# Adipose tissue and androgens: the ins and outs

Yiyue Jia, Mathilde Lacombe, Catherine Muller, Delphine Milhas

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Yiyue Jia, Mathilde Lacombe, Catherine Muller, Delphine Milhas. Adipose tissue and androgens: the ins and outs. Adipocyte, 2025, 14 (1), pp.2508885. 10.1080/21623945.2025.2508885. hal-05460294

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# Adipose tissue and androgens: the ins and outs

Yiyue Jia, Mathilde Lacombe, Catherine Muller & Delphine Milhas

**To cite this article:** Yiyue Jia, Mathilde Lacombe, Catherine Muller & Delphine Milhas (2025) Adipose tissue and androgens: the ins and outs, Adipocyte, 14:1, 2508885, DOI: 10.1080/21623945.2025.2508885

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Published online: 09 Jun 2025.

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# Adipose tissue and androgens: the ins and outs

Yiyue Jia*, Mathilde Lacombe*, Catherine Muller, and Delphine Milhas

Équipe Labellisée Ligue Nationale contre le Cancer, Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR, Toulouse, France

## ABSTRACT

Adipose tissue (AT), one of the largest endocrine tissues in the human body, is an important site for the storage and production of steroid hormones. In particular, AT's capacity to produce androgens could enable it to have a regulatory role in local or general hormone homoeostasis. The links between obesity, polycystic ovary syndrome (PCOS), metabolic disorders, and hormonal balance emphasise the importance of understanding the intricate relationships between AT and androgen dynamics within AT. This review, focusing on androgen metabolism, summarises the androgen profile in white adipose tissue (WAT) and brown adipose tissue (BAT) of humans and animal models, along with the androgen-metabolising enzymes present in WAT, and explores the role of androgens on AT physiology.

## ARTICLE HISTORY

Received 20 March 2025
Revised 13 May 2025
Accepted 15 May 2025

## KEYWORDS

Adipose tissue; sex steroids;
androgens; metabolism;
obesity

## Introduction

Androgens, particularly testosterone, have long been acknowledged for their pivotal roles in the development and maintenance of masculine traits in reproductive tissues, particularly in the genital tract, secondary sexual characteristics, and fertility, while also playing a role in the anabolic state of somatic tissues [1]. Traditionally, it was believed that the testes were the only source of androgens through the regulation of the hypothalamic-pituitary-gonadal axis [2]. Androgens are also produced in the ovaries [3]. However, contemporary research has revealed that androgen production is not exclusively confined to gonadal cells. Alternative synthesis sites, notably the adrenal glands and various peripheral tissues, have emerged as unexpected contributors to the androgen orchestra. For instance, the human adrenal gland is an important source of androgens and its precursors, including dehydroepiandrosterone (DHEA), androstenedione, and DHEA sulphate (DHEA-S) [4]. In addition to the gonads and adrenal glands, the brain also has the capacity to synthesise the androgen precursor DHEA and other androgens from pregnenolone [5]. Androgens, including testosterone and 5α-dihydrotestosterone (5α-DHT), can also be produced in the skin via circulating DHEA-S synthesised from the gonadal and adrenal glands [6]. The production of active androgens in the skin markedly contributes to the systemic presence and overall impact of

circulating androgens [6]. Beyond the brain and skin, adipose tissue (AT) is also an important organ that contains and produces androgens [7]. The fact that steroid hormones, including androgens, are detectable in AT has long been known by physiologists. Initially, it was reported that a large fraction of the peripheral conversion of androgens to oestrogens occurs in AT [8]. Rapidly, a growing interest occurred to decipher whether AT is an important site of steroid metabolism. This capacity to produce androgens was further explored because of the intricate links between AT and hormonal balance. Indeed, obesity is associated with alterations in androgen physiology; men with obesity exhibit a decrease in testosterone levels, while women with obesity often develop hyperandrogenism [9]. Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in premenopausal women and is characterised by androgen excess and ovarian dysfunction. It is frequently associated with obesity [10]. The differences in AT distribution between men and women strongly suggest a role of androgens on AT [11]. Indeed, androgens affect lipolysis, lipogenesis, adipokine secretion, and insulin sensitivity [12]. As AT responds to and produces androgens, the relationship between AT and androgens is therefore dual. The capacity of AT to store and secrete androgens could play a role in hormone

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<footnote>*These authors contributed equally to this work.</footnote>
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homoeostasis, particularly in pathological conditions (obesity, cancer, and others). This review aimed to provide an overview of the current knowledge on androgens and AT, by summarizing the androgen metabolism of AT and the functional effects of androgens on AT.

## Androgen metabolite quantification and metabolism in AT

### Androgen quantification in AT of humans and animal models

DHEA is the most abundant androgen in AT. Human white adipose tissue (WAT) is a reservoir of sex steroids including androgens, oestrogens, and progestogens [7]. Most sex steroid dosage studies have been conducted using whole AT, such as subcutaneous adipose tissue (SCAT) [13–15] and visceral adipose tissue (VAT) [14,16]. Because of the major role of oestrogens in the development of breast cancer [17], a large number of studies have been conducted on mammary adipose tissue (MAT) [14,15,18–20], whose large amounts can be obtained from mastectomy. Many studies have also been conducted in women with PCOS, in which high levels of androgens induce excess VAT [10]. The most abundant androgen in WAT is dehydroepiandrosterone (DHEA) (Figure 1), which is synthesised

from cholesterol and is mainly secreted by the adrenal gland. DHEA concentration was highest among all other androgens in women MAT, independently of menopausal status, and in abdominal SCAT in both men and women [13,14]. It was also found to be 1000 times more elevated than other metabolites detected, such as androstenediol, androstenedione, testosterone, oestradiol, and oestrone in both MAT and women's abdominal SCAT [15]. DHEA represented the highest percentage (35%) of 31 measured metabolites, including 27 androgens, progestogens, and four oestrogens in MAT [18]. Generally, androgen precursor concentrations are higher than those of the downstream active forms of androgens or oestrogens. Several studies have shown the following concentration order in women MAT: androstenedione >> oestrone > testosterone > 17β oestradiol [19,20] in accordance with another study showing that testosterone levels were higher than 17β oestradiol in MAT [14]. The most active form of androgens, 5α-DHT, was dosed in omental AT from men with obesity, but it was the metabolite with the lowest concentration compared to the other four metabolite concentrations following this order: androstenedione >testosterone>oestrone >5α-DHT [16]. The sex steroid dosage profile of human AT is generally not depot- or sex-dependent. Accordingly, the mean concentrations of DHEA, DHEA-S,

<figure><img src="image_15.png" /><figcaption>**Figure 1.** Sex steroid metabolism in adipose tissue. Sex steroid metabolites identified in adipose tissue are in bold. The active androgen dihydrotestosterone (5α DHT) is highlighted by a blue box. The most abundant androgen in adipose tissue dehydroepiandrosterone is highlighted by a yellow box.</figcaption></figure>
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androstenedione, androstenediol, oestrone, and 17β oestradiol were similar in omental AT and SCAT [14]. Regardless of sex, the concentration of sex steroids followed the same order (DHEA > androstenedione > progesterone > testosterone > 17α hydroxyprogesterone > 17β oestradiol and oestrone) in both female and male abdominal AT [13]. However, age has an influence on sex steroid production in AT. Androgens decreased with age in abdominal SCAT of men and women over 60 years of age [14]. In conclusion, all studies have shown that DHEA is the most abundant androgen metabolite found in AT. AT tends to accumulate more inactive precursors of testosterone and 5α DHT, the active androgens. This could partly be explained by the fact that active androgens could be more difficult to extract, as they would be mainly bound to the androgen receptor (AR) or quickly metabolised or inactivated. Whether DHEA is synthesised *in situ* from progestogens or up taken from circulation is still debated and will be discussed in a further paragraph.

