Circulating gonadotropins and ovarian adiponectin system are modulated by acupuncture independently of sex steroid or β-adrenergic action in a female hyperandrogenic rat model of polycystic ovary syndrome

Maliqueo, Manuel; Benrick, Anna; Alvi, Asif; Johansson, Julia; Sun, Miao; Labrie, Fernand; Ohlsson, Claes; Stener-Victorin, Elisabet

doi:10.1016/j.mce.2015.04.026

Cited by 30 publications

(28 citation statements)

References 56 publications

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“…We have shown that adiponectin receptors 1 and 2 are increased in ovaries in PCOS rat models (19,20), and accumulating evidence suggests a direct role for adiponectin in female reproductive tissues (18). Moreover, a lower proportion of theca cells express adiponectin receptors in polycystic ovaries compared with normal ovaries (21).…”

mentioning

confidence: 93%

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Benrick

Chanclón

Micallef

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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100

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Adiponectin, together with adipocyte size, is the strongest factor associated with insulin resistance in women with polycystic ovary syndrome (PCOS). This study investigates the causal relationship between adiponectin levels and metabolic and reproductive functions in PCOS. Prepubertal mice overexpressing adiponectin from adipose tissue (APNtg), adiponectin knockouts (APNko), and their wild-type (WT) littermate mice were continuously exposed to placebo or dihydrotestosterone (DHT) to induce PCOS-like traits. As expected, DHT exposure led to reproductive dysfunction, as judged by continuous anestrus, smaller ovaries with a decreased number of corpus luteum, and an increased number of cystic/atretic follicles. A two-way between-groups analysis showed that there was a significant main effect for DHT exposure, but not for genotype, indicating adiponectin does not influence follicle development. Adiponectin had, however, some protective effects on ovarian function. Similar to in many women with PCOS, DHT exposure led to reduced adiponectin levels, larger adipocyte size, and reduced insulin sensitivity in WTs. APNtg mice remained metabolically healthy despite DHT exposure, while APNko-DHT mice were even more insulin resistant than their DHT-exposed littermate WTs. DHT exposure also reduced the mRNA expression of genes involved in metabolic pathways in gonadal adipose tissue of WT and APNko, but this effect of DHT was not observed in APNtg mice. Moreover, APNtg-DHT mice displayed increased pancreatic mRNA levels of insulin receptors, Pdx1 and Igf1R, suggesting adiponectin stimulates beta cell viability/hyperplasia in the context of PCOS. In conclusion, adiponectin improves metabolic health but has only minor effects on reproductive functions in this PCOS-like mouse model. polycystic ovary syndrome | insulin resistance | adipose tissue P olycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder occurring in females (1). PCOS is one of the leading causes of poor fertility and is associated with abdominal obesity, metabolic syndrome, and an increased risk of developing type 2 diabetes (1, 2). Indeed, it has been demonstrated that 30-40% of women with PCOS have impaired glucose tolerance, and as many as 10% develop diabetes by the age of 40 y (3, 4). Despite the negative effect of PCOS on women's health, very little is known about its etiology, including the causal relationship between the reproductive and metabolic features of PCOS. Adipose tissue dysfunction is implicated as a key feature, and both lean and obese women with PCOS have aberrant adipose tissue morphology (5-7). Specifically, we have found that large adipocyte size, low circulating adiponectin levels, and increased waist circumference, but surprisingly, not androgen excess, are factors that are most strongly associated with insulin resistance in women with PCOS (8). Others have shown that hyperandrogenism is associated with intra-abdominal fat deposition (9). Adiponectin is an adipocyte-derived hormone exerting potent positive effec...

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confidence: 93%

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Benrick

Chanclón

Micallef

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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100

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“…Letrozole in different dosing protocols has been used in a large number of studies to induced PCOS in animals. The oral as well as sustained release pellets have been administered in rodents aging from 21 day to 18 weeks for a period ranging from 21 to 90 days (Baravalle, Salvetti, Mira, Pezzone, & Ortega, ; Kafali et al, ; Maliqueo et al, ; Manneras et al, ). All of these studies have shown the development of cysts in ovaries and hormonal disturbance.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of ovarian and metabolic effects of GnRH modulators in two rat models of polycystic ovary syndrome

