Skeletal Muscle Endogenous Estrogen Production Ameliorates the Metabolic Consequences of a High-Fat Diet in Male Mice

Abstract

AIMS The role of skeletal muscle estrogen and its ability to mitigate the negative impact of a high-fat diet (HFD) on obesity-associated metabolic impairments is unknown. To address this, we developed a novel mouse model to determine the role of endogenous estrogen (E2) production in males in skeletal muscle via inducible, skeletal-muscle-specific aromatase overexpression (SkM-Arom↑). METHODS Male SkM-Arom↑ mice and littermate controls were fed a HFD for 14 weeks prior to induction of SkM-Arom↑ for a period of 6.5 weeks. Glucose tolerance, insulin action, adipose tissue inflammation, and body composition were assessed. Indirect calorimetry and behavioral phenotyping experiments were performed using metabolic cages. Liquid chromatography-mass spectrometry was used to determine circulating and tissue (skeletal muscle, hepatic, and adipose) E2 and testosterone concentrations. RESULTS SkM-Arom↑ significantly increased E2 in skeletal muscle, circulation, the liver, and adipose tissue. SkM-Arom↑ ameliorated high fat diet induced hyperglycemia, hyperinsulinemia, impaired glucose tolerance, adipose tissue inflammation, and reduced hepatic lipid accumulation without causing skeletal muscle hypertrophy. CONCLUSION Enhanced skeletal muscle aromatase activity in male mice induces weight loss, improves metabolic and inflammatory outcomes and mitigates the negative effects of a HFD. Additionally, our data demonstrate for the first time skeletal muscle E2 has anabolic effects on the musculoskeletal system.

17β-Estradiol Effects in Skeletal Muscle: A 31P MR Spectroscopic Imaging (MRSI) Study of Young Females during Early Follicular (EF) and Peri-Ovulation (PO) Phases

“…During or before menstruation, when blood estrogen levels decrease, many women frequently experience increased fatigue and diminished energy levels [6,7]. Additionally, estrogen deficiency, often seen in menopausal women, has been linked to a range of musculoskeletal and neuromuscular disorders, such as sarcopenia, 2 of 16 osteoporosis, frailty, obesity, dementia, atherosclerosis, metabolic syndrome, and type 2 diabetes, with reported benefits when endogenous estrogen levels rise or exogenous estrogen is supplemented [2,[8][9][10][11][12][13][14][15][16].…”

“…Despite these observations, a comprehensive understanding of the effects of 17βestradiol on the energy metabolism in skeletal muscle remains elusive due to the complex and fluctuating nature of sex hormones throughout the menstrual cycle [4,14]. In our study, we utilized advanced 2D 31 P FID-MRSI (31-Phosphorus Magnetic Resonance Spectroscopic Imaging) at the ultrahigh magnetic field 7T to investigate alterations in phosphoryl metabolites within the soleus muscle of young females during two distinct menstrual phases: the early follicular (EF) and peri-ovulation (PO) phases.…”

“…In our study, we utilized advanced 2D 31 P FID-MRSI (31-Phosphorus Magnetic Resonance Spectroscopic Imaging) at the ultrahigh magnetic field 7T to investigate alterations in phosphoryl metabolites within the soleus muscle of young females during two distinct menstrual phases: the early follicular (EF) and peri-ovulation (PO) phases. Importantly, these phases were selected for their significant disparities in blood 17β-estradiol levels, while other potentially interfering hormones, such as progesterone and parathyroid hormone (PTH), remained consistently low [14].…”