**Androgens and WAT of animal models.** Even though only a few androgen metabolites were able to be detected in rodents compared to humans, the sex and depot differences concerning androgen contents are more obvious in rodents than in humans, with male active hormones (testosterone) being mainly found in male AT and female hormones (progesterone and 17β oestradiol) in female AT. In mice, testosterone and its sulphated form, testosterone-S, were detected in male inguinal WAT (iWAT) and epididymal WAT (eWAT), but not in female mice AT [21]. Progesterone, androstenedione, testosterone and 5α-DHT were detected in WAT (retroperitoneal and gonadal AT) of male mice [22,23]. Interestingly, in orchiectomized and adrenalectomized mice, testosterone was not detected in AT, while low concentrations of 5α-DHT were still present. This suggests a non-gonadal and non-adrenal contribution to local androgen levels, potentially due to high remaining levels of progesterone serving as a precursor for 5α-DHT synthesis [23]. Free DHEA was detected only in iWAT and eWAT of obese male mice and parametrial WAT (pmWAT) of female mice [21]. 17β oestradiol was only detected in female mice, but not in male mice WAT in one study [24]. In rats, testosterone levels were higher, whereas progesterone levels were lower in males than in females in all investigated AT, including inguinal, retroperitoneal, epididymal, and mesenteric AT [25]. Depot- and age-specific differences were observed in AT of rats. For example, testosterone levels were higher in retroperitoneal AT than in

inguinal AT [25]. Inguinal WAT contained higher levels of 17β oestradiol compared to other adipose depots, including retroperitoneal, gonadal, and mesenteric WAT from both male and female rats [25]. The testosterone concentration in the periovarian AT was four times higher than that in the inguinal depot of young animals, whereas it was similar between the depots in adult animals [26]. Testosterone levels were decreased 6-fold in periovarian AT and 2-fold in inguinal AT in adult rats (60 days old) compared to prepubertal rats (20 days old) [26]. Similar to humans, testosterone levels were three times higher than the more active form 5α-DHT in male mice WAT [24] but were not affected by obesity, contrary to humans [21]. These studies highlight the fact that animal models do not fully reflect the androgenic landscape of human AT.

**Androgens and brown adipose tissue (BAT).** Brown AT (BAT) is a specialised type of AT located in the cervical, supraclavicular, axillary, peri-aortic, paravertebral, and suprarenal regions in adult humans [27]. It plays a role in thermogenesis and energy expenditure owing to its unique expression of UCP1, which enables the release of energy as heat [28]. There exists a sex dimorphism when it comes to BAT activation in humans, as women generally have a higher prevalence of active BAT than men, as observed in positron emission tomography – computed tomography (PET/CT) scans [29,30]. Androsterone was first identified in BAT of the alp-marmot, badger, and rat in 1991 [31]. Testosterone and testosterone-S were detected in BAT of male mice [21]. Both DHEA-S and free DHEA were identified in BAT from female mice. DHEA-S levels were found to be higher than those of free DHEA [21]. However, other studies were unable to detect any sex steroid production or steroidogenic enzyme expression in the BAT of mice [24,32,33]. While there is evidence for the presence of certain androgens in BAT, limited research and contradictory findings with no human studies to our knowledge highlight that further studies are needed to characterize androgen metabolism in BAT.

## Androgen metabolism in WAT

Androgens can be synthesised in AT because they express a wide range of steroidogenic enzyme isoforms (Figure 2). Whether AT is capable of *de novo* androgen synthesis remains debated and will be discussed in the following paragraph. Here, we mainly focus on androgen metabolism in whole AT and adipocytes.
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<figure><img src="image_18.png" /><figcaption>**Figure 2.** Pathways of sex steroid synthesis in adipose tissue. Enzymes are in coloured boxes, grouping those that perform the same enzymatic reaction with the same colour. Pathways identified in adipose tissue are represented by bold arrows. In grey, CYP17A1, for which the expression is still debated. CYP11A1: cytochrome P450 family 11; CYP17A1: cytochrome P450 family 11; CYP19A1: cytochrome P450 family 19 also called aromatase; 3β-HSD: 3β-hydroxysteroid dehydrogenase; SRD5A: 5α-reductase; 17β-HSD: 17β-hydroxysteroid dehydrogenase; AKR1C: aldo-keto reductase family 1.</figcaption></figure>

*Are adipose tissues capable of de novo androgen synthesis?* This remains an important question because if AT cannot produce androgens *de novo*, its capacity to produce active metabolites will be dictated by the downstream metabolites of cholesterol. *De novo* production of androgens can be classified as the ability to convert endogenous cholesterol into pregnenolone through the activity of the cholesterol side-chain cleavage enzyme or P450scc, encoded by CYP11A1 [34] (Figure 2). The presence of this enzyme has not been studied in all AT depots, which should be taken into account when studying a specific depot, as it could be differentially expressed. Several studies reported CYP11A1 mRNA expression in women omental AT and SCAT as well as CYP11A1 protein expression and activity in differentiated mouse 3T3-L1 adipocytes [35–39]. However, the AT expression of the following downstream enzyme, 17α-hydroxylase, encoded by CYP17A1 remains controversial. This enzyme is also crucial for androgen biosynthesis, as it catalyses the conversion of pregnenolone and progesterone to down-stream androgen metabolites, such as DHEA and androstenedione, respectively [40] (Figure 2). While most studies reported CYP17A1 gene expression and protein expression in women SCAT [37,38,41–43] and

VAT [38,41], some studies could not detect its expression in women SCAT [35,39] and omental AT [35]. Thus, *de novo* synthesis of androgens from pregnenolone in human AT needs to be confirmed. Nevertheless, human AT contains all the other enzymes (described below) required for active androgen synthesis from DHEA (Figure 2). AT also expresses enzymes involved in the inactivation of active androgens [44,45]. This is consistent with the fact that approximately 95% of active androgens are inactivated locally before being released into the blood as inactive metabolites, thus avoiding inappropriate exposure of the other tissues [46,47] and highlights that androgens synthesised in AT probably also act in an autocrine manner. As described below, steroidogenic enzyme expression varies between AT depots and in pathological conditions, such as PCOS and obesity.

**3β-HSD.** 3β-hydroxysteroid dehydrogenase (3β-HSD) catalyses the conversion of DHEA to androstenedione, 5 androstenediol to 17β testosterone, 3β androstanediol to 5α-DHT [48–50], and the conversion of pregnenolone and 17-OH pregnenolone to progesterone and 17-OH progesterone, respectively [49,50] (Figure 2). As shown in Figure 2, regardless of the pathway, the
production of active androgens relies on this enzyme. Two distinct isoforms of 3β-HSD encoded by HSD3B1 and HSD3B2 have been identified in women SCAT [35,51] and omental AT [51], with higher mRNA expression in SCAT [35,51]. Apart from being detected in whole AT, 3β-HSD activity has also been demonstrated in breast adipose stromal cells [52]; however, its expression in adipocytes needs to be investigated.

**17β-HSD enzymes.** 17β-hydroxysteroid dehydrogenases (17β-HSD) control the inter-conversion of DHEA, androstenedione, 5α androstanedione, androstosterone, and oestrone with downstream and more active androgen metabolites, including androstenediol, 17β testosterone, 5α-DHT, 3α androstanediol and also 17β oestradiol [53] (Figure 2). These enzymes are expressed in different human tissues and AT, depending on the isoform [54]. The isoforms of 17β-HSD have various functions and can be differentially expressed in different AT depots.

17β-HSD type 5, also called aldoketoreductase family 1 member 3 (AKR1C3), and 17β-HSD type 3 are encoded by AKR1C3 and HSD17B3, respectively. HSD17B3 and AKR1C3 are expressed in multiple ATs including SCAT, omental AT and VAT with their expression being higher in SCAT than omental AT in women [45,51,55-57] and men [58]. However, HSD17B3 expression is controversial, as other studies have not detected its expression in paired omental AT and SCAT in women [39,56]. Both enzymes are involved in adipocyte differentiation. Increased expression of HSD17B3 was associated with the differentiation process of adipocytes isolated from SCAT in women [51]. AKR1C3 expression was increased in omental and subcutaneous (SC) mature adipocytes of women compared to that in preadipocytes [51,56].

17β-HSD type 2 and 17β-HSD type 4, encoded respectively by HSD17B2 and HSD17B4, catalyse the conversion of active androgens to inactive metabolites.

17β-HSD type 2 is responsible for the conversion of 5 androstenediol to DHEA, testosterone to androstenedione, and 5α-DHT to 5α-androstanedione [53] (Figure 2). This enzyme seems to be expressed exclusively in the stroma vascular fraction, as in men and women, it was detected in the blood vessels of omental AT and SCAT, with a higher expression in omental AT in women [59,60], but not in adipocytes [59]. HSD17B2 was found to be expressed in women and men omental AT [55,58] and SCAT [55,58,59] with its expression being higher in omental AT compared to SCAT in both [55,58]. However, in other studies, no relevant mRNA expression was detected in women paired omental AT and SCAT [39,56]. 17β-HSD type 4 mainly

degrades 5 androstenediol into DHEA [53,61] (Figure 2). Its expression was higher in omental AT than in SCAT in women [56]. However, in another study, the expression of this enzyme was not detected in women SCAT [39].

### 5α-reductases

Another important enzyme family is 5α-reductases. They are microsomal enzymes responsible for the formation of the active metabolite 5α-DHT through direct conversion of testosterone to 5α-DHT or through conversion of androstenedione to 5α-androstanedione and subsequent 17-oxoreduction [62]. Interestingly, in human preadipocytes, androstenedione serves as the primary source of 5α-DHT rather than the direct transformation of testosterone [63]. There are different expression levels of the three isoforms of this enzyme, SRD5A1, SRD5A2, and SRD5A3, in different adipose depots. SRD5A1 was found to be expressed in omental AT and SCAT in men and women, whereas SRD5A3 was only expressed in male omental AT and SCAT [39,51,63]. SRD5A3 mRNA levels were higher than those of SRD5A1 in both tissues; however, no such difference was observed in their protein expression [63]. SRD5A1 and SRD5A3 mRNA were expressed in both preadipocytes and adipocytes after differentiation [51,63]. As for SRD5A2, its expression in omental AT and SCAT is not clear and seems to be sex dependent; one study did not detect SRD5A2 mRNA expression in men [63] whereas another study detected SRD5A2 mRNA at similar levels in eight paired women omental AT and SCAT [35].

### AKR1C isoenzymes

They are mainly responsible for the conversion of 5α-DHT into inactive metabolites. AKR1C enzymes, including AKR1C1, AKR1C2, and AKR1C3, are homologous with different substrate specificities. They display ketosteroid reductase activity (3α-HSD (AKR1C2), 20α-HSD (AKR1C1), and 17β-HSD (AKR1C3) [64,65]. As AKR1C3 has already been described above, we will only describe AKR1C1 and AKR1C2 enzymes in this paragraph. More specifically, AKR1C1 forms testosterone from androstenedione (3-4% of its 20α-HSD activity) and inactivates 5α-DHT into 3α androstanediol (8% of its 20α-HSD activity) and 3β androstanediol [64] (Figure 2). It could be responsible for 30% of 3α androstanediol and 40-60% of 3β androstanediol production in AT [58]. AKR1C2 is responsible for converting 5α-DHT into the inactive metabolites androstanediols. It is responsible for the production of approximately 70% of the 3α androstanediol and 40-60% of the 3β androstanediol, as AKR1C2
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inhibition reduced the formation of these metabolites in AT [58] (Figure 2). AKR1C enzymes were strongly expressed in both SCAT and omental AT in women when compared with mRNAs of other steroidogenic enzymes [58]. AKR1C2 was the predominant isoform in human SCAT, followed by AKR1C3 and then AKR1C1 [66,67]. AKR1C1 mRNA expression and AKR1C2 activity were higher in SCAT than in omental AT [58,68]. Similarly, AKR1C2 was expressed in SCAT and VAT, with a tendency towards a decrease in VAT [57]. All AKR1C enzymes were expressed in the stroma-vascular fraction, but their mRNA expression was lower than in adipocytes. Indeed, mRNA expression of these enzymes was lower in preadipocytes than in differentiated adipocytes [58,69]. In conclusion, AKR1C enzymes seem to be more highly expressed in SCAT than in VAT and in preadipocytes than in mature adipocytes.

Since we mainly focused on androgen metabolism, we will not discuss aromatase encoded by CYP19A1 (Figure 2). However, it is worth mentioning that AT is an important site for the conversion of androgens to oestrogens, also called aromatisation, particularly after menopause in women [15].

## Androgen metabolism in AT of patients with PCOS and obesity

Patients with PCOS or obesity exhibit elevated androgen levels and increased expression of androgenic enzymes in AT. Interestingly, it is known that obese patients have fewer circulating androgens; however, this is not the case in AT, in which there is an increase in androgens with obesity [70]. Both conditions present hyperinsulinemia [10] which could increase steroidogenic enzyme expression, as has been shown in adrenal cells [71]. Obesity and polycystic ovary syndrome (PCOS) are also associated with chronic low-grade inflammation [72]. Interestingly, synovial tissue macrophages from patients with active rheumatoid arthritis demonstrated inflammation-driven differential expression of steroidogenic enzymes (AKR1C3, AKR1C2, SRD5A1, and HSD11B1), promoting local metabolism and activation of glucocorticoids and androgens, which modulated inflammatory responses through intracrine and paracrine actions, revealing that these enzymes can be regulated by inflammation [73]. DHEA, androstenedione, testosterone, and 5α-DHT levels were significantly increased in abdominal SCAT in women with PCOS compared to healthy women [74,75]. HSD3B1 and HSD3B2 mRNA expression increased in SCAT of women with PCOS [39] which is in accordance with higher levels of androstenedione [74]. AKR1C3 mRNA

levels also increased in SCAT of women with PCOS, in favour of increased testosterone and 5α-DHT levels [39,74]; however, one recent study reported no change in expression [75]. Metabolic *in vivo* experiments indicated that AKR1C3 and SRD5A1 activities were higher in AT than in circulation, suggesting that AT could be a major site for active androgen production in women with PCOS [74]. However, SRD5A1 mRNA expression [39] and activity [74] were decreased in SCAT of women with PCOS compared to the control group, which is contradictory to an accumulation of 5α-DHT in AT. Moreover, CYP19A1 expression was decreased in SCAT of women with PCOS, suggesting a decrease in oestrogen synthesis from androstenedione and testosterone [39]. AKR1C1/2 mRNA expression was significantly increased in SCAT of women with PCOS compared with that in healthy controls [39]. Overall, these studies confirm a more active androgen metabolism in AT of women with PCOS, characterised by changes in steroidogenic enzyme expression favouring local testosterone synthesis. In men with obesity, DHEA accounts for 70% of the total five metabolites that were quantified including androstenedione, testosterone, oestrone, and 5α-DHT, in both omental AT and SCAT [16]. Patients with obesity, including women and men weighing over 10 kg more than normal weight, had 10 to 20 times higher concentrations of metabolites, including DHEA, androstenedione, progesterone, testosterone, 17α hydroxyprogesterone, 17β oestradiol and oestrone in MAT and abdominal AT [13]. In men with obesity, testosterone levels were increased in SCAT [76]. In women with obesity, both SCAT and VAT exhibited slightly elevated levels of androstenedione and 5α-DHT compared to women who were lean, whereas testosterone levels were increased by 7-to 9-fold, specifically in VAT [38]. Some depot differences have been observed in obesity. For example, omental AT contained more DHEA, androstenedione, and 5α-DHT than SCAT in men with obesity [16]. The expression and activity of multiple enzymes were positively correlated with body mass index (BMI). In human SCAT, AKR1C3 mRNA expression was positively correlated with BMI in women [56], trunk fat mass in women [67], and central obesity (identified by the waist-to-hip ratio) in both men and women [66]. AKR1C3 expression decreased with diet-induced weight loss [56,77] and was positively correlated with serum leptin levels and mRNA expression in subjects with obesity, supporting a connection with adiposity [77]. SRD5A1 mRNA expression in whole SCAT was also positively correlated with BMI in men [63]. Both of these regulations (AKR1C3 and SRD5A1) favour testosterone and 5α-DHT accumulation in AT. Fouad
<figure><img src="image_20.png" /></figure>

