We hypothesize that cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) are involved in the modulation of metabolic regulation of food intake by fatty acids in fish. Therefore, we assessed in rainbow trout (Oncorhynchus mykiss) the effects of intracerebroventricular treatment with 1 ng/g of CCK-8 and with 2 ng/g of GLP-1 on food intake, expression of neuropeptides involved in food intake control and the activity of fatty acid-sensing systems in hypothalamus and hindbrain. Food intake decreased up to 24 h post-treatment to 49.8–72.3% and 3.1–17.8% for CCK-8 and GLP-1, respectively. These anorectic responses are associated with changes in fatty acid metabolism and an activation of fatty acid-sensing mechanisms in the hypothalamus and hindbrain. These changes occurred in parallel with those in the expression of anorexigenic and orexigenic peptides. Moreover, we observed that the activation of fatty acid sensing and the enhanced anorectic potential elicited by CCK-8 and GLP-1 treatments occurred in parallel with the activation of mTOR and FoxO1 and the inhibition of AMPKα, BSX and CREB. The results are discussed in the context of metabolic regulation of food intake in fish.
Cristina Velasco, Sara Comesaña, Marta Conde-Sieira, Jesús M Míguez, and José L Soengas
Shu-Ching M Wang, Dennis H Dowhan, and George E O Muscat
Breast cancer is a heterogeneous disease, and the complexity of breast carcinogenesis is associated with epigenetic modification. There are several major classes of epigenetic enzymes that regulate chromatin activity. This review will focus on the nine mammalian protein arginine methyltransferases (PRMTs) and the dysregulation of PRMT expression and function in breast cancer. This class of enzymes catalyse the mono- and (symmetric and asymmetric) di-methylation of arginine residues on histone and non-histone target proteins. PRMT signalling (and R methylation) drives cellular proliferation, cell invasion and metastasis, targeting (i) nuclear hormone receptor signalling, (ii) tumour suppressors, (iii) TGF-β and EMT signalling and (iv) alternative splicing and DNA/chromatin stability, influencing the clinical and survival outcomes in breast cancer. Emerging reports suggest that PRMTs are also implicated in the development of drug/endocrine resistance providing another prospective avenue for the treatment of hormone resistance and associated metastasis. The complexity of PRMT signalling is further underscored by the degree of alternative splicing and the scope of variant isoforms (with distinct properties) within each PRMT family member. The evolution of PRMT inhibitors, and the ongoing clinical trials of PRMT inhibitors against a subgroup of solid cancers, coupled to the track record of lysine methyltransferases inhibitors in phase I/II clinical trials against cancer underscores the potential therapeutic utility of targeting PRMT epigenetic enzymes to improve survival outcomes in aggressive and metastatic breast cancer.
Junye Chen, Yi Lu, Mengyuan Tian, and Qiren Huang
Forkhead box-O1 (FOXO1) is a downstream target of AKT and plays crucial roles in cell cycle control, apoptosis, metabolism and adipocyte differentiation. It is thought that FOXO1 affects adipocyte differentiation by regulating lipogenesis and cell cycle. With the deepening in the understanding of this field, it is currently believed that FOXO1 translocation between nuclei and cytoplasm is involved in the regulation of FOXO1 activity, thus affecting adipocyte differentiation. Translocation of FOXO1 depends on its post-translational modifications and interactions with 14-3-3. Based on these modifications and interactions, FOXO1 could regulate lipogenesis through PPARγ and the adipocyte cell cycle through p21 and p27. In this review, we aim to provide a comprehensive FOXO1 regulation network in adipocyte differentiation by linking together distinct functions mentioned above to explain their effects on adipocyte differentiation and to emphasize the regulatory role of FOXO1. In addition, we also focus on the novel findings such as the use of miRNAs in FOXO1 regulation and highlight the improvable issues, such as RNA modifications, for future research in the field.
