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Tabata M Bohlen, Thais T Zampieri, Isadora C Furigo, Pryscila D S Teixeira, Edward O List, John J Kopchick, Jose Donato Jr and Renata Frazao

Growth hormone (GH) is a key factor in the regulation of body growth, as well as a variety of other cellular and metabolic processes. Neurons expressing kisspeptin and leptin receptors (LepR) have been shown to modulate the hypothalamic-pituitary-gonadal (HPG) axis and are considered GH responsive. The presence of functional GH receptors (GHR) in these neural populations suggests that GH may regulate the HPG axis via a central mechanism. However, there have been no studies evaluating whether or not GH-induced intracellular signaling in the brain plays a role in the timing of puberty or mediates the ovulatory cycle. Toward the goal of understanding the influence of GH on the central nervous system as a mediator of reproductive functions, GHR ablation was induced in kisspeptin and LepR-expressing cells or in the entire brain. The results demonstrated that GH signaling in specific neural populations can potentially modulate the hypothalamic expression of genes related to the reproductive system or indirectly contribute to the progression of puberty. GH action in kisspeptin cells or in the entire brain was not required for sexual maturation. On the other hand, GHR ablation in LepR cells delayed puberty progression, reduced serum leptin levels, decreased body weight gain and compromised the ovulatory cycle in some individuals, while the lack of GH effects in the entire brain prompted shorter estrous cycles. These findings suggest that GH can modulate brain components of the HPG axis, although central GH signaling is not required for the timing of puberty.

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Ying Zhang, Nan Meng, Haili Bao, Yufei Jiang, Ningjie Yang, Kejia Wu, Jinxiang Wu, Haibin Wang, Shuangbo Kong and Yuanzhen Zhang

Progesterone is an important hormone for female reproduction; however, how the fluctuation of progesterone acts upon reproductive processes remains largely unknown. Mounting evidence indicates a pivotal role of the circadian clock in sensing hormone dynamics for homeostatic regulation of physiological functions. Therefore, we sought to determine whether clock genes respond to progesterone signaling in female reproductive system. In this study, we tested the hypothesis that the circadian system could respond to progesterone signaling during human endometrial decidual transformation. The expression of the circadian gene PER1 increased immediately and remained elevated during human endometrial decidualization. The progesterone receptor activated PER1 transcription by directly binding to its promoter from the onset of the stromal proliferation-differentiation transition. PER1 knockout significantly downregulated the expression of some PGR target genes, and attenuated human endometrial decidual transformation by expediting FOXO1 protein degradation. In conclusion, progesterone could control the female reproductive process through sustained feedback from the circadian gene PER1, which is probably involved to P4-PR signaling responsiveness in the initiation and maintenance of decidualization.

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Rosalia C M Simmen, Dustin M Brown, Charles M Quick, Iad Alhallak, Tyler Rose, Shi J Liu and Angela S Kelley

Type 1 diabetes mellitus and endometriosis separately affect millions of women worldwide. Reproductive-age women diagnosed with type 1 diabetes may also suffer from endometriosis, but the asymptomatic pre-clinical period of highly variable duration for each condition can lead to challenges in the timely recognition of co-morbid disease onset and misdiagnosis. While knowledge of the pathogenesis of each condition has grown substantially, co-morbid endometriosis and type 1 diabetes has not been widely considered and much less addressed. This review discusses the molecular rationale for the likelihood of their co-existence, and prospects for improvements in therapeutic strategies and reduced complications, if this paradigm is included as a significant variable in disease management.

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Andrew T Major, Katie L Ayers, Justin Chue, Kelly N Roeszler and Craig A Smith

FOXL2 is a conserved transcription factor with a central role in ovarian development and function. Studies in humans and mice indicate that the main role of FOXL2 is in the postnatal ovary, namely folliculogenesis. To shed light on the function and evolution of FOXL2 in the female gonad, we examined its role in embryonic avian gonads, using in ovo overexpression and knockdown. FOXL2 mRNA and protein are expressed female specifically in the embryonic chicken gonad, just prior to the onset of sexual differentiation. FOXL2 is expressed in the medullary cord cells, in the same cell type as aromatase (CYP19A1). In addition, later in development, expression also becomes localised in a subset of cortical cells, distinct from those expressing oestrogen receptor alpha. Misexpression of FOXL2 in the male chicken embryonic gonad suppresses the testis developmental pathway, abolishing local expression of the male pathway genes SOX9, DMRT1 and AMH and repressing Sertoli cell development. Conversely, knockdown of FOXL2 expression allows ectopic activation of SOX9 in female gonads. However, misexpression of FOXL2 alone was insufficient to activate aromatase expression in male gonads, while FOXL2 knockdown did not affect aromatase expression in females. These results indicate that FOXL2 plays an important role in embryonic differentiation of the avian ovary via antagonism of SOX9, but may be dispensable for aromatase activation at embryonic stages. The data suggest that FOXL2 has different roles in different species, more central for embryonic ovarian differentiation in egg-laying vertebrates.