Mansour et al. showed a positive correlation between BMI or SC adipocyte diameter and 17β-HSD2 activity in whole AT of men [63], in accordance with an increase in DHEA and androstenedione observed in patients with obesity. In contrast, enzymes inactivating 5α-DHT into the less active metabolites androstenediols were also increased in obesity, which could be explained by a more active androgen metabolism. AKR1C2 3α-HSD activity in VAT was positively associated with its area, BMI and adipocyte size in women [44,45]. Waist-to-hip ratio in men and trunk fat mass in women was positively associated with AKR1C2 and AKR1C3 mRNA expression [66,67]. AKR1C1 and AKR1C2 mRNA expression was higher in isolated adipocytes and AT from men and women who were heavier than their twin siblings [78,79]. Accordingly, higher omental 5α-DHT inactivation rates were found in men with obesity than in men who were lean and positively correlated with omental adipocyte diameters in women [44,58]. In rodents, obesity favours androgen synthesis in AT. CYP11A1 and CYP17A1 mRNA levels were increased with obesity in female rats, suggesting increased *de novo* synthesis of androgens [26,80]. In female rats and male mice, HSD17B3 mRNA expression was higher in AT from animals with obesity compared to lean animals, which would favour testosterone and 5α-DHT accumulation in AT [26,80]. HSD3B1 mRNA expression was decreased in VAT from mice with obesity [81] but HSD3B2 was higher expressed in VAT from rats and male mice with obesity [26,80] which does not allow us to draw conclusions about their impact on androgen metabolism. In conclusion, patients with PCOS or obesity display a more active androgen metabolism in their AT, characterised by an increased production of androgens and mechanisms inactivating excess androgens.

## Androgen synthesis and storage in AT and its contribution to general circulation

AT functions as an energy-storage depot and is a potent endocrine and paracrine regulator. AT could play a complex role in androgen homeostasis, functioning as a site of androgen uptake, storage, and/or synthesis. It expresses steroidogenic enzymes necessary to convert precursors such as DHEA into active androgens, but also enzymes inactivating them, further underscoring a possible role in local androgen metabolism. Its ability to uptake androgens has been demonstrated by the retention of radioactive androgens in AT [82,83]. *In vivo*, radioactive testosterone

and pregnenolone were taken up by mouse AT [82]. *In vitro*, 96% of medium radioactive androstenedione was absorbed by adipocytes within 1 min and it was still detectable after 120 min with a localization mostly in adipocyte lipid fraction [83]. The concentration of androgens within AT generally exceeds that in plasma, supporting the idea that AT could be both a reservoir for circulating androgens and an *in situ* synthesis site of androgens. The levels of androstenedione, oestrone, testosterone and 17β oestradiol in women MAT were approximately 10 times greater than those in serum [20]. Concentrations of oestrone, 17β oestradiol, androstenedione, and DHEA were 3–17 times higher in MAT or abdominal SCAT than in plasma, with the exception of testosterone [15]. Similarly, the total amount of sex steroids within men SCAT and women MAT was found to be 40 to 400 times greater than that in plasma [14]. Correlations between AT and serum androgen levels suggest either uptake, local synthesis, or a potential contribution of AT to circulating androgen levels. In women, oestrone and testosterone levels in MAT were positively correlated with plasma levels (r = 0.75 and r = 0.57, respectively) [15]. Oestrone (r = 0.79) and androstenediol (r = 0.63) also showed positive correlations between abdominal AT and plasma [15]. Hormone levels in adipocytes mirrored serum rankings, with androstenedione being 20–30 times higher than oestrone in serum; accordingly, androstenedione levels were 10-fold higher than oestrone in AT [19]. In men, significant associations were found between circulating hormone levels and those in omental AT and SCAT for oestrone, testosterone, and DHT, along with a correlation for DHEA [16]. These correlations are exacerbated in obesity and PCOS, reflecting enhanced uptake and/or synthesis and disrupted local androgen metabolism. Sex steroid tissue/serum ratios (DHEA, androstenedione, testosterone, 17β oestradiol, oestrone, and progesterone) ranged from 2.2 to 13.2, but were significantly higher (2.4 to 86.5 times) in subjects with obesity, particularly for DHEA and androstenedione (53.7 and 86.5, respectively) [13]. In healthy subjects, testosterone and 5α-DHT levels were similar in serum and abdominal SCAT, whereas women with PCOS had higher androgen levels in AT [74]. Men with obesity had lower circulating testosterone but higher concentrations in SCAT than normal-weight individuals [16]. Overall, this duality supports that AT's role in androgen metabolism involves both passive uptake and active local synthesis. Its role is probably mostly
<figure><img src="image_21.png" /></figure>

local and could be more significant in adipose depots in close proximity to organs and in pathological settings.

# Effects of androgens on AT physiology

## Androgen receptor expression in AT

It is not surprising that androgens regulate AT physiology, which could be independent of plasma levels of sex hormones, because AT expresses the androgen receptor (AR) [12]. Androgens exert their effects through the AR which is a nuclear hormone receptor that is broadly expressed in various tissues, including AT [84,85]. The mechanism of AR action involves the formation of a complex between the receptor, its corresponding ligands, and co-regulator proteins, which interact with basal transcription factors to regulate the transcription of target genes [86].

## Human WAT

AR is differentially expressed in ATs. AR gene and protein expression was detected in both preadipocytes and mature adipocytes, with differential expression in these two cell types [84,85]. Its gene and protein expression decreased in mature adipocytes compared to preadipocytes during differentiation, suggesting that preadipocytes are more sensitive to androgens and more active with regard to androgen signalling than mature adipocytes [84]. Expression in preadipocytes is different between adipose depots, with the AR being more highly expressed in visceral than in SC preadipocytes [85]. Moreover, intra-abdominal preadipocytes (visceral) contained 2-fold more androgen-binding sites than SC preadipocytes quantified using the synthetic radioligand [3 h]-R1881, with no difference between men and women in the same adipose depot [84]. The higher expression of AR in VAT compared to SCAT aligns with the greater androgen-mediated effects observed in VAT, as described next. In women SCAT, AR protein expression was negatively correlated with 5α-DHT concentration, which was perceived as AR desensitization, a protective mechanism [87].

## WAT of animal models

Similar to humans, lower AR expression was found in male rat inguinal (SCAT) and retroperitoneal depots (non-SCAT, non-VAT) than in VAT (gonadal and mesenteric depots). However, these differences were not observed in female rats [25,84]. Testosterone could promote the synthesis of AR in adipose precursor cells from male rat fat pads [88]. In 3T3-L1 preadipocytes, testosterone did not affect AR mRNA levels [25].

## BAT of rat

AR expression in BAT varies between the sexes. Higher AR mRNA levels were found in male BAT than in female BAT of rats [89]. AR mRNA expression tended to decrease upon testosterone treatment of BAT *ex vivo* culture [89]. This was contrary in WAT, indicating that different factors could regulate the response to androgens in WAT and BAT [89].

