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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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
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.
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.
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.
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.
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.
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.
Mingjuan Deng, Fang Qu, Long Chen, Chang Liu, Ming Zhang, Fazheng Ren, Huiyuan Guo, Hao Zhang, Shaoyang Ge, Chaodong Wu and Liang Zhao
This study aimed to assess the effects of three major SCFAs (acetate, propionate, and butyrate) on NASH phenotype in mice. C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet and treated with sodium acetate, sodium propionate, or sodium butyrate during the 6-week feeding period. SCFA treatment significantly reduced serum levels of alanine aminotransferase and aspartate transaminase, the numbers of lipid droplets, and the levels of triglycerides and cholesterols in livers of the mice compared with control treatment. SCFAs also reduced MCD-induced hepatic aggregation of macrophages and proinflammatory responses. Among the three SCFAs, sodium acetate (NaA) revealed the best efficacy at alleviating MCD-induced hepatic steatosis and inflammation. Additionally, NaA increased AMP-activated protein kinase activation in the liver and induced the expression of fatty acid oxidation gene in both the liver and cultured hepatocytes. In vitro, NaA decreased MCD-mimicking media-induced proinflammatory responses in macrophages to a greater extent than in hepatocytes. These results indicated that NaA alleviates steatosis in a manner involving AMPK activation. Also, NaA alleviation of hepatic inflammation appears to be due to, in large part, suppression of macrophage proinflammatory activation. SCFAs may represent as a novel and viable approach for alleviating NASH.
Amanda E Garza, Elijah Trefts, Isis A Katayama Rangel, Danielle Brooks, Rene Baudrand, Burhanuddin Moize, Jose R Romero, Sanjay Ranjit, Thitinan Treesaranuwattana, Tham M Yao, Gail K Adler, Luminita H Pojoga and Gordon H Williams
Aldosterone modulates the activity of both epithelial (specifically renal) and non-epithelial cells. Binding to the mineralocorticoid receptor (MR), activates two pathways: the classical genomic and the rapidly activated non-genomic that is substantially modulated by the level of striatin. We hypothesized that disruption of MR’s non-genomic pathway would alter aldosterone-induced cardiovascular/renal damage. To test this hypothesis, wild type (WT) and striatin heterozygous knockout (Strn+/ −) littermate male mice were fed a liberal sodium (1.6% Na+) diet and randomized to either protocol one: 3 weeks of treatment with either vehicle or aldosterone plus/minus MR antagonists, eplerenone or esaxerenone or protocol two: 2 weeks of treatment with either vehicle or L-NAME/AngII plus/minus MR antagonists, spironolactone or esaxerenone. Compared to the WT mice, basally, the Strn+/ − mice had greater (~26%) estimated renal glomeruli volume and reduced non-genomic second messenger signaling (pAkt/Akt ratio) in kidney tissue. In response to active treatment, the striatin-associated-cardiovascular/renal damage was limited to volume effects induced by aldosterone infusion: significantly increased blood pressure (BP) and albuminuria. In contrast, with aldosterone or L-NAME/AngII treatment, striatin deficiency did not modify aldosterone-mediated damage: in the heart and kidney, macrophage infiltration, and increases in aldosterone-induced biomarkers of injury. All changes were near-normalized following MR blockade with spironolactone or esaxerenone, except increased BP in the L-NAME/AngII model. In conclusion, the loss of striatin amplified aldosterone-induced damage suggesting that aldosterone’s non-genomic pathway is protective but only related to effects likely mediated via epithelial, but not non-epithelial cells.
Sandra K Szlapinski, Anthony A Botros, Sarah Donegan, Renee T King, Gabrielle Retta, Brenda J Strutt and David J Hill
Gestational diabetes mellitus increases the risk of dysglycemia postpartum, in part, due to pancreatic β-cell dysfunction. However, no histological evidence exists comparing endocrine pancreas after healthy and glucose-intolerant pregnancies. This study sought to address this knowledge gap, in addition to exploring the contribution of an inflammatory environment to changes in endocrine pancreas after parturition. We used a previously established mouse model of gestational glucose intolerance induced by dietary low protein insult from conception until weaning. Pancreas and adipose samples were collected at 7, 30 and 90 days postpartum for histomorphometric and cytokine analyses, respectively. Glucose tolerance tests were performed prior to euthanasia and blood was collected via cardiac puncture. Pregnant female mice born to dams fed a low protein diet previously shown to develop glucose intolerance at late gestation relative to controls continued to be glucose intolerant until 1 month postpartum. However, glucose tolerance normalized by 3 months postpartum. Glucose intolerance at 7 days postpartum was associated with lower beta- and alpha-cell fractional areas and higher adipose levels of pro-inflammatory cytokine, interleukin-6. By 3 months postpartum, a compensatory increase in the number of small islets and a higher insulin to glucagon ratio likely enabled euglycemia to be attained in the previously glucose-intolerant mice. The results show that impairments in endocrine pancreas compensation in hyperglycemic pregnancy persist after parturition and contribute to prolonged glucose intolerance. These impairments may increase the susceptibility to development of future type 2 diabetes.