Neuronal AR Regulates Glucose Homeostasis and Energy Expenditure in Lean Female Mice With Androgen Excess

Vaibhave Ubba; Serene Joseph; Olubusayo Awe; Dustin Jones; Milan K Dsilva; Mingxiao Feng; Junjiang Wang; Xiaomin Fu; Razeen J Akbar; Brittany H Bodnar; Wenhui Hu; Hong Wang; Xiaofeng Yang; Ling Yang; Peixin Yang; Rexford Ahima; Sara Divall; Sheng Wu

doi:10.1210/endocr/bqad141

Neuronal AR Regulates Glucose Homeostasis and Energy Expenditure in Lean Female Mice With Androgen Excess

Endocrinology. 2023 Sep 23;164(11):bqad141. doi: 10.1210/endocr/bqad141.

Authors

Vaibhave Ubba¹, Serene Joseph¹, Olubusayo Awe², Dustin Jones², Milan K Dsilva¹, Mingxiao Feng³, Junjiang Wang³, Xiaomin Fu³, Razeen J Akbar¹, Brittany H Bodnar¹, Wenhui Hu¹, Hong Wang¹, Xiaofeng Yang¹, Ling Yang⁴, Peixin Yang⁵, Rexford Ahima⁶, Sara Divall⁷, Sheng Wu^{1

3}

Affiliations

¹ Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
² Department of Cellular and Molecular Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
³ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21087, USA.
⁴ Department of Medical Genetics & Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA.
⁵ Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁶ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁷ Department of Pediatrics, University of Washington, Seattle's Children's Hospital, Seattle, WA 98145-5005, USA.

PMID: 37738624
DOI: 10.1210/endocr/bqad141

Abstract

Hyperandrogenemia and polycystic ovary syndrome are a result of the imbalance of androgen levels in females. Androgen receptor (Ar) mediates the effect of androgen, and this study examines how neuronal Ar in the central nervous system mediates metabolism under normal and increased androgen conditions in female mice. The neuron-specific ARKO mouse (SynARKO) was created from female (Ar fl/wt; synapsin promoter driven Cre) and male (Ar fl/y) mice. A glucose tolerance test revealed impaired glucose tolerance that was partially alleviated in the SynARKO-dihydrotestosterone (DHT) mice compared with Con-DHT mice after 4 months of DHT treatment. Heat production and food intake was higher in Con-DHT mice than in Con-veh mice; these effects were not altered between SynARKO-veh and SynARKO-DHT mice, indicating that excess androgens may partially alter calorie intake and energy expenditure in females via the neuronal Ar. The pAkt/Akt activity was higher in the hypothalamus in Con-DHT mice than in Con-veh mice, and this effect was attenuated in SynARKO-DHT mice. Western blot studies show that markers of inflammation and microglia activation, such as NF-kB p-65 and IBA1, increased in the hypothalamus of Con-DHT mice compared with Con-veh. These studies suggest that neuronal Ar mediates the metabolic impacts of androgen excess in females.

Keywords: DHT; PCOS; androgen receptor; energy expenditure; glucose; neuron.