## Adipocyte differentiation

Adipogenesis is the process of differentiation of adipose derived stem cells into mature adipocytes. To date, most results obtained suggest that androgens have a negative effect on adipogenesis (Figure 3(a), Table 1). In humans, androgens inhibit preadipocyte proliferation and differentiation independent of sex. Indeed, it has been shown that testosterone, 5α-DHT, and DHEA inhibit the differentiation of SC and omental preadipocytes in both men and women with DHEA, inhibiting the proliferation of omental preadipocytes [90–93]. 5α-DHT did not affect the proliferation of human preadipocytes from abdominal SCAT or omental AT in men and women [94]. Moreover, in women SCAT, testosterone can inhibit the commitment of human adipose-stem cells to preadipocytes [93]. However, in a 3D model of *in vitro* human adipose-derived stem cells, testosterone did not affect the differentiation and maturation of adipocytes [95]. Androgen inhibition of early stage adipocyte differentiation was shown to be mediated in part through AR action by decreasing PPARγ, C/EBPα, and C/EBPβ mRNA levels in SCAT through BMP4 signalling [93]. Interestingly, there were differences between adipose depots with DHEA only inhibiting differentiation of omental adipocytes, but not SC [92]. Moreover, 10⁻⁷ M DHEA was necessary to inhibit the proliferation of human SC preadipocytes whereas only 10⁻⁸ M DHEA impeded the proliferation of omental preadipocytes [92]. This highlights that AT depots seem to have different sensitivities to androgens, which could be explained by the differential expression of AR. In male and female mice, transcriptome analysis on retroperitoneal AT by RT-qPCR revealed an upregulation, in response to 5α-DHT, of four genes CDKN1Ad (Cyclin Dependent Kinase Inhibitor 1A), FKBP5 (FK506 binding protein 5), GADD45 (Growth Arrest and DNA Damage protein), and MT1A (Metallothionein 1A) which are involved in negative regulation of adipogenesis [96]. After castration, male rats exhibited an increased proliferative capacity of preadipocytes in epidermal and perirenal AT, whereas the differentiation capacity was enhanced only in perirenal AT and
<figure><img src="image_22.png" /></figure>

<figure><img src="image_23.png" /><figcaption>**Figure 3.** Effect of androgens on human WAT. A- Effects of testosterone, 5α-DHT and DHEA on adipogenesis. Androgens inhibit adipogenesis through inhibition of commitment of adipose stem cells (ASC), proliferation and differentiation of preadipocytes into mature adipocytes. In purple are the effects only mediated by testosterone. B- Effects of androgens on lipolysis and lipogenesis. In blue are the effects of androgens on women AT, in green on men AT. In general, androgens have opposite effects on men and women AT. They tend to inhibit lipogenesis and stimulate lipolysis in men at and vice versa in women. However, the effect of androgens on LPL are controversial in women AT (represented by a grey arrow). T: testosterone, DHEA: dehydroepiandrosterone, DHT : dihydrotestosterone, DHEA-S : dehydroepiandrosterone sulphate, LPL: lipoprotein lipase, FFA: free fatty acid, DGAT: Diglyceride acyltransferase, DG: diacylglycerol, MG: monoacylglycerol, ATGL: Adipose triglyceride lipase; HSL: Hormone-sensitive lipase; cAMP/ PKA: cyclic adenosine monophosphate/protein kinase A; T: testosterone.</figcaption></figure>

decreased in epididymal AT [97]. In contrast, no sig-
nificant effect was observed on the proliferation and
differentiation of femoral SCAT [97]. Similarly, castra-
tion in mice increased the proliferation of High fat diet
(HFD)-induced visceral and SC adipocyte precursors,
which was reduced by testosterone and 5α-DHT sup-
plementation [98]. Testosterone treatment also inhib-
ited the differentiation of porcine preadipocytes in an
AR-dependent manner, as flutamide treatment reversed
this effect [99]. These findings suggest that androgens
inhibit the proliferation and differentiation of visceral
adipose tissue (VAT) preadipocytes, but not SCAT,
highlighting the differing sensitivities of these depots
to androgens. This is consistent with androgen receptor
(AR) expression being higher in VAT than in SCAT in
male rats [25,84]. Studies on adipocyte cell lines corro-
borate the inhibitory effect of androgens on primary
adipocyte differentiation. Indeed, testosterone, 5α-
DHT, and DHEA were shown to inhibit murine pre-
adipocyte cell lines 3T3-L1 and 3T3-F442A differentia-
tion with DHEA also having a negative effect on 3T3-

L1 preadipocytes proliferation [92,100-102]. DHEA has been shown to impede the differentiation and proliferation of Chub-S7 cells derived from human SC preadipocytes, but this was independent of the AR [103]. However, the inhibitory effect of testosterone and 5α-DHT on 3T3-L1 differentiation was AR dependent [100]. Whether DHEA has a direct effect on adipocytes or if it relies on its conversion into other steroid hormones or not, to display these effects, still needs to be validated. One study showed that DHEA conversion into oestrogens or androgens was not involved [103]; however, the effects of DHEA on 3T3-F442A/L1 cell differentiation could be inhibited by 3β-HSD inhibitors, indicating that conversion to androgens or other steroids is necessary to elicit the effect of DHEA in these cells [92].

Lipogenesis and lipolysis

Although androgens are known to modulate AT dis-
tribution in humans, their role in lipolysis (hydrolysis
<figure><img src="image_24.png" /><figcaption>**Table 1.** Effect of androgens on adipogenesis.</figcaption></figure>

<table><thead><tr><th>Biological process</th><th>Androgen</th><th>Effect</th><th>Type of tissue/cells</th><th>Species</th><th>Female</th><th>Male</th><th>Ref</th></tr></thead><tbody><tr><td rowspan="3">Adipogenesis<br>Preadipocyte proliferation</td><td>DHEA</td><td>inhibition</td><td>SC and OM preadipocytes</td><td>human</td><td>+</td><td>+</td><td>Rice 2010</td></tr><tr><td>DHEA</td><td>inhibition</td><td>Chub S7 cell line</td><td></td><td></td><td></td><td>McNelis 2013</td></tr><tr><td>DHEA</td><td>inhibition</td><td>3T3-L1</td><td></td><td></td><td></td><td>Singh 2006 - Lea-Curie 1998</td></tr><tr><td rowspan="6">Differentiation</td><td>5α-DHT</td><td>no effect</td><td>abdominal SC or OM preadipocytes</td><td>human</td><td>+</td><td>+</td><td>Anderson 2001</td></tr><tr><td>castration</td><td>stimulation</td><td>perirenal and epididymal preadipocytes</td><td>rats</td><td></td><td>+</td><td>Garcia 1999</td></tr><tr><td>castration</td><td>no effect</td><td>femoral SC preadipocytes</td><td>rats</td><td></td><td>+</td><td>Garcia 1999</td></tr><tr><td>Castration of HFD-mice</td><td>Increase</td><td>visceral and subcutaneous adipocyte precursors</td><td>mice</td><td></td><td>+</td><td>Sebo 2021</td></tr><tr><td>T</td><td>inhibition</td><td>OM and SC preadipocytes</td><td>human</td><td>+</td><td>+</td><td>Blouin 2010</td></tr><tr><td>T</td><td>inhibition</td><td>SC preadipocytes</td><td>human</td><td>+</td><td>+</td><td>Chazenbalk 2013</td></tr><tr><td></td><td>T</td><td>no effect</td><td>3D in vitro human derived adipose stem cell culture model</td><td>human</td><td>+</td><td>+</td><td>Pal 2024</td></tr><tr><td></td><td>T</td><td>inhibition</td><td>3T3-L1</td><td></td><td></td><td></td><td>Singh 2006</td></tr><tr><td></td><td>T</td><td>inhibition</td><td>porcine preadipocytes</td><td>Pigs</td><td></td><td>+</td><td>Xie 2024</td></tr><tr><td></td><td>DHEA</td><td>inhibition</td><td>OM preadipocytes</td><td>human</td><td>+</td><td>+</td><td>Rice 2010</td></tr><tr><td></td><td>DHEA</td><td>inhibition</td><td>3T3-L1, 3T3 F442A, Chub S7 cell line,</td><td></td><td></td><td></td><td>Gordon 1986, Lea Curie 1998, McNelis 2013,</td></tr><tr><td rowspan="5">Upregulation of genes involved in negative regulation of adipogenesis</td><td>5α-DHT</td><td>inhibition</td><td>OM and SC preadipocytes</td><td>human</td><td>+</td><td>+</td><td>Blouin 2010</td></tr><tr><td>5α-DHT</td><td>inhibition</td><td>SC, mesenteric, OM preadipocytes</td><td>human</td><td></td><td>+</td><td>Gupta 2008</td></tr><tr><td>5α-DHT</td><td>inhibition</td><td>3T3-L1</td><td></td><td></td><td></td><td>Singh 2006</td></tr><tr><td>castration</td><td>inhibition</td><td>perirenal preadipocytes</td><td>rats</td><td></td><td></td><td>Garcia 1999</td></tr><tr><td>castration</td><td>stimulation</td><td>epididymal preadipocytes</td><td>rats</td><td></td><td></td><td>Garcia 1999</td></tr><tr><td></td><td>castration</td><td>no effect</td><td>femoral SC preadipocytes</td><td>rats</td><td></td><td></td><td>Garcia 1999</td></tr><tr><td></td><td>5α-DHT</td><td>upregulation</td><td>retroperitoneal AT</td><td>mice</td><td>+</td><td>+</td><td>Zhang 2008</td></tr></tbody></table>