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Jing Zhou, Honggui Li, Yuli Cai, Linqiang Ma, Destiny Matthews, Bangchao Lu, Bilian Zhu, Yanming Chen, Xiaoxian Qian, Xiaoqiu Xiao, Qifu Li, Shaodong Guo, Yuqing Huo, Liang Zhao, Yanan Tian, Qingsheng Li and Chaodong Wu

Adenosine 2A receptor (A2AR) exerts a protective role in obesity-related non-alcoholic fatty liver disease. Here, we examined whether A2AR protects against non-alcoholic steatohepatitis (NASH). In C57BL/6J mice, feeding a methionine- and choline-deficient diet (MCD) resulted in significant weight loss, overt hepatic steatosis, and massive aggregation of macrophages in the liver compared with mice fed a chow diet. MCD feeding also significantly increased the numbers of A2AR-positive macrophages/Kupffer cells in liver sections although decreasing A2AR amount in liver lysates compared with chow diet feeding. Next, MCD-induced NASH phenotype was examined in A2AR-disrupted mice and control mice. Upon MCD feeding, A2AR-disruptd mice and control mice displayed comparable decreases in body weight and fat mass. However, MCD-fed A2AR-disrupted mice revealed greater liver weight and increased severity of hepatic steatosis compared with MCD-fed control mice. Moreover, A2AR-disupted mice displayed increased severity of MCD-induced liver inflammation, indicated by massive aggregation of macrophages and increased phosphorylation states of Jun-N terminal kinase (JNK) p46 and nuclear factor kappa B (NFκB) p65 and mRNA levels of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6. In vitro, incubation with MCD-mimicking media increased lipopolysaccharide (LPS)-induced phosphorylation states of JNK p46 and/or NFκB p65 and cytokine mRNAs in control macrophages and RAW264.7 cells, but not primary hepatocytes. Additionally, MCD-mimicking media significantly increased lipopolysaccharide-induced phosphorylation states of p38 and NFκB p65 in A2AR-deficient macrophages, but insignificantly decreased lipopolysaccharide-induced phosphorylation states of JNK p46 and NFκB p65 in A2AR-deficient hepatocytes. Collectively, these results suggest that A2AR disruption exacerbates MCD-induced NASH, which is attributable to, in large part, increased inflammatory responses in macrophages.

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Dan Wang, Chu-Dan Liu, Meng-Li Tian, Cheng-Quan Tan, Gang Shu, Qing-Yan Jiang, Lin Zhang and Yu-Long Yin

Dietary fibers and their microbial fermentation products short-chain fatty acids promote metabolic benefits, but the underlying mechanisms are still unclear. Recent studies indicate that intestinal lipid handling is under regulatory control and has broad influence on whole body energy homeostasis. Here we reported that dietary inulin and propionate significantly decreased whole body fat mass without affecting food intake in mice fed with chow diet. Meanwhile, triglyceride (TG) content was decreased and lipolysis gene expression, such as adipose triglyceride lipase (A tgl), hormone-sensitive lipase (H sl) and lysosomal acid lipase (L al) was elevated in the jejunum and ileum of inulin- and propionate-treated mice. In vitro studies on Caco-2 cells showed propionate directly induced enterocyte Atgl, Hsl and Lal gene expression and decreased TG content, via activation of phosphorylation of AMP-activated protein kinase (p-AMPK) and lysine-specific demethylase 1 (LSD1). Moreover, inulin and propionate could increase intestinal lipolysis under high-fat diet (HFD)-fed condition which contributed to the prevention of HFD-induced obesity. Our study suggests that dietary fiber inulin and its microbial fermentation product propionate can regulate metabolic homeostasis through regulating intestinal lipid handling, which may provide a novel therapeutic target for both prevention and treatment of obesity.

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Thomas M Braxton, Dionne E A Sarpong, Janine L Dovey, Anne Guillou, Bronwen A J Evans, Juan M Castellano, Bethany E Keenan, Saja Baraghithy, Sam L Evans, Manuel Tena-Sempere, Patrice Mollard, Joseph Tam and Timothy Wells

