The two closely related RabGAPs TBC1D1 and TBC1D4 are key signaling factors of skeletal muscle substrate utilization. In mice, deficiency in both RabGAPs leads to reduced skeletal muscle glucose transport in response to insulin and lower GLUT4 abundance. Conversely, Tbc1d1 and Tbc1d4 deficiency results in enhanced lipid use as fuel in skeletal muscle, through yet unknown mechanisms. In humans, variants in TBC1D1 and TBC1D4 are linked to obesity, insulin resistance and type 2 diabetes. While the specific function in metabolism of each of the two RabGAPs remains to be determined, TBC1D1 emerges to be controlling exercise endurance and physical capacity, whereas TBC1D4 may rather be responsible for maintaining muscle insulin sensitivity, muscle contraction, and exercise. There is growing evidence that TBC1D1 also plays an important role in skeletal muscle development, since it has been found to be associated to meat production traits in several livestock species. In addition, TBC1D1 protein abundance in skeletal muscle is regulated by both, insulin receptor and insulin-like growth factor-1 (IGF-1) receptor signaling. This review focuses on the specific roles of the two key signaling factors TBC1D1 and TBC1D4 in skeletal muscle metabolism, development and exercise physiology.
Lena Espelage, Hadi Al-Hasani, and Alexandra Chadt
Salman Azhar, Dachuan Dong, Wen-Jun Shen, Zhigang Hu, and Fredric B Kraemer
miRNAs are endogenous noncoding single-stranded small RNAs of ~22 nucleotides in length that post-transcriptionally repress the expression of their various target genes. They contribute to the regulation of a variety of physiologic processes including embryonic development, differentiation and proliferation, apoptosis, metabolism, hemostasis and inflammation. In addition, aberrant miRNA expression is implicated in the pathogenesis of numerous diseases including cancer, hepatitis, cardiovascular diseases and metabolic diseases. Steroid hormones regulate virtually every aspect of metabolism, and acute and chronic steroid hormone biosynthesis is primarily regulated by tissue-specific trophic hormones involving transcriptional and translational events. In addition, it is becoming increasingly clear that steroidogenic pathways are also subject to post-transcriptional and post-translational regulations including processes such as phosphorylation/dephosphorylation, protein‒protein interactions and regulation by specific miRNAs, although the latter is in its infancy state. Here, we summarize the recent advances in miRNA-mediated regulation of steroidogenesis with emphasis on adrenal and gonadal steroidogenesis.
Isadora C Furigo, Pryscila D S Teixeira, Paula G F Quaresma, Naira S Mansano, Renata Frazão, and Jose Donato Jr
AgRP neurons are important players in the control of energy homeostasis and are responsive to several hormones. In addition, STAT5 signalling in the brain, which is activated by metabolic hormones and growth factors, modulates food intake, body fat and glucose homeostasis. Given that, and the absence of studies that describe STAT5 function in AgRP cells, the present study investigated the metabolic effects of Stat5a/b gene ablation in these neurons. We observed that STAT5 signalling in AgRP neurons regulates body fat in female mice. However, male and female STAT5-knockout mice did not exhibit altered food intake, energy expenditure or glucose homeostasis compared to control mice. The counter-regulatory response or glucoprivic hyperphagia induced by 2-deoxy-d-glucose treatment were also not affected by AgRP-specific STAT5 ablation. However, under 60% food restriction, AgRP STAT5-knockout mice had a blunted upregulation of hypothalamic Agrp mRNA expression and corticosterone serum levels compared to control mice, suggesting a possible role for STAT5 in AgRP neurons for neuroendocrine adaptations to food restriction. Interestingly, ad libitum fed knockout male mice had reduced Pomc and Ucp-1 mRNA expression compared to control group. Taken together, these results suggest that STAT5 signalling in AgRP neurons regulates body adiposity in female mice, as well as some neuroendocrine adaptations to food restriction.