T: testosterone; SC: subcutaneous; OM: omental; DHEA: dehydroepiandrosterone; 5α-DHT: 5α-dehydrotestosterone. HFD: high-fat diet.

of triglycerides (TG) into glycerol and free fatty acids (FA)) and lipogenesis (conversion of free fatty acids and glycerol into triglycerides) remains controversial and seems to be sex-and AT depot-specific (Table 2).

## FA uptake and TG storage

Few studies have investigated the effects of androgens on FA uptake in humans. Testosterone inhibited FA uptake in human intra-abdominal AT depots, but not in SCAT in men [104] (Figure 3(b)). Furthermore, the VAT mass in men with obesity and diabetes was more specifically decreased after testosterone supplementation for 3 months [105]. Thus, VAT seems to be more responsive to androgens than is SCAT. This depot-specific response highlights the varying sensitivity of adipose depots to androgenic signals. However, in women with PCOS, plasma testosterone and DHEA-S were positively correlated with VAT accumulation in the lower or upper body parts, suggesting a positive effect on lipogenesis [106]. Testosterone inhibits FA uptake in rats. Indeed, castrated rats exhibited higher FA uptake in retroperitoneal and mesenteric AT than the non-castrated group, and testosterone administration reduced FA uptake [107]. Moreover, in rat adipocytes from different AT locations, higher AR nuclear binding was associated with lower FA uptake [108]. These findings

suggest that AR-mediated signalling in adipocytes plays an important role in the regulation of FA uptake. Controversial effects have been reported in simian animals. For example, 5α-DHT increased FA uptake in ovariectomized female rhesus macaques in an AR-dependent manner [109]. In female macaques, FA uptake in omental AT was increased by chronic testosterone treatment. However, this effect was only observed during the menstrual period and not during the luteal phase, suggesting that the balance between androgens and oestrogens plays a role in the lipid metabolism of AT [110].

## Lipoprotein lipase (LPL) activity

5α-DHT and testosterone inhibited LPL activity in men omental AT, with testosterone also inhibiting LPL activity in SCAT [90]. 5α-DHT has the same effect in women's omental AT, but higher 5α-DHT concentrations were necessary to inhibit LPL activity [90]. However, another study found that 5α-DHT treatment of isolated adipocytes from women abdominal SCAT stimulated LPL protein expression in an AR-dependent manner [87]. Moreover, 6-week oral testosterone treatment in men with obesity decreased LPL activity in abdominal VAT but not in femoral SCAT [111]. These observations suggest that androgenic regulation of LPL activity is not only
<figure><img src="image_25.png" /><figcaption>Table 2. Effect of androgens on lipolysis and lipogenesis.</figcaption></figure>

<table><thead><tr><th>Biological process</th><th>Androgen</th><th>Effect</th><th>Type of tissue/cells</th><th>Species</th><th>Female</th><th>Male</th><th>Ref</th></tr></thead><tbody><tr><td><strong>Lipogenesis</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>FA uptake</td><td>T<br>T<br>T<br>castration<br>5α-DHT</td><td>decrease<br>no effect<br>decrease<br>increase<br>increase<br>T</td><td>intra-abdominal AT depots<br>SCAT<br>retroperitoneal and mesenteric AT<br>retroperitoneal and mesenteric AT<br>retroperitoneal AT<br>VAT</td><td>human<br>human<br>rats<br>rats<br>macaques<br>human<br>(obesity)<br>rats</td><td>+</td><td>+</td><td>Mårin 1996<br>Mårin 1996<br>Li 1995<br>Li 1995<br>Varlamov 2012<br>Boyanov 2003</td></tr><tr><td>Association of AR nuclear binding and FA uptake</td><td>N/A</td><td>negative</td><td>pooled inguinal, mesenteric, epididymal and retroperitoneal fat</td><td>human<br>human<br>(obesity)</td><td>+</td><td>+</td><td>Sjogren 1995</td></tr><tr><td>LPL activity</td><td>T<br>T<br>T</td><td>inhibition<br>increase<br>no effect</td><td>OM and SC adipocytes<br>abdominal VAT<br>femoral SCAT</td><td>human<br>human<br>(obesity)</td><td>+</td><td>+</td><td>Blouin 2010<br>Rebufé-Scrive<br>1991<br>Rebufé-Scrive<br>1991</td></tr><tr><td><strong>Lipolysis</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lipolysis</td><td>T<br>T<br>T<br>T</td><td>inhibition<br>inhibition<br>increase<br>no effect</td><td>differentiated SCAT adipocytes<br>SCAT isolated adipocytes<br>abdominal SCAT<br>femoral SCAT</td><td>human<br>human<br>human<br>(obesity)<br>human<br>(obesity)<br>human</td><td>+</td><td>+</td><td>Dicker 2004<br>Anderson 2002<br>Rebuffé-Scrive<br>1991<br>Rebuffé-Scrive<br>1991<br>Hernadez-Morante 2008</td></tr><tr><td></td><td>DHEA-S</td><td>stimulation</td><td>SCAT and VAT explants</td><td>human</td><td>+</td><td>+</td><td>Tagliaferro 1995<br>Xu 1991</td></tr><tr><td></td><td>DHEA<br>castration<br>+T</td><td>decrease</td><td>isolated epididymal adipocytes<br>epididymal adipocytes</td><td>rats<br>rats</td><td>+</td><td>+</td><td></td></tr><tr><td>HSL protein expression</td><td>AR-KO<br>5α-DHT<br>castration<br>AR-KO<br>castration</td><td>decrease<br>no effect<br>decrease<br>decrease<br>no effect</td><td>WAT<br>isolated adipocytes SCAT<br>epididymal AT<br>epididymal AT<br>WAT<br>epididymal AT</td><td>mice<br>human<br>mice<br>mice<br>mice<br>mice</td><td>+</td><td>+</td><td>Fan 2005<br>Anderson 2002<br>Floryk 2011<br>Floryk 2011<br>Fan 2005<br>Floryk 2011</td></tr></tbody></table>

T: testosterone. SC: subcutaneous; OM: omentalDHEA: dehydroepiandrosterone; DHEA-S: dehydroepiandrosterone sulfate; 5α-DHT: 5α-dehydrotestosterone; AR-KO: androgen receptor knock out; N/A: non applicable.

depot-specific, but also sex-dependent, which could provide insights into how androgens modulate AT distribution and metabolic function in both men and women.