Human Prader–Willi syndrome (PWS) is characterised by impairments of multiple systems including the growth hormone (GH) axis and skeletal growth. To address our lack of knowledge of the influence of PWS on skeletal integrity in mice, we have characterised the endocrine and skeletal phenotype of the PWS-ICdel mouse model for ‘full’ PWS and determined the impact of thermoneutrality. Tibial length, epiphyseal plate width and marrow adiposity were reduced by 6, 18 and 79% in male PWS-ICdel mice, with osteoclast density being unaffected. Similar reductions in femoral length accompanied a 32% reduction in mid-diaphyseal cortical diameter. Distal femoral Tb.N was reduced by 62%, with individual trabeculae being less plate-like and the lattice being more fragmented (Tb.Pf increased by 63%). Cortical strength (ultimate moment) was reduced by 26% as a result of reductions in calcified tissue strength and the geometric contribution. GH and prolactin contents in PWS-ICdel pituitaries were reduced in proportion to their smaller pituitary size, with circulating IGF-1 concentration reduced by 37–47%. Conversely, while pituitary luteinising hormone content was halved, circulating gonadotropin concentrations were unaffected. Although longitudinal growth, marrow adiposity and femoral geometry were unaffected by thermoneutrality, strengthened calcified tissue reversed the weakened cortex of PWS-ICdel femora. While underactivity of the GH axis may be due to loss of Snord116 expression and impaired limb bone geometry and strength due to loss of Magel2 expression, comprehensive analysis of skeletal integrity in the single gene deletion models is required. Our data imply that thermoneutrality may ameliorate the elevated fracture risk associated with PWS.

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Cátia F Gonçalves and Qing-Jun Meng

The circadian system in mammals is responsible for the temporal coordination of multiple physiological and behavioural processes that are necessary for homeostasis. In the skeleton, it has long been known that metabolic functions of chondrocytes, osteoblasts and osteoclasts exhibit intrinsic circadian rhythms. In addition, results from animal models reveal a close connection between the disruption of circadian rhythms and skeletal disorders such as rheumatoid arthritis, osteoarthritis and osteoporosis. In this review, we summarise the latest insights into the genetic and biochemical mechanisms linking cartilage and bone physiology to the circadian clock system. We also discuss how this knowledge can be utilised to improve human health.

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Wang-Yang Xu, Yan Shen, Houbao Zhu, Junhui Gao, Chen Zhang, Lingyun Tang, Shun-Yuan Lu, Chun-Ling Shen, Hong-Xin Zhang, Ziwei Li, Peng Meng, Ying-Han Wan, Jian Fei and Zhu-Gang Wang

Obesity and type 2 diabetes (T2D) are both complicated endocrine disorders resulting from an interaction between multiple predisposing genes and environmental triggers, while diet and exercise have key influence on metabolic disorders. Previous reports demonstrated that 2-aminoadipic acid (2-AAA), an intermediate metabolite of lysine metabolism, could modulate insulin secretion and predict T2D, suggesting the role of 2-AAA in glycolipid metabolism. Here, we showed that treatment of diet-induced obesity (DIO) mice with 2-AAA significantly reduced body weight, decreased fat accumulation and lowered fasting glucose. Furthermore, Dhtkd1−/− mice, in which the substrate of DHTKD1 2-AAA increased to a significant high level, were resistant to DIO and obesity-related insulin resistance. Further study showed that 2-AAA induced higher energy expenditure due to increased adipocyte thermogenesis via upregulating PGC1α and UCP1 mediated by β3AR activation, and stimulated lipolysis depending on enhanced expression of hormone-sensitive lipase (HSL) through activating β3AR signaling. Moreover, 2-AAA could alleviate the diabetic symptoms of db/db mice. Our data showed that 2-AAA played an important role in regulating glycolipid metabolism independent of diet and exercise, implying that improving the level of 2-AAA in vivo could be developed as a strategy in the treatment of obesity or diabetes.

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Hong Ma, Jin Yuan, Jinyu Ma, Jie Ding, Weiwei Lin, Xinlei Wang, Mingliang Zhang, Yi Sun, Runze Wu, Chun Liu, Cheng Sun and Yunjuan Gu

Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-β (TGF-β) family, plays pivotal roles in energy expenditure. However, whether and how BMP7 regulates hepatic insulin sensitivity is still poorly understood. Here, we show that hepatic BMP7 expression is reduced in high-fat diet (HFD)-induced diabetic mice and palmitate (PA)-induced insulin-resistant HepG2 and AML12 cells. BMP7 improves insulin signaling pathway in insulin resistant hepatocytes. On the contrary, knockdown of BMP7 further impairs insulin signal transduction in PA-treated cells. Increased expression of BMP7 by adenovirus expressing BMP7 improves hyperglycemia, insulin sensitivity and insulin signal transduction. Furthermore, BMP7 inhibits mitogen-activated protein kinases (MAPKs) in both the liver of obese mice and PA-treated cells. In addition, inhibition of MAPKs recapitulates the effects of BMP7 on insulin signal transduction in cultured hepatocytes treated with PA. Activation of p38 MAPK abolishes the BMP7-mediated upregulation of insulin signal transduction both in vitro and in vivo. Together, our results show that hepatic BMP7 has a novel function in regulating insulin sensitivity through inhibition of MAPKs, thus providing new insights into treating insulin resistance-related disorders such as type 2 diabetes.