Márcia Faria, Daniela Félix, Rita Domingues, Maria João Bugalho, Paulo Matos, and Ana Luísa Silva
Thyroid cancer (TC) is the most common endocrine malignancy. The sodium–iodide symporter (NIS), responsible for active transport of iodide into thyroid cells, allows the use of radioactive iodine (RAI) as the systemic treatment of choice for TC metastatic disease. Still, patients with advanced forms of TC often lose the ability to respond to RAI therapy, which results in worse survival rates. We have shown that the overexpression of RAC1b, a tumor-related RAC1 splice variant, is associated with less favorable clinical outcomes in differentiated TCs derived from the follicular epithelial (DTCs). RAC1b overexpression is also significantly associated with the presence of MAPK-activating BRAFV600E mutation, which has been previously implicated in the loss of NIS expression. Here, we show that increased RAC1b levels are associated with NIS downregulation in DTCs and demonstrate that ectopic overexpression of RAC1b in non-transformed thyroid cells is sufficient to decrease TSH-induced NIS expression, antagonizing the positive effect of the canonically spliced RAC1 GTPase. Moreover, we clearly document for the first time in thyroid cells that both NIS expression and iodide uptake are hampered by RAC1 inhibition, highlighting the role of RAC1 in promoting TSH-induced NIS expression. Our findings support a role for RAC1 and RAC1b signaling in the regulation of NIS expression in thyroid cells and suggest that RAC1b in cooperation with other cancer-associated signaling cues may be implicated in the response of DTCs to RAI therapy.
Kimberly H Cox and Joseph S Takahashi
The mammalian circadian clock has evolved as an adaptation to the 24-h light/darkness cycle on earth. Maintaining cellular activities in synchrony with the activities of the organism (such as eating and sleeping) helps different tissue and organ systems coordinate and optimize their performance. The full extent of the mechanisms by which cells maintain the clock are still under investigation, but involve a core set of clock genes that regulate large networks of gene transcription both by direct transcriptional activation/repression as well as the recruitment of proteins that modify chromatin states more broadly.
Shalinee Dhayal, Francesco P Zummo, Matthew W Anderson, Patricia Thomas, Hannah J Welters, Catherine Arden, and Noel G Morgan
Long-chain saturated fatty acids are lipotoxic to pancreatic β-cells, whereas most unsaturates are better tolerated and some may even be cytoprotective. Fatty acids alter autophagy in β-cells and there is increasing evidence that such alterations can impact directly on the regulation of viability. Accordingly, we have compared the effects of palmitate (C16:0) and palmitoleate (C16:1) on autophagy in cultured β-cells and human islets. Treatment of BRIN-BD11 β-cells with palmitate led to enhanced autophagic activity, as judged by cleavage of microtubule-associated protein 1 light chain 3-I (LC3-I) and this correlated with a marked loss of cell viability in the cells. In addition, transfection of these cells with an mCherry-YFP-LC3 reporter construct revealed the accumulation of autophagosomes in palmitate-treated cells, indicating an impairment of autophagosome-lysosome fusion. This was also seen upon addition of the vacuolar ATPase inhibitor, bafilomycin A1. Exposure of BRIN-BD11 cells to palmitoleate (C16:1) did not lead directly to changes in autophagic activity or flux, but it antagonised the actions of palmitate. In parallel, palmitoleate also improved the viability of palmitate-treated BRIN-BD11 cells. Equivalent responses were observed in INS-1E cells and in isolated human islets. Taken together, these data suggest that palmitate may cause an impairment of autophagosome-lysosome fusion. These effects were not reproduced by palmitoleate which, instead, antagonised the responses mediated by palmitate suggesting that attenuation of β-cell stress may contribute to the improvement in cell viability caused by the mono-unsaturated fatty acid.
Jiayu Jin, Xinhong Wang, Xiuling Zhi, and Dan Meng
Cardiovascular disease (CVD), the main complication of diabetes mellitus (DM), accounts for a high percentage of mortality in diabetic patients. Endothelial dysfunction is a major causative event in the pathogenesis of diabetes-related vascular disease and the earliest symptom of vascular injury. Epigenetic modification plays a key role in the initiation, maintenance, and progression of both endothelial dysfunction and diabetes. Epigenetic alterations respond to the environment and mediate the ‘legacy effect’ of uncontrolled hyperglycaemia early in the disease despite thorough glycaemic control in a phenomenon called metabolic memory. Therefore, an understanding of the integrated system of different epigenetic mechanisms in DM and its vascular complications is urgently needed. This review summarizes aberrant epigenetic regulation under diabetic conditions, including histone modifications, DNA methylation, and non-coding RNAs (ncRNAs). Understanding the connections between these processes and DM may reveal a novel potential therapeutic target for diabetic vascular complications.