## Lipolysis

The effect of androgens on lipolysis appeared to be depot- and sex-specific (Figure 3(b)). Generally, studies have observed a lipolytic effect of testosterone in men and male animals. Indeed, 6-week oral testosterone treatment in men with obesity increased lipolytic response to norepinephrine specifically in abdominal VAT, but not in femoral SCAT [111]. In isolated epididymal and perirenal adipocytes from castrated male rats, testosterone, but not 5α-DHT, promoted lipolysis induced by catecholamines (isoproterenol and norepinephrine). These effects were mediated by binding to the AR without conversion to oestrogens [112,113]. Castration decreased phosphorylated-HSL protein levels in epididymal AT [114]. Moreover, AR-KO male mice developed late-onset obesity due to decreased lipolysis and HSL transcription levels in WAT [115]. Finally, oral administration of DHEA stimulated lipolysis in male rats by enhancing the response to adrenergic stimulation in

isolated epididymal adipocytes [116]. Hernadez-Morante et al. highlighted that DHEA has sex- and depot-specific effects on lipolysis. Indeed, serum DHEA-S was inversely correlated with VAT area in men with obesity and women; *in vitro*, DHEA-S increased lipolysis specifically in SCAT explants from women and in VAT explants from men [117]. This inverse correlation indicates that DHEA may have a role in modulating AT distribution differently in men and women in accordance with the sex specificity of AT distribution observed in humans [11]. The regulation of lipolysis by androgens in women appears to be the opposite of that in men. In women SCAT, 5α-DHT treatment of isolated adipocytes decreased HSL protein expression and basal lipolysis [87]. In differentiated preadipocytes from women SCAT, testosterone reduced catecholamine-stimulated lipolysis, which was associated with a decrease in β2-adrenoreceptor and HSL protein expression [118]. In addition, lower HSL protein expression has been found in omental AT from women with PCOS than in the control group [119]. Lastly, findings from female rhesus macaques indicate that the regulation of lipolysis by sex hormones
<figure><img src="image_26.png" /></figure>

is complex. During the luteal phase of the menstrual cycle, characterised by elevated levels of oestrogen and progesterone, basal lipolysis and HSL expression were higher specifically in VAT than in menstruating controls. Administration of testosterone supplementation during the prepubertal period alleviated the impact of the luteal phase on basal lipolysis. Interestingly, these hormonal effects were not observed during stimulated lipolysis induced by isoproterenol, a β-adrenergic agonist [110]. These findings highlight the complex interaction between androgens and other sex hormones in regulating lipolysis, with implications for understanding how hormonal fluctuations in women (e.g. during the menstrual cycle or in PCOS) affect AT metabolism. In conclusion, androgens are prone to diminish AT mass by inhibition of adipogenesis and lipogenesis and stimulation of lipolysis, mainly in men, whereas

in women androgens seem to have opposing effects (Figure 3(a,b), Table 2). These observations underscore the need for sex- and depot-specific approaches when studying androgenic effects on AT metabolism. Local synthesis and inactivation of androgens could partly explain these sex and depot specificities [120].

## Impact of androgens on AT adipokine expression and secretion

### Adiponectin

Very few studies have evaluated adiponectin secretion by human adipocytes in response to androgens, but most studies have reported a negative effect of androgens and a negative correlation between androgens and adiponectin serum levels (Table 3). It is interesting to remember that adiponectin is predominantly produced by adipocytes; therefore, serum adiponectin levels

<table><caption>**Table 3.** Effects of androgens on adipokine secretion or gene expression.</caption><thead><tr><th>Biological process</th><th>Androgen</th><th>Effect</th><th>Type of tissue/cells</th><th>Species</th><th>Female</th><th>Male</th><th>Ref</th></tr></thead><tbody><tr><td><strong>Adipokines</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Adiponectin secretion</td><td>T</td><td>no effect</td><td>primary SC and OM adipocytes</td><td>human</td><td></td><td>+</td><td>blouin 2010</td></tr><tr><td></td><td>T</td><td>decrease</td><td>3T3-L1</td><td></td><td></td><td></td><td>Nishizawa 2002</td></tr><tr><td></td><td>T</td><td>no effect</td><td>SGBS cell line</td><td></td><td></td><td></td><td>Horenburg 2008</td></tr><tr><td>(only HMW adiponectin)</td><td>T</td><td>decrease</td><td>differentiated adipocytes from epididymal fat precursor cells</td><td>rats</td><td></td><td>+</td><td>Xu 2005</td></tr><tr><td></td><td>5α-DHT</td><td>decrease</td><td>3T3-L1</td><td></td><td></td><td></td><td>Sato 2013</td></tr><tr><td rowspan="10">Leptin secretion</td><td>T</td><td>decrease</td><td>differentiated SCAT adipocytes</td><td>human</td><td>+</td><td></td><td>Wabitsch 1997</td></tr><tr><td>T</td><td>increase</td><td>SCAT</td><td>human</td><td>+</td><td></td><td>Machinal Quelin 2002</td></tr><tr><td>T</td><td>no effect</td><td>SCAT</td><td>human</td><td></td><td>+</td><td>Machinal Quelin 2002</td></tr><tr><td>T</td><td>decrease</td><td>OM an SC adipocytes</td><td>human</td><td>pool</td><td></td><td>Dicker 2004</td></tr><tr><td>T</td><td>no effect</td><td>OM AT</td><td>human</td><td>+</td><td></td><td>Kirstensen 2000</td></tr><tr><td>5α-DHT</td><td>decrease</td><td>OM AT</td><td>human</td><td></td><td>+</td><td>Pineiro 1999</td></tr><tr><td>5α-DHT</td><td>no effect</td><td>OM AT</td><td>human</td><td></td><td>+</td><td>Pineiro 1999</td></tr><tr><td>5α-DHT</td><td>decrease</td><td>SCAT</td><td>human</td><td></td><td>+</td><td>Machinal Quelin 2002</td></tr><tr><td>5α-DHT</td><td>no effect</td><td>SCAT</td><td>human</td><td>+</td><td></td><td>Machinal Quelin 2002</td></tr><tr><td>5α-DHT</td><td>no effect</td><td>SCAT</td><td>human</td><td></td><td>+</td><td>Kirstensen 2000</td></tr><tr><td>5α-DHT</td><td>no effect</td><td>perirenal, parametrial and femoral isolated adipocytes</td><td>rats</td><td>+</td><td></td><td>Machinal Quelin 2002</td></tr><tr><td>DHEA-S</td><td>decrease</td><td>OM AT</td><td>human</td><td>+</td><td></td><td>Pineiro 1999</td></tr><tr><td>DHEA</td><td>increase</td><td>SCAT</td><td>human</td><td>+</td><td></td><td>Machinal Quelin 2002</td></tr><tr><td>DHEA</td><td>no effect</td><td>SCAT</td><td>human</td><td></td><td>+</td><td>Machinal Quelin 2002</td></tr><tr><td></td><td>androstand editione</td><td>decrease</td><td>OM AT</td><td>human</td><td>+</td><td></td><td>Pineiro 1999</td></tr><tr><td rowspan="5">Leptin gene expression</td><td>T</td><td>no effect</td><td>SCAT isolated adipocytes</td><td>human</td><td></td><td>+</td><td>Machinal Quelin 2002</td></tr><tr><td>T</td><td>decrease</td><td>3T3-L1</td><td>human</td><td></td><td>+</td><td>Jenks 2017</td></tr><tr><td>5α-DHT</td><td>decrease</td><td>SCAT isolated adipocytes</td><td>human</td><td></td><td>+</td><td>Machinal Quelin 2002</td></tr><tr><td>5α-DHT</td><td>decrease</td><td>3T3-L1</td><td>human</td><td></td><td>+</td><td>Jenks 2017</td></tr><tr><td></td><td>decrease</td><td>perirenal, parametrial and femoral isolated adipocytes</td><td>rats</td><td>+</td><td></td><td>Machinal 1999</td></tr><tr><td></td><td>DHEA</td><td>no effect</td><td>SCAT isolated adipocytes</td><td>human</td><td></td><td>+</td><td>Machinal Quelin 2002</td></tr><tr><td>Resistin gene expression</td><td>DHEA</td><td>increase</td><td>epididymal AT</td><td>rats</td><td></td><td>+</td><td>Kochan & Karbowska 2004 – Ling 2001</td></tr></tbody></table>

