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Lisa L Koorneef, Jan Kroon, Eva M G Viho, Lucas F Wahl, Kim M L Heckmans, Marloes M A R van Dorst, Menno Hoekstra, René Houtman, Hazel Hunt, and Onno C Meijer

Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR antagonist CORT125281. We evaluated the antagonistic effects of CORT125281 upon acute and subchronic corticosterone exposure in mice. In the acute corticosterone setting, hypothalamus-pituitary-adrenal-axis activity was investigated by measurement of basal- and stress-induced corticosterone levels, adrenocorticotropic hormone levels and pituitary proopiomelanocortin expression. GR signaling was evaluated by RT-PCR analysis of GR-responsive transcripts in liver, muscle, brown adipose tissue (BAT), white adipose tissue (WAT) and hippocampus. Pretreatment with a high dose of CORT125281 antagonized GR activity in a tissue-dependent manner. We observed complete inhibition of GR-induced target gene expression in the liver, partial blockade in muscle and BAT and no antagonism in WAT and hippocampus. Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity.

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Alejandra Abeledo-Machado, Pablo Anibal Pérez, María Andrea Camilletti, Erika Yanil Faraoni, Florencia Picech, Juan Pablo Petiti, Silvina Gutiérrez, and Graciela Diaz-Torga

Serum prolactin levels gradually increase from birth to puberty in both male and female rats, with higher levels observed in female since the first days of life. The increase in lactotroph secretion was attributed to the maturation of prolactin-inhibiting and prolactin-releasing factors; however, those mechanisms could not fully explain the gender differences observed. Prolactin secretion from isolated lactotrophs, in the absence of hypothalamic control, also increases during the first weeks of life, suggesting the involvement of intra-pituitary factors. We postulate that pituitary transforming growth factor beta 1 (TGFβ1) is involved in the regulation of prolactin secretion as well as in the gender differences observed at early postnatal age. Several components of the local TGFβ1 system were evaluated during postnatal development (11, 23, and 45 days) in female and male Sprague–Dawley rats. In vivo assays were performed to study local TGFβ1 activation and its impact on prolactin secretion. At day 11, female pituitaries present high levels of active TGFβ1, concomitant with the highest expression of TGFβ1 target genes and the phospho-Smad3 immunostaining in lactotrophs. The steady increase in prolactin secretion inversely correlates with active TGFβ1 levels only in females. Dopamine and estradiol induce TGFβ1 activation at day 11, in both genders, but its activation induces the inhibition of prolactin secretion only in females. Our findings demonstrate that: (1) TGFβ1 activation is regulated by dopamine and estradiol; (2) the inhibitory regulation of local TGFβ1 on prolactin secretion is gender specific; and (3) this mechanism is responsible, at least partially, for the gender differences observed being relevant during postnatal development.

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Sisi Luan, Wenkai Bi, Shulong Shi, Li Peng, Zhanbin Li, Jie Jiang, Ling Gao, Yifeng Du, Xu Hou, Zhao He, and Jiajun Zhao

Subclinical hyperthyroidism, a condition characterized by decreased thyroid-stimulating hormone (TSH) and normal concentration of thyroid hormone, is associated with an elevated risk for cognitive impairment. TSH is the major endogenous ligand of the TSH receptor (TSHR) and its role is dependent on signal transduction of TSHR. It has not, however, been established whether TSHR signaling is involved in the regulation of cognition. Here, we utilized Tshr knockout mice and found that Tshr deletion led to significantly compromised performance in learning and memory tests. Reduced dendritic spine density and excitatory synaptic density as well as altered synaptic structure in CA1 subfield of the hippocampus were also noted. Furthermore, the synapse-related gene expression was altered in the hippocampus of Tshr -/- mice. These findings suggest that TSHR signaling deficiency impairs spatial learning and memory, which discloses a novel role of TSHR signaling in brain function.

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Ali Aflatounian, Melissa C Edwards, Valentina Rodriguez Paris, Michael J Bertoldo, Reena Desai, Robert B Gilchrist, William L Ledger, David J Handelsman, and Kirsty A Walters

