Genetic Manipulation of NR5A1 in VMHdm/c Neurons in Adults

• Published in: Obesity (Silver Spring, Md.) Md.), 2023-11, Vol.31, p.262-262
• Main Authors: Fujitani, Mina, Bideyan, Lara, Elmquist, Joel, Fujikawa, Teppei
• Format: Article
• Language: English
• Subjects: Glucose; Insulin resistance; Metabolism
• ISSN: 1930-7381; 1930-739X

Background: Exercise benefits metabolism. However, the mechanisms underlying the metabolic benefits of exercise remain to be elucidated. Despite the clear evidence of a dominant role of the hypothalamus on metabolism, its contributions to the metabolic benefits of exercise remain largely unknown. Our previous work has shown that an exercise intervention in mice increased expression of Nr5al (also known as steroidogenic factor-1; SF-1) in the dorsomedial and central parts of the ventromedial hypothalamic nucleus (VMHdm/c) and knockdown of NR5A1 in VMHdm/c neurons hampers exercise-induced fat reduction, muscle mass growth, and improves blood glucose levels. These data suggest that NR5A1 in VMHdm/c neurons is key to the manifestation of metabolic benefits of exercise. These results led us to hypothesize that augmented NR5A1 in VMHdm/c neurons is critical for metabolic benefits of exercise, such as improvements in blood glucose and lipid levels and restoration of insulin sensitivity. Methods: To test our hypothesis, we developed genetically-engineered adeno-associated virus (AAV) bearing Cre-dependent NR5A1 cDNA (AAV-DIO-NR5A1-OE), allowing us to overexpress NR5A1 specifically in VMHdm/c neurons. Using this AAV, we assessed effects of overexpression of NR5A1 in VMHdm/c neurons (VMHdm/cOE"NR5A1). We injected AAV-DIO-NR5A1-OE into Sf-l-BAC-Cre mice (5-6 months old). To complement overexpression studies, we also knockdowned NR5A1 in adults by injections of AAV containing Cre recombinase into Sf-1 floxed mice (3 cohorts; injected at 10 weeks, 5-6 months, and 11-12 months old) and measured metabolic parameters. Results: We found that VMHdm/cOE"NR5A1 improved body weight in high-fat diet (HFD)-induced obesity and insulin resistance. Surprisingly, adult knockdown of NR5A1 in VMHdm/c neurons (VMHdm/cKD"NR5A1) caused increased body weight on a normal diet, although previous studies have shown that postnatal (~P21) knockdown of NR5A1 does not affect body weight on a normal diet. VMHdm/cKD"NR5A1 increased food intake but did not change energy expenditure. VMHdm/cKD"NR5A1 exaggerated HFD-induced insulin resistance. Conclusions: Our studies revealed the role of NR5A1 in VMHdm/c neurons in adults in the regulation of body weight and glucose homeostasis.