T: testosterone. SC: subcutaneous; OM: omental. DHEA: dehydroepiandrosterone; 5α-DHT: 5α-dihydrotestosterone.
<figure><img src="image_27.png" /></figure>

should be mainly due to adipocytes. 5α-DHT and testosterone had no significant effect on adiponectin secretion by primary human cultures of SC and omental adipocytes [90]. Testosterone also had no effect on adiponectin secretion by human SCAT primary *in vitro* differentiated adipocytes or on adiponectin expression in Simpson-Golabi-Behmel Syndrome (SGBS) adipocytes [121]. However, in murine models, androgens decreased adiponectin secretion and were negatively correlated with serum adiponectin levels. *In vitro*, 3T3-L1 adipocytes showed reduced adiponectin secretion when treated with testosterone and 5α-DHT [122,123]. Moreover, testosterone reduced the secretion of adiponectin in rat epididymal differentiated adipocytes [124]. Regarding serum levels, there were mostly negative correlations between androgen and adiponectin levels. Indeed, serum adiponectin levels decreased with puberty in boys [125] and compared to eugonadal men, hypogonadal men have higher adiponectin concentration in serum, which was reduced by testosterone replacement therapy [126]. In postmenopausal women, biologically active testosterone and free testosterone serum levels were inversely associated with adiponectin [127]. Free testosterone also had an inverse correlation with adiponectin levels in men; however, this correlation was only positive for total testosterone [127]. Moreover, castrated mice had increased serum adiponectin levels, which were decreased by testosterone treatment [114,122]. Similarly, serum adiponectin levels were inversely correlated with serum testosterone levels in young male and female rats, and testosterone reduced total circulating adiponectin concentrations in a dose-dependent manner in young male rats [128].

## Leptin

Most studies have reported a negative effect of androgens on leptin secretion or expression by AT (Table 3). This effect seems to be androgen species-, depot-, and sex-specific. Indeed, Machinal-Quelin et al. found that the effects of androgens on SCAT differed depending on the androgen species and sex. Testosterone and DHEA increased leptin secretion in SCAT in women but had no effect on SCAT in men [129]. In contrast, 5α-DHT decreased leptin secretion in SCAT in men, but had no effect in women [129]. The effect of androgens on leptin secretion by SCAT was AR-dependent in men, whereas in women, it was dependent on aromatization, suggesting that the observed effects in women are mediated by oestrogens [129]. 5α-DHT and testosterone reduced leptin secretion in women differentiated SCAT adipocytes [130]. 5α-DHT, DHEA-S, and androstenedione reduced leptin secretion of omental AT in women [131]. SCAT and omental adipocytes

from men and women show reduced leptin secretion upon testosterone treatment [118]. However, in some studies, treatment of women SCAT with 5α-DHT and treatment of women omental AT with testosterone had no effect on leptin secretion [131,132]. *In vitro*, 5α-DHT and testosterone treatment reduced leptin mRNA levels and secretion in 3T3-L1 adipocytes [133]. There was a negative correlation between 5α-DHT (in women) and testosterone (in men) serum levels with leptin serum levels [127,132]. Similarly, there was a negative correlation between DHEA and serum leptin levels in male rats [134].

## Resistin

The relationship between androgens and resistin has been little studied, with studies showing either a negative or no effect in humans (Table 3). To the best of our knowledge, no studies have investigated the effect of androgens on AT resistin secretion. In male rats, DHEA and testosterone were found to increase resistin gene expression in epididymal AT [134,135]. In humans, higher serum testosterone levels were associated with lower resistin levels in men; however, no correlation was observed in women [127]. Castration of mice induced an increase in resistin serum levels, and treatment with testosterone after castration restored resistin levels back to those observed in control mice [114]. Furthermore, in hypogonadal men with type 2 diabetes, there was no correlation between baseline testosterone levels and resistin serum levels, and testosterone replacement therapy did not increase these levels [136].

## Effects of androgens on BAT

Androgens can modulate UCP1 expression since an androgen response element in the UCP1 promoter has been described [115]. However, the function of androgens on BAT is controversial, and additional research is required to provide further insights into these effects. Most of the literature reported that in rodent brown adipocytes, androgens could inhibit mitochondrial biogenesis and respiration, isoproterenol-stimulated UCP1 gene expression, adipocyte differentiation, lipolysis and downregulate PGC1 α (peroxisome proliferator-activated receptor gamma coactivator 1, alpha) mRNA expression [89,137–139]. In humans, women with PCOS exhibited lower BAT activity, as indicated by a decrease in supraclavicular skin temperature, which was inversely correlated with testosterone levels compared to healthy groups [140]. This suggests that testosterone inhibits thermogenesis *in vivo*, but the inhibitory effect of androgens on
thermogenesis remains controversial especially in animal models. The protein expression of UCP1 was increased after castration in murine BAT, and 5α-DHT treatment reversed this effect [141]. However, the expression of thermogenic genes was reduced in BAT of AR-KO male mice [115]. Furthermore, androgens can exert indirect effects on BAT through central mechanisms in addition to direct effects. For example, chronic exposure to 5α-DHT in female mice has been shown to diminish hypothalamic leptin sensitivity and inhibit leptin-induced BAT thermogenesis by altering the melanocortin system [142].

## Discussion and conclusions

This review highlights that AT is a complex site for androgen metabolism with the ability to uptake, metabolize, and inactivate androgens. Although it is capable of metabolizing androgen precursors, such as DHEA, into active androgens, its ability to perform *de novo* androgen synthesis is still debated. The presence and activity of key enzymes, such as CYP11A1 and CYP17A1, are not clear in the literature and vary between AT depots, leading to uncertainty about whether AT can be considered a steroidogenic tissue. However, AT can be considered a secondary steroidogenic tissue, such as the brain and skin [5,6]. There is a dual relationship between AT and androgens, as androgens themselves regulate AT, influencing AT distribution, adipocyte differentiation, and metabolic functions, such as lipolysis, lipogenesis, and adipokine secretion. The synthesis of androgens by AT may thus serve in an autocrine manner. Overall, androgens most often inhibit adipocyte differentiation and adipokine secretion in both male and female. However, they stimulate lipolysis and prevent lipogenesis in AT in men, but display opposite effects in women. AT's contribution to androgen levels in the general circulation and on hormonal homeostasis is difficult to pinpoint, but AT's impact may be more significant locally in producing androgens for proximal organs. It is the primary source of oestrogens in postmenopausal women, and its role in the conversion of androgens to oestrogens has already been well established [15]. Thus, AT-derived androgens may have significant implications in PCOS, obesity, other endocrine related disorders and endocrine cancers, exacerbating the metabolic and pathological outcomes associated with these conditions. For instance, AT in the breast serves as a critical site for local androgen and oestrogen metabolism, with aromatase converting androgens into oestrogens. In breast cancer, the local production of oestrogens through aromatization of androgens in AT creates a hormone-enriched microenvironment that may fuel tumour progression, especially in hormone

receptor-positive cancers [17]. Beyond breast cancer, AT could influence the hormonal microenvironment and contribute to the progression of other cancers, such as prostate cancer, for which tumour growth is dependent on androgens. The prostate gland is surrounded by the periprostatic tissue (PPAT) which actively participates in prostate cancer aggressiveness [143,144]. A metabolic crosstalk implicating androgens could also exist between PPAT and prostate cancer cells. This could be particularly relevant in castration-resistant prostate cancer, where tumour progression is no longer mainly modulated by circulating testosterone, but by circulating DHEA produced by the adrenal gland. Overall, AT is a neglected player in androgen metabolism, and it is important to consider AT-derived androgens in the context of metabolic and endocrine disorders, as well as in hormone-dependent cancers. Further research is essential to elucidate the mechanisms and clinical implications of androgen metabolism in AT.

## Disclosure statement

No potential conflict of interest was reported by the author(s).

## Author contributions

CRediT: **Yiyue Jia**: Writing – original draft; **Mathilde Lacombe**: Writing – original draft; **Catherine Muller**: Validation, Writing – review & editing; **Delphine Milhas**: Supervision, Validation, Writing – review & editing.

## Funding

Research in our team is supported by the "Ligue Nationale contre le Cancer" [LNCCMU24] and the ARTP (Association for Prostate Tumor Research). Yiyue Jia is supported by a doctoral fellowship from the Chinese Scholarship Council.

## Data availability statement

Data sharing is not applicable to this article as no new data were created or analysed in this study.

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