Yingdi Yuan, Xinguo Cao, Jiaojiao Hu, Jingyun Li, Dan Shen, Lianghui You, Xianwei Cui, Xing Wang, Yahui Zhou, Yao Gao, Lijun Zhu, Pengfei Xu, Chenbo Ji, Xirong Guo, and Juan Wen
Obesity is a major risk factor for metabolic diseases, while adipocyte differentiation is closely related to obesity occurrence. Long noncoding RNAs (lncRNAs) are a unique class of transcripts in regulation of various biological processes. Using lncRNA microarray, we found lncRNA AC092159.2 was highly expressed in differentiated HPA-v and located ~247 bp upstream of the TMEM18, which was associated with BMI and obesity. We aimed to explore the role of AC092159.2 in adipogenesis and the underlying mechanisms. The effects of AC092159.2 gain- and loss-of-function on HPA-v adipogenesis were determined with lentivirus and siRNA-mediated cell transduction, respectively. Lipid accumulation was evaluated by oil red O staining; the expression of AC092159.2, TMEM18 and several adipogenesis makers in HPA-v were analyzed by qPCR/Western blot. We found that the expression of AC092159.2 gradually increased during HPA-v differentiation, and its expression in omental adipose tissue was positively related with BMI among 48 human subjects. Overexpression of AC092159.2 promoted adipocytes differentiation while knockdown of it led to an adipogenic defect. Moreover, the expression of AC092159.2 and TMEM18 were positively correlated during adipogenic differentiation. AC092159.2 overexpression boosted TMEM18 expression while AC092159.2 knockdown restrained TMEM18 expression. Further rescue experiments showed that TMEM18 knockdown partially restrained adipogenic differentiation in AC092159.2 overexpressed HPA-v and adipogenic defect caused by AC092159.2 knockdown could be rescued by TMEM18 overexpression. Luciferase reporter assays revealed that AC092159.2 had a transcriptional activation effect on TMEM18. We concluded that lncRNA AC092159.2 promoted human adipocytes differentiation possibly by regulating TMEM18.
Megumi Iwahashi and Satoshi Narumi
Thyroid-specific transcription factor PAX8 has an indispensable role in the thyroid gland development, which is evidenced by the facts that PAX8/Pax8 mutations cause congenital hypothyroidism in humans and mice. More than 90% of known PAX8 mutations were located in the paired domain, suggesting the central role of the domain in exerting the molecular function. Structure-function relationships of PAX8, as well as other PAX family transcription factors, have never been investigated in a systematic manner. Here, we conducted the first alanine scanning mutagenesis study, in which 132 alanine variants located in the paired domain of PAX8 were created and systematically evaluated in vitro. We found that 76 alanine variants (55%) were loss of function (LOF) variants (defined by <30% activity as compared with wild type PAX8). Importantly, the distribution of LOF variants were skewed, with more frequently observed in the N-subdomain (65% of the alanine variants in the N-subdomain) than in the C-subdomain (45%). Twelve out of 13 alanine variants in residues that have been affected in patients with congenital hypothyroidism were actually LOF, suggesting that the alanine scanning data can be used to evaluate the functional importance of mutated residues. Using our in vitro data, we tested the accuracy of seven computational algorithms for pathogenicity prediction, showing that they are sensitive but not specific to evaluate on the paired domain alanine variants. Collectively, our experiment-based data would help better understand the structure-function relationships of the paired domain, and would provide a unique resource for pathogenicity prediction of future PAX8 variants.
Yingkai Sun, Rui Wang, Shaoqian Zhao, Wen Li, Wen Liu, Lingyun Tang, Zhugang Wang, Weiqing Wang, Ruixin Liu, Guang Ning, Jiqiu Wang, and Jie Hong
Browning of white adipose tissue has been proven to be a potential target to fight against obesity and its metabolic commodities, making the exploration of molecules involved in browning process important. Among those browning agents reported recently, FGF21 play as a quite promising candidate for treating obesity for its obvious enhancement of thermogenic capacity in adipocyte and significant improvement of metabolic disorders in both mice and human. However, whether other members of fibroblast growth factor (FGF) family play roles in adipose thermogenesis and obese development is still an open question. Here, we examined the mRNA expression of all FGF family members in three adipose tissues of male C57BL/6 mice and found that FGF9 is highly expressed in adipose tissue and decreased under cold stress. Furthermore, FGF9 treatment inhibited thermogenic genes in the process of beige adipocytes differentiation from stromal vascular fraction (SVF) in a dose-dependent manner. Similar results were obtained with FGF9 overexpression. Consistently, knockdown of FGF9 in SVF cells by using lentiviral shRNA increased thermogenic genes in differentiated beige adipocytes. RNA sequencing analysis revealed a significant increment of hypoxia-inducible factor (HIF) pathway in the early stage of beige adipocytes differentiation under FGF9 treatment, which was validated by real-time PCR. FGF9 expression was increased in subcutaneous WAT of obese human and mice. This study shows that adipose-derived FGF9 play as an inhibitory role in the browning of white adipocytes. Activation of hypoxia signaling at early stage of adipose browning process may contribute to this anti-thermogenic effect of FGF9.
Gauthier Schang, Chirine Toufaily, and Daniel J Bernard
Fertility is dependent on follicle-stimulating hormone (FSH), a product of gonadotrope cells of the anterior pituitary gland. Hypothalamic gonadotropin-releasing hormone (GnRH) and intra-pituitary activins are regarded as the primary drivers of FSH synthesis and secretion. Both stimulate expression of the FSH beta subunit gene (Fshb), although the underlying mechanisms of GnRH action are poorly described relative to those of the activins. There is currently no consensus on how GnRH regulates Fshb transcription, as results vary across species and between in vivo and in vitro approaches. One of the more fully developed models suggests that the murine Fshb promoter is tonically repressed by histone deacetylases (HDACs) and that GnRH relieves this repression, at least in immortalized murine gonadotrope-like cells (LβT2 and αT3-1). In contrast, we observed that the class I/II HDAC inhibitor trichostatin A (TSA) robustly inhibited basal, activin A-, and GnRH-induced Fshb mRNA expression in LβT2 cells and in primary murine pituitary cultures. Similar results were obtained with the class I specific HDAC inhibitor, entinostat, whereas two class II-specific inhibitors, MC1568 and TMP269, had no effects on Fshb expression. Collectively, these data suggest that class I HDACs are positive, not negative, regulators of Fshb expression in vitro and that, contrary to earlier reports, GnRH may not stimulate Fshb by inhibiting HDAC-mediated repression of the gene.
Chunmei Wang and Yong Xu
Sex differences exist in the regulation of energy homeostasis. Better understanding of the underlying mechanisms for sexual dimorphism in energy balance may facilitate development of gender-specific therapies for human diseases, e.g. obesity. Multiple organs, including the brain, liver, fat and muscle, play important roles in the regulations of feeding behavior, energy expenditure and physical activity, which therefore contribute to the maintenance of energy balance. It has been increasingly appreciated that this multi-organ system is under different regulations in male vs female animals. Much of effort has been focused on roles of sex hormones (including androgens, estrogens and progesterone) and sex chromosomes in this sex-specific regulation of energy balance. Emerging evidence also indicates that other factors (not sex hormones/receptors and not encoded by the sex chromosomes) exist to regulate energy homeostasis differentially in males vs females. In this review, we summarize factors and signals that have been shown to regulate energy homeostasis in a sexually dimorphic fashion and propose a framework where these factors and signals may be integrated to mediate sex differences in energy homeostasis.
Gill Holdsworth, Scott J Roberts, and Hua Zhu Ke
The discovery that two rare autosomal recessive high bone mass conditions were caused by the loss of sclerostin expression prompted studies into its role in bone homeostasis. In this article, we aim to bring together the wealth of information relating to sclerostin in bone though discussion of rare human disorders in which sclerostin is reduced or absent, sclerostin manipulation via genetic approaches and treatment with antibodies that neutralise sclerostin in animal models and in human. Together, these findings demonstrate the importance of sclerostin as a regulator of bone homeostasis and provide valuable insights into its biological mechanism of action. We summarise the current state of knowledge in the field, including the current understanding of the direct effects of sclerostin on the canonical WNT signalling pathway and the actions of sclerostin as an inhibitor of bone formation. We review the effects of sclerostin, and its inhibition, on bone at the cellular and tissue level and discuss new findings that suggest that sclerostin may also regulate adipose tissue. Finally, we highlight areas in which future research is expected to yield additional insights into the biology of sclerostin.
Afreen Idris Shariff, Sohail Syed, Rebecca A Shelby, Jeremy Force, Jeffrey Melson Clarke, David D’Alessio, and Leonor Corsino
Over the last decade, there has been a shift in the focus of cancer therapy from conventional cytotoxic drugs to therapies more specifically directed to cancer cells. These novel therapies include immunotherapy, targeted therapy and precision medicine, each developed in great part with a goal of limiting collateral destruction of normal tissues, while enhancing tumor destruction. Although this approach is sound in theory, even new, specific therapies have some undesirable, ‘off target effects’, in great part due to molecular pathways shared by neoplastic and normal cells. One such undesirable effect is hyperglycemia, which results from either the loss of immune tolerance and autoimmune destruction of pancreatic β-cells or dysregulation of the insulin signaling pathway resulting in insulin resistance. These distinct pathogenic mechanisms lead to clinical presentations similar to type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. Both types of diabetes have been reported in patients across clinical trials, and data on the mechanism(s) for developing hyperglycemia, prevalence, prognosis and effect on cancer mortality is still emerging. With the rapidly expanding list of clinical indications for new cancer therapies, it is essential to understand the impact of their adverse effects. In this review, we focus on hyperglycemia and diabetes related to cancer therapies, describe what is known about mechanism(s) leading to dysregulated glucose metabolism and provide a guide to management of complex oncology patients with a new diagnosis of diabetes.