As the mechanistic basis of polycystic ovary syndrome (PCOS) remains unknown, current management relies on symptomatic treatment. Hyperandrogenism is a major PCOS characteristic and evidence supports it playing a key role in PCOS pathogenesis. Classically, androgens can act directly through the androgen receptor (AR) or, indirectly, following aromatization, via the estrogen receptor (ER). We investigated the mechanism of androgenic actions driving PCOS by comparing the capacity of non-aromatizable dihydrotestosterone (DHT) and aromatizable testosterone to induce PCOS traits in WT and Ar-knockout (ARKO) mice. DHT and testosterone induced the reproductive PCOS-like features of acyclicity and anovulation in WT females. In ARKO mice, DHT did not cause reproductive dysfunction; however, testosterone treatment induced irregular cycles and ovulatory disruption. These findings indicate that direct AR actions and indirect, likely ER, actions of androgens are important mediators of PCOS reproductive traits. DHT, but not testosterone, induced an increase in body weight, body fat, serum cholesterol and adipocyte hypertrophy in WT mice, but neither androgen induced these metabolic features in ARKO mice. These data infer that direct AR-driven mechanisms are key in driving the development of PCOS metabolic traits. Overall, these findings demonstrate that differing PCOS traits can be mediated via different steroid signaling pathways and indicate that a phenotype-based treatment approach would ensure effective targeting of the underlying mechanisms.

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Chunchun Wei, Xianhua Ma, Kai Su, Shasha Qi, Yuangang Zhu, Junjian Lin, Chenxin Wang, Rui Yang, Xiaowei Chen, Weizhong Wang, and Weiping J Zhang

Brown adipose tissue (BAT) plays a critical role in energy expenditure by uncoupling protein 1 (UCP1)-mediated thermogenesis. Carbohydrate response element-binding protein (ChREBP) is one of the key transcription factors regulating de novo lipogenesis (DNL). As a constitutively active form, ChREBP-β is expressed at extremely low levels. Up to date, its functional relevance in BAT remains unclear. In this study, we show that ChREBP-β inhibits BAT thermogenesis. BAT ChREBP-β mRNA levels were elevated upon cold exposure, which prompted us to generate a mouse model overexpressing ChREBP-β specifically in BAT using the Cre/LoxP approach. ChREBP-β overexpression led to a whitening phenotype of BAT at room temperature, as evidenced by increased lipid droplet size and decreased mitochondrion content. Moreover, BAT thermogenesis was inhibited upon acute cold exposure, and its metabolic remodeling induced by long-term cold adaptation was significantly impaired by ChREBP-β overexpression. Mechanistically, ChREBP-β overexpression downregulated expression of genes involved in mitochondrial biogenesis, autophagy, and respiration. Furthermore, thermogenic gene expression (e.g. Dio2, UCP1) was markedly inhibited in BAT by the overexpressed ChREBP-β. Put together, our work points to ChREBP-β as a negative regulator of thermogenesis in brown adipocytes.

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Muraly Puttabyatappa, Robert M Sargis, and Vasantha Padmanabhan

Insulin resistance is a common feature of many metabolic disorders. The dramatic rise in the incidence of insulin resistance over the past decade has enhanced focus on its developmental origins. Since various developmental insults ranging from maternal disease, stress, over/undernutrition, and exposure to environmental chemicals can all program the development of insulin resistance, common mechanisms may be involved. This review discusses the possibility that increases in maternal androgens associated with these various insults are key mediators in programming insulin resistance. Additionally, the intermediaries through which androgens misprogram tissue insulin sensitivity, such as changes in inflammatory, oxidative, and lipotoxic states, epigenetic, gut microbiome and insulin, as well as data gaps to be filled are also discussed.

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Yan Su, Sujuan Guo, Chunyan Liu, Na Li, Shuang Zhang, Yubin Ding, Xuemei Chen, Junlin He, Xueqing Liu, Yingxiong Wang, and Rufei Gao

Embryo implantation is essential for normal pregnancy. Decidualization is known to facilitate embryo implantation and maintain pregnancy. Uterine stromal cells undergo transformation into decidual cells after embryo attachment to the endometrium. Pyruvate kinase M2 (PKM2) is a rate limiting enzyme in the glycolysis process which catalyzes phosphoenolpyruvic acid into pyruvate. However, little is known regarding the role of PKM2 during endometrial decidualization. In this study, PKM2 was found to be mainly located in the uterine glandular epithelium and luminal epithelium on day 1 and day 4 of pregnancy and strongly expressed in the decidual zone after embryo implantation. PKM2 was dramatically increased with the onset of decidualization. Upon further exploration, PKM2 was found to be more highly expressed at the implantation sites than at the inter-implantation sites on days 5 to 7 of pregnancy. PKM2 expression was also significantly increased after artificial decidualization both in vivo and in vitro. After PKM2 expression was knocked down by siRNA, the number of embryo implantation sites in mice on day 7 of pregnancy was significantly reduced, and the decidualization markers BMP2 and Hoxa10 were also obviously downregulated in vivo and in vitro. Downregulated PKM2 could also compromise cell proliferation in primary endometrial stromal cells and in Ishikawa cells. The migration rate of Ishikawa cells was also obviously suppressed by si-PKM2 according to the wound healing assay. In conclusion, PKM2 might play an important role in decidualization during early pregnancy, and cell proliferation might be one pathway for PKM2 regulated decidualization.

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Breno Picin Casagrande, Daniel Vitor de Souza, Daniel Araki Ribeiro, Alessandra Medeiros, Luciana Pellegrini Pisani, and Debora Estadella

The negative aspects of unhealthy eating on obesity and hepatic health are well described. The axis between the adipose tissue and the liver participates in most of the damage caused to this tissue regarding obesogenic diets (OD). At the same time that the effects of consuming simple carbohydrates and saturated fatty acids are known, the effects of the cessation of its intake are scarce. Withdrawing from OD is thought to improve health; despite some studies had shown improvement in hepatic conditions in the long-term, short-term studies were not found. Therefore, we aimed to determine how OD intake and withdrawal would influence visceral and hepatic fat accumulation and inflammation. To this end, male 60-days-old Wistar rats received standard chow (n = 16) or a high-sugar/high-fat diet (HSHF) for 30 days (n = 32), a cohort of the HSHF-fed animals was then kept 48 h on standard chow (n = 16). In opposition to the generally reported, the results indicate that hepatic inflammation preceded hepatic steatosis. Additionally, inflammatory markers on the liver positively correlated visceral adipokines and visceral fat accumulation mediated them in a deposit-dependent manner. At the same time, a 48-h withdrawal was capable of reverting most of the risen inflammatory mediators, although MyD88 and TNFα persisted and serum non-HDL cholesterol was higher than control levels.

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Ya Liu, Xiaoqing Zhou, Ye Xiao, Changjun Li, Yan Huang, Qi Guo, Tian Su, Lei Fu, and Liping Luo

Nonalcoholic fatty liver disease (NAFLD) is becoming the most prevalent liver disease worldwide, is characterized by liver steatosis and is often accompanied with other pathological features such as insulin resistance. However, the underlying mechanisms are not fully understood, and specific pharmacological agents need to be developed. Here, we investigated the role of microRNA-188 (miR-188) as a negative regulator in hepatic glucose and lipid metabolism. miR-188 was upregulated in the liver of obese mice. Loss of miR-188 alleviated diet-induced hepatosteatosis and insulin resistance. In contrast, liver-specific overexpression of miR-188 aggravated hepatic steatosis and insulin resistance during high-fat diet feeding. Mechanistically, we found that the negative effects of miR-188 on lipid and glucose metabolism were mediated by the autophagy pathway via targeting autophagy-related gene 12 (Atg12). Furthermore, suppressing miR-188 in the liver of obese mice improved liver steatosis and insulin resistance. Taken together, our findings reveal a new regulatory role of miR-188 in glucose and lipid metabolism through the autophagy pathway, and provide a therapeutic insight for NAFLD.

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Shan-xue Jin, David A Dickson, Jamie Maguire, and Larry A Feig

RASGRF1 (GRF1) is a calcium-stimulated guanine-nucleotide exchange factor that activates RAS and RAC GTPases. In hippocampus neurons, it mediates the action of NMDA and calcium-permeable AMPA glutamate receptors on specific forms of synaptic plasticity, learning, and memory in both male and female mice. Recently, we showed GRF1 also regulates the HPA axis response to restraint stress, but only in female mice before puberty. In particular, we found that after 7 days of restraint stress (7DRS) (30 min/day) both elevated serum CORT levels and induction of an anxiolytic phenotype normally observed in early adolescent (EA) female mice are blocked in GRF1-knockout mice. In contrast, no effects were observed in EA male or adult females. Here, we show this phenotype is due, at least in part, to GRF1 loss in CRF cells of the paraventricular nucleus of the hypothalamus, as GRF1 knockout specifically in these cells suppressed 7DRS-induced elevation of serum CORT levels specifically in EA females, but only down to levels found in comparably stressed EA males. Nevertheless, it still completely blocked the 7DRS-induced anxiolytic phenotype observed in EA females. Interestingly, loss of GRF1 in CRF cells had no effect after only three restraint stress exposures, implying a role for GRF1 in 7DRS stress-induced plasticity of CRF cells that appears to be specific to EA female mice. Overall, these findings indicate that GRF1 in CRF cells makes a key contribution to the distinct response EA females display to repeated stress.