Patel¹,

Shah

2018

Molecular Reproduction Devel

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Gonadotropin-releasing hormone (GnRH) modulators are widely used in numerous reproductive conditions including infertility. Several clinical studies showed mixed results regarding the efficacy of GnRH modulators in patients with polycystic ovary syndrome (PCOS). Along with this, few preclinical studies focus on the effect of GnRH modulators in PCOS-induced animals. Therefore, the present study was designed to study the effect of leuprolide and cetrorelix on hormonal, metabolic, and menstrual dysfunction PCOS rats. Prepubertal female rats were divided into four groups: Group I received a normal pellet diet and Groups II, III, and IV received 40% high-fat diet for 105 days. Similarly, adult female rats were divided into four groups: Group I received 1% carboxymethylcellulose (CMC) and Groups II, III, and IV received letrozole (1 mg/kg, per oral [p.o.] in 1% CMC) for 21 days. Thereafter, leuprolide (2.5 µg/rat, s.c.) and cetrorelix (10 µg/kg, subcutaneous [s.c.]) treatment were given to Group III and Group IV animals, respectively, for 21 days. Oral glucose tolerance test, lipid profile, fasting glucose, insulin, estrus cycle, hormonal profile, ovary weight, ovarian histopathological changes, and LHR and FSHR expressions were measured. Treatment with leuprolide and cetrorelix did not improve glucose intolerance, insulin level, insulin sensitivity indices, sex hormone levels, lipid profile, and estrus cycle. Only testosterone level, total cholesterol level, and follicular development were improved. Therefore, it was concluded that both leuprolide and cetrorelix showed improvement in follicular development, which could be helpful for improving fertility in PCOS.

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“…Previously, we reported the reproductive features of the present study (Maliqueo et al . ). Interestingly, those rats exposed to letrozole that did not respond to low‐frequency EA tended to have higher circulating testosterone concentrations compared with rats responding to the treatment (data not shown).…”

Section: Discussionmentioning

confidence: 97%

“…In this regard, we have described that rats in the letrozole‐induced PCOS model show elevated circulating androgen concentrations but low or normal estradiol concentrations (Maliqueo et al . , ). Moreover, letrozole reduced the lean mass and BMC, which is in agreement with observations in aromatase knockout mice (Jones et al .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in letrozole‐induced PCOS rats, 5–6 weeks of low‐frequency EA improves the gonadotrophin profile and ovarian adiponectin signalling (Maliqueo et al . ). Also, in DHT‐induced PCOS rats, EA for 4–5 weeks results in normalization of the expression of opioid receptors in the hypothalamic arcuate nucleus and an improvement in oestrous cyclicity (Feng et al .…”

Section: Introductionmentioning

confidence: 97%

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Acupuncture does not ameliorate metabolic disturbances in the P450 aromatase inhibitor‐induced rat model of polycystic ovary syndrome

Maliqueo

Benrick

Marcondes

et al. 2017

Experimental Physiology

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Edited by: Paula Brunton New Findings r What is the central question of this study?The effectiveness of low-frequency electroacupuncture in the treatment of metabolic disorders associated with polycystic ovary syndrome (PCOS), an endocrine-metabolic disorder characterized by an imbalance in sex steroid production, is controversial. r What is the main finding and its importance?In a rat model of PCOS induced by the inhibition of P450 aromatase, low-frequency electroacupuncture increased low-density lipoprotein-cholesterol but did not improve the insulin resistance or the adipose tissue dysfunction, suggesting that a balance of sex steroids is needed to restore the metabolic function in this rat model of PCOS.Low-frequency electroacupuncture restores sex steroid synthesis and sympathetic activity in women with polycystic ovary syndrome, which may ameliorate its metabolic disturbances, probably by modulating sympathetic nerve activity or sex steroid synthesis. We investigated whether low-frequency electroacupuncture regulates the metabolic function to the same extent as treatment with estradiol or β-adrenergic blocking in a rat model of polycystic ovary syndrome induced by a P450 aromatase inhibitor (letrozole). Letrozole (200 μg day −1 ) or placebo pellets were implanted in prepubertal Wistar rats. Six weeks thereafter, rats were treated for 5-6 weeks with the following: low-frequency electroacupuncture (5 days per week); a β-adrenergic blocker (propranolol hydrochloride, 0.1 mg kg −1 , 5 days per week); or 17β-estradiol (2.0 μg) every fourth day. Body weight development, body composition, locomotor activity, insulin sensitivity, tissue-specific glucose uptake, lipid profile, adipocyte size, serum concentrations of adiponectin and insulin, and gene expression in inguinal fat were measured. All treatments increased circulating levels of low-density lipoprotein-cholesterol. Estradiol treatment restored locomotor activity and increased insulin sensitivity but did not modify the glucose uptake in muscle and fat. An upregulation of genes related to insulin sensitivity and downregulation of genes related to adipogenesis were observed in subcutaneous adipose tissue from rats exposed to letrozole. Only

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Circulating gonadotropins and ovarian adiponectin system are modulated by acupuncture independently of sex steroid or β-adrenergic action in a female hyperandrogenic rat model of polycystic ovary syndrome

Cited by 30 publications

References 56 publications

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Evaluation of ovarian and metabolic effects of GnRH modulators in two rat models of polycystic ovary syndrome

Acupuncture does not ameliorate metabolic disturbances in the P450 aromatase inhibitor‐induced rat model of polycystic ovary syndrome

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