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Quinn Dufurrena, Nils Bäck, Richard Mains, Louis Hodgson, Herbert Tanowitz, Prashant Mandela, Betty Eipper, and Regina Kuliawat

Key features for progression to pancreatic β-cell failure and disease are loss of glucose responsiveness and an increased ratio of secreted proinsulin to insulin. Proinsulin and insulin are stored in secretory granules (SGs) and the fine-tuning of hormone output requires signal-mediated recruitment of select SG populations according to intracellular location and age. The GTPase Rac1 coordinates multiple signaling pathways that specify SG release, and Rac1 activity is controlled in part by GDP/GTP exchange factors (GEFs). To explore the function of two large multidomain GEFs, Kalirin and Trio in β-cells, we manipulated their Rac1-specific GEF1 domain activity by using small-molecule inhibitors and by genetically ablating Kalirin. We examined age-related SG behavior employing radiolabeling protocols. Loss of Kalirin/Trio function attenuated radioactive proinsulin release by reducing constitutive-like secretion and exocytosis of 2-h-old granules. At later chase times or at steady state, Kalirin/Trio manipulations decreased glucose-stimulated insulin output. Finally, use of a Rac1 FRET biosensor with cultured β-cell lines demonstrated that Kalirin/Trio GEF1 activity was required for normal rearrangement of Rac1 to the plasma membrane in response to glucose. Rac1 activation can be evoked by both glucose metabolism and signaling through the incretin glucagon-like peptide 1 (GLP-1) receptor. GLP-1 addition restored Rac1 localization/activity and insulin secretion in the absence of Kalirin, thereby assigning Kalirin’s participation to stimulatory glucose signaling.

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Yisheng Yang, Stephanie Workman, and Megan J Wilson

The body of knowledge surrounding reproductive development spans the fields of genetics, anatomy, physiology and biomedicine, to build a comprehensive understanding of the later stages of reproductive development in humans and animal models. Despite this, there remains much to learn about the bi-potential progenitor structure that the ovary and testis arise from, known as the genital ridge (GR). This tissue forms relatively late in embryonic development and has the potential to form either the ovary or testis, which in turn produce hormones required for the development of the rest of the reproductive tract. It is imperative that we understand the genetic networks underpinning GR development if we are to begin to understand abnormalities in the adult. This is particularly relevant in the contexts of disorders of sex development (DSDs) and infertility, two conditions that many individuals struggle with worldwide, with often no answers as to their aetiology. Here, we review what is known about the genetics of GR development. Investigating the genetic networks required for GR formation will not only contribute to our understanding of the genetic regulation of reproductive development, it may in turn open new avenues of investigation into reproductive abnormalities and later fertility issues in the adult.

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Ming Zhu, Meng Wang, Yijun Chen, and Chao Zhang

Melanocortin receptor accessory protein 2 (MRAP2) plays an important role in regulating melanocortin receptors. In zebrafish, MRAP2a and MRAP2b show distinct pharmacological effects on MC4R activity, but how MRAP2 protein regulates other zebrafish melanocortin receptors is barely studied. Zebrafish have two mc5r genes: mc5ra and mc5rb, it is still vague which one is the homologous isoform to the mammalian paralog. Here, we utilize synteny and phylogenetic analysis to demonstrate the evolutionary conservation of zebrafish MC5Ra and MC5Rb among different species. We also show that MRAP2a and MRAP2b could interact and regulate surface expression of two MC5R receptors. Bimolecular fluorescence complementation (BiFC) studies suggest that zebrafish MC5Rs could form homo- and heterodimers, which are suppressed by co-expression with MRAP2 proteins. In comparison with mammalian MC5R-MRAP2 system and different pharmacological effects of zMRAP2 protein on MC5Rs, zmc5ra is identified as the evolutionary homologous paralog to the mammals, and it is regulated by metabolic state in zebrafish brain region.

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Qianqian Lu, Yuying Yang, Sheng Jia, Shaoqiang Zhao, Bin Gu, Peng Lu, Yang He, Ruixin Liu, Jiqiu Wang, Guang Ning, and Qinyun Ma

Appetite is tightly controlled by neural and hormonal signals in animals. In general, steroid receptor coactivator 1 (SRC1) enhances steroid hormone signalling in energy balance and serves as a common coactivator of several steroid receptors, such as oestrogen and glucocorticoid receptors. However, the key roles of SRC1 in energy balance remain largely unknown. We first confirmed that SRC1 is abundantly expressed in the hypothalamic arcuate nucleus (ARC), which is a critical centre for regulating feeding and energy balance; it is further co-localised with agouti-related protein and proopiomelanocortin neurons in the arcuate nucleus. Interestingly, local SRC1 expression changes with the transition between sufficiency and deficiency of food supply. To identify its direct role in appetite regulation, we repressed SRC1 expression in the hypothalamic ARC using lentivirus shRNA and found that SRC1 deficiency significantly promoted food intake and body weight gain, particularly in mice fed with a high-fat diet. We also found the activation of the AMP-activated protein kinase (AMPK) signalling pathway due to SRC1 deficiency. Thus, our results suggest that SRC1 in the ARC regulates appetite and body weight and that AMPK signalling is involved in this process. We believe that our study results have important implications for recognising the overlapping and integrating effects of several steroid hormones/receptors on accurate appetite regulation in future studies.

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Karen Jesus Oliveira, Maria Isabel Chiamolera, Gisele Giannocco, Carmen Cabanelas Pazos-Moura, and Tania Maria Ortiga-Carvalho

The modern concept of thyroid disruptors includes synthetic chemicals and bioactive compounds from food that interfere with any aspect of the hypothalamus–pituitary–thyroid axis, thyroid hormone biosynthesis and secretion, blood and transmembrane transport, metabolism and local actions of thyroid hormones. This review highlights relevant disruptors that affect populations through their diet: directly from food itself (fish oil and polyunsaturated fatty acids, pepper, coffee, cinnamon and resveratrol/grapