Direct Effects of Testosterone, 17β-Estradiol, and Progesterone on Adrenergic Regulation in Cultured Brown Adipocytes: Potential Mechanism for Gender-Dependent Thermogenesis

Abstract

Previous studies suggest that sex hormones could be responsible, at least in part, for the gender-dependent thermogenesis found in the adrenergic control of brown adipose tissue (BAT) under control conditions and in response to diet and cold. Catecholamines, as well as several hormones, including sex hormones, may alter the function or expression of different adrenoceptor subtypes in brown adipocytes in vivo, and a confirmation could be provided by in vitro experiments. Therefore, the effect of testosterone, 17 beta-estradiol, progesterone, and norepinephrine (NE) on adrenergic receptor (AR) gene expression (alpha 2A-, beta 1-, -, and beta 3-AR) and lipolytic activity was investigated in differentiated brown adipocytes in culture. We report that the expression of each AR subtype gene was distinctively regulated by NE and sex hormones in brown adipocytes. Testosterone-treated cells had lower lipolytic activity and increased expression of antilipolytic receptors alpha 2A-AR. Both 17 beta-estradiol and progesterone decreased alpha 2A-AR expression and alpha 2A/beta 3-AR protein ratio, but progesterone had higher potency than 17 beta-estradiol, increasing beta-AR levels, mainly beta 3-AR expression, and enhancing lipolysis stimulated by NE. In conclusion, our results support the idea that male and female sex hormones, as a part of the hormonal environment of BAT, have direct and opposite effects on the AR balance and lipolytic activity, and they might play a role in the gender dimorphism for the recruitment process in BAT.

Role of sex hormones in modulation of brown adipose tissue activity

“…Indeed, progesterone stimulates Ucp1 mRNA expression and NE-mediated lipolysis (Monjo et al 2003) in cultured brown adipocytes. Further indirect findings highlight the role of progesterone as an enhancer of BAT activity.…”

Depot differences in steroid receptor expression in adipose tissue: possible role of the local steroid milieu

“…In this respect, we have previously investigated in rats the overall effect of sex and regional locations of the adipose tissue on some of the mechanisms affecting the lipolytic capacity, such as adrenergic receptor balance (45, 48) and several cascade steps at the postreceptor level, such as adenylyl cyclase, protein kinase A and hormone-sensitive lipase (45). It has been suggested that these sex-dependent differences are due to variations in the hormonal environment, as sex hormones play an important role in the adipose tissue metabolism (32,48).Previous studies in rodents and humans have demonstrated that sex hormones are involved in the direct modulation of adipose tissue metabolism at multiple levels, acting at different steps of the lipolytic and lipogenic pathways (18, 23); coactivating or modulating the expression of adipogenic transcription factors (23); and altering the adipocyte proliferation (1), the glucose metabolism (15), and the expression of several adipocyte hormones (26,35,50,56).In addition to serving as a steroidal reservoir, adipose tissue is one of the most important extragonadal sources of steroids, due to the specific expression of steroidogenic enzymes, such as aromatase (4), suggesting a potential impact on the local adipose tissue metabolism that would be independent of the sex hormone plasma milieu (53). Steroid hormones exert their effects through specific receptors that belong to the superfamily of nuclear hormone receptors, which are widely expressed in several tissues including adipose tissue (7,10,20,21,31,36).…”

“…In this respect, we have previously investigated in rats the overall effect of sex and regional locations of the adipose tissue on some of the mechanisms affecting the lipolytic capacity, such as adrenergic receptor balance (45, 48) and several cascade steps at the postreceptor level, such as adenylyl cyclase, protein kinase A and hormone-sensitive lipase (45). It has been suggested that these sex-dependent differences are due to variations in the hormonal environment, as sex hormones play an important role in the adipose tissue metabolism (32,48).…”

Fat atrophy at the site of a subdermal contraceptive implant

“…Although currently undetermined, this process may involve altered expression of adrenoreceptors. 4 Of relevance are the reported effects of levonorgestrel-releasing intrauterine devices on endometrial glands, causing atrophy of endometrial glands and, on occasion, the whole functional layer. 5 Fat atrophy at the site of a subdermal contraceptive implant may be specific to the constituents of that particular device.…”