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Testosterone Reduces Body Fat in Male Mice by Stimulation of Physical Activity Via Extrahypothalamic ERα Signaling
Na Ri Kim1, Karel David1, Katrien Corbeels1
1Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven 3000, Belgium.
Abstract:
Testosterone (T) reduces male fat mass, but the underlying mechanisms remain elusive, limiting its clinical relevance in hypogonadism-associated obesity. Here, we subjected chemically castrated high-fat diet-induced adult obese male mice to supplementation with T or the nonaromatizable androgen dihydrotestosterone (DHT) for 20 weeks. Both hormones increased lean mass, thereby indirectly increasing oxygen consumption and energy expenditure. In addition, T but not DHT decreased fat mass and increased ambulatory activity, indicating a role for aromatization into estrogens. Investigation of the pattern of aromatase expression in various murine tissues revealed the absence of Cyp19a1 expression in adipose tissue while high levels were observed in brain and gonads. In obese hypogonadal male mice with extrahypothalamic neuronal estrogen receptor alpha deletion (N-ERαKO), T still increased lean mass but was unable to decrease fat mass. The stimulatory effect of T on ambulatory activity was also abolished in N-ERαKO males. In conclusion, our work demonstrates that the fat-burning action of T is dependent on aromatization into estrogens and is at least partially mediated by the stimulation of physical activity via extrahypothalamic ERα signaling. In contrast, the increase in lean mass upon T supplementation is mediated through the androgen receptor and indirectly leads to an increase in energy expenditure, which might also contribute to the fat-burning effects of T.
Insights
Testosterone (T) reduces male fat mass by converting to estrogen, which stimulates physical activity. Lean mass gains from T are androgen receptor-mediated, indirectly boosting energy expenditure.
Area of Science:
- Endocrinology
- Metabolism
- Obesity Research
Background:
- Testosterone (T) is known to reduce male fat mass, but the precise mechanisms are not fully understood.
- Obesity in hypogonadal males is a growing clinical concern, highlighting the need to clarify T's metabolic effects.
Purpose of the Study:
- To elucidate the mechanisms by which testosterone influences body composition and energy expenditure in obese male mice.
- To determine the roles of estrogen conversion and androgen signaling in T's effects on fat mass, lean mass, and physical activity.
Main Methods:
- Chemically castrated, diet-induced obese male mice were supplemented with testosterone (T) or dihydrotestosterone (DHT) for 20 weeks.
- Investigated tissue-specific aromatase expression (Cyp19a1) and utilized neuronal estrogen receptor alpha knockout (N-ERαKO) mice.
Main Results:
- Both T and DHT increased lean mass, leading to higher oxygen consumption and energy expenditure.
- Only T decreased fat mass and increased ambulatory activity, suggesting a role for estrogen.
- T's fat-reducing and activity-stimulating effects were abolished in N-ERαKO mice, indicating extrahypothalamic estrogen receptor alpha signaling.
Conclusions:
- Testosterone's fat-reducing effects depend on aromatization to estrogens, which stimulate physical activity via extrahypothalamic ERα.
- Lean mass increases are mediated by the androgen receptor, indirectly enhancing energy expenditure.
- These findings clarify T's dual mechanisms in regulating body composition and energy balance in males.
