adipocytes plays a critical role in insulin sensitivity in Friedreich’s ataxia mouse model

• Published in: Scientific reports 2024-08, Vol.14 (1), p.19876-14
• Main Authors: Wu, Lin, Huang, Fei, Yang, Lu, Yang, Liu, Sun, Zichen, Zhang, Jinghua, Xia, Siyu, Zhao, Hongting, Ding, Yibing, Bian, Dezhi, Li, Kuanyu
• Format: Article
• Language: English
• Subjects: 631/443/319; 631/80/304; Adipocytes; Adipocytes, White - metabolism; Adipocytes, White - pathology; Adipose tissue; Age; Animals; Ataxia; Diabetes mellitus; Disease Models, Animal; Forskolin; Frataxin; Friedreich Ataxia - genetics; Friedreich Ataxia - metabolism; Friedreich Ataxia - pathology; Friedreich's ataxia; Homeostasis; Humanities and Social Sciences; Humans; Hyperglycemia; Hypertrophy; Insulin Resistance; Insulin sensitivity; Iron-Binding Proteins - genetics; Iron-Binding Proteins - metabolism; Lipase; Lipase - genetics; Lipase - metabolism; Lipogenesis; Lipolysis; Male; Metabolism; Mice; multidisciplinary; Neurodegenerative diseases; Pioglitazone; PPARγ; Science; Science (multidisciplinary); Sulfur; Susceptibility
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-71099-7

Frataxin (FXN) is required for iron-sulfur cluster biogenesis, and its loss causes the early-onset neurodegenerative disease Friedreich ataxia (FRDA). Loss of FXN is a susceptibility factor in the development of diabetes, a common metabolic complication after myocardial hypertrophy in patients with FRDA. The underlying mechanism of FXN deficient-induced hyperglycemia in FRDA is, however, poorly understood. In this study, we confirmed that the FXN deficiency mouse model YG8R develops insulin resistance in elder individuals by disturbing lipid metabolic homeostasis in adipose tissues. Evaluation of lipolysis, lipogenesis, and fatty acid β-oxidation showed that lipolysis is most severely affected in white adipose tissues. Consistently, FXN deficiency significantly decreased expression of lipolytic genes encoding adipose triglyceride lipase (Atgl) and hormone-sensitive lipase (Hsl) resulting in adipocyte enlargement and inflammation. Lipolysis induction by fasting or cold exposure remarkably upregulated FXN expression, though FXN deficiency lessened the competency of lipolysis compared with the control or wild type mice. Moreover, we found that the impairment of lipolysis was present at a young age, a few months earlier than hyperglycemia and insulin resistance. Forskolin, an activator of lipolysis, or pioglitazone, an agonist of PPARγ, improved insulin sensitivity in FXN-deficient adipocytes or mice. We uncovered the interplay between FXN expression and lipolysis and found that impairment of lipolysis, particularly the white adipocytes, is an early event, likely, as a primary cause for insulin resistance in FRDA patients at later age.