Mitochondria in Sex Hormone-Induced Disorder of Energy Metabolism in Males and Females

Abstract

Androgens have a complex role in the regulation of insulin sensitivity in the pathogenesis of type 2 diabetes. In male subjects, a reduction in androgens increases the risk for insulin resistance, which is improved by androgen injections. However, in female subjects with polycystic ovary syndrome (PCOS), androgen excess becomes a risk factor for insulin resistance. The exact mechanism underlying the complex activities of androgens remains unknown. In this review, a hormone synergy-based view is proposed for understanding this complexity. Mitochondrial overactivation by substrate influx is a mechanism of insulin resistance in obesity. This concept may apply to the androgen-induced insulin resistance in PCOS. Androgens and estrogens both exhibit activities in the induction of mitochondrial oxidative phosphorylation. The two hormones may synergize in mitochondria to induce overproduction of ATP. ATP surplus in the pancreatic β-cells and α-cells causes excess secretion of insulin and glucagon, respectively, leading to peripheral insulin resistance in the early phase of type 2 diabetes. In the skeletal muscle and liver, the ATP surplus contributes to insulin resistance through suppression of AMPK and activation of mTOR. Consistent ATP surplus leads to mitochondrial dysfunction as a consequence of mitophagy inhibition, which provides a potential mechanism for mitochondrial dysfunction in β-cells and brown adipocytes in PCOS. The hormone synergy-based view provides a basis for the overactivation and dysfunction of mitochondria in PCOS-associated type 2 diabetes. The molecular mechanism for the synergy is discussed in this review with a focus on transcriptional regulation. This view suggests a unifying mechanism for the distinct metabolic roles of androgens in the control of insulin action in men with hypogonadism and women with PCOS.

WITHDRAWN: Serum metabolomics probes the molecular mechanism of action of acupuncture on metabolic pathways related to glucose metabolism in obese PCOS: a randomized controlled trial

“…More importantly, PCOS patients with IR exhibited signi cantly lower mitochondrial copy numbers, suggesting that mitochondrial dysfunction may be associated with IR symptoms in PCOS patients [49][50]. Overactivated mitochondria produce excess reactive oxygen species (ROS), which exacerbate oxidative stress [51], leading to IR in the skeletal muscle and liver [52]. In the current study, acupuncture treatment was effective in improving mitochondrial dysfunction in PCOS patients.…”

Niacin supplementation attenuates the regression of three‐dimensional capillary architecture in unloaded female rat skeletal muscle

“…The primary objective was to examine the influence of NA supplementation on capillary regression, emphasizing its effects on mitochondrial biogenesis and the expression of PGC-1α. It is acknowledged that both testosterone and estrogen can influence the mitochondrial pathway through PGC-1α (Yin et al, 2021). Additionally, Mortreux et al (2021) reported that following 14 days of hindlimb suspension, female rats exhibited more stable hormonal levels compared to their male counterparts.…”

Serum metabolomics probes the molecular mechanism of action of acupuncture on metabolic pathways related to glucose metabolism in patients with polycystic ovary syndrome–related obesity

“…More importantly, patients with PCOS with IR exhibited significantly lower mitochondrial copy numbers, suggesting that mitochondrial dysfunction may be associated with IR symptoms in patients with PCOS (Ding et al, 2017; Saeed et al, 2019). Overactivated mitochondria produce excess reactive oxygen species, which exacerbate oxidative stress (Zhang, Zhao, et al, 2019), leading to IR in the skeletal muscle and liver (Yin et al, 2021). In the current study, acupuncture treatment was effective in improving mitochondrial dysfunction in patients with PCOS.…”