Yun-Qing Zhu, Yun Hu, Ke He, Na Li, Peng Jiang, Yu-Qin Pan, Hong Zhou, and Xiao-Ming Mao
The follicles are the minimal functional unit of the thyroid; the morphology and the function of each follicle can vary significantly. However, the reasons for the apparent follicular heterogeneity are poorly understood. Some tissue-resident regulatory T cells (Tregs) have a special phenotype that expresses unique molecules related to local tissue and regulates the tissue functions. The aim of this study was to identify the phenotype of thyroid Tregs and the roles of thyroid Tregs in thyroid physiological regulation. Thyroid tissue and peripheral blood samples were obtained from patients with benign thyroid nodules. Microarray-based gene expression, flow cytometry, immunofluorescence microscopy, and functional analysis of thyroid Tregs were performed. Here, we demonstrated that human thyroid Tregs expressed high level of thyroglobulin (Tg), both gene and protein. The immunofluorescence microscopy of thyroid section showed that the FOXP3+Tg+ cells concentrated in some of the thyroid follicles, at the side of the thyroid follicle. The peripheral blood Tregs expressed minimal levels of Tg, and low levels of Tg could effectively induce peripheral blood Tregs to express Tg, which was independent of thyrotropin simulation. Furthermore, the Tg secreted freely from thyroid Tregs that negatively regulated some thyroid-related genes expression. Our results revealed that the thyroid Tregs was a distinct population of Tregs, which expressed high level of Tg. The thyroid Tregs regulate thyroid function by Tg that is paracrine from the cells.
Giulia Cantini, Martina Trabucco, Alessandra Di Franco, Edoardo Mannucci, and Michaela Luconi
Glucagon-like peptide 1 receptor agonists (GLP-1RAs), which are currently used for the treatment of type 2 diabetes, have recently been proposed as anti-obesity drugs, due to their relevant effects on weight loss. Furthermore, dual agonists for both GLP-1R and glucagon receptor (GCGR) are under investigation for their promising action on adiposity, although underlying mechanisms still need to be clarified. We have recently demonstrated that GLP-1 and liraglutide interfere with the proliferation and differentiation of human adipose precursors, supporting the hypothesis of a peripheral action of GLP-1RA on weight. Here, we investigated glucagon activity in an in vitro model of primary human adipose-derived stem cells (ASCs). Glucagon significantly inhibited ASC proliferation in a dose- and time-dependent manner, as evaluated by cell count and thymidine incorporation. When added during in vitro-induced adipogenesis, glucagon significantly reduced adipocyte differentiation, as demonstrated by the evaluation of intracellular fat content and quantitative expression of early and mature adipocyte markers (PPARγ and FABP4, HSL). Notably, the inhibitory effect of glucagon on cell proliferation and adipogenesis was reversed by specific GLP-1R (exendin-9) and GCGR (des-His1-Glu9-glucagon(1–29)) antagonists. The presence of both receptors was demonstrated by Western blot, immunofluorescence and cytofluorimetric analysis of ASCs. In conclusion, we demonstrated a direct inhibitory action of glucagon on the proliferation and differentiation of human adipose precursors, which seems to involve both GLP-1R and GCGR. These findings suggest that the adipose stem compartment is a novel target of glucagon, possibly contributing to the weight loss obtained in vivo with dual GLP-1R/glucagon agonists.
O.R. Vaughan, T.L. Powell, and T. Jansson
Excess maternal glucocorticoids reduce placental amino acid transport and fetal growth, but whether these effects are mediated directly on the syncytiotrophoblast remains unknown. We hypothesised that glucocorticoids inhibit mechanistic target of rapamycin (mTOR) signaling and insulin-stimulated System A amino acid transport activity in primary human trophoblast (PHT) cells. Syncytialised PHTs, isolated from term placentas (n = 15), were treated with either cortisol (1 μM) or dexamethasone (1 μM), ± insulin (1 nM) for 24 h. Compared to vehicle, dexamethasone increased mRNA expression, but not protein abundance of the mTOR suppressor, regulated in development and DNA damage response 1 (REDD1). Dexamethasone enhanced insulin receptor abundance, activated mTOR complex 1 and 2 signaling and stimulated System A activity, measured by Na+-dependent 14C-methylaminoisobutyric acid uptake. Cortisol also activated mTORC1 without significantly altering insulin receptor or mTORC2 read-outs or System A activity. Both glucocorticoids downregulated expression of the glucocorticoid receptor and the System A transporter genes SLC38A1, SLC38A2 and SLC38A4, without altering SNAT1 or SNAT4 protein abundance. Neither cortisol nor dexamethasone affected System L amino acid transport. Insulin further enhanced mTOR and System A activity, irrespective of glucocorticoid treatment and despite downregulating its own receptor. Contrary to our hypothesis, glucocorticoids do not inhibit mTOR signaling or cause insulin resistance in cultured PHT cells. We speculate that glucocorticoids stimulate System A activity in PHT cells by activating mTOR signaling, which regulates amino acid transporters post-translationally. We conclude that downregulation of placental nutrient transport in vivo following excess maternal glucocorticoids is not mediated by a direct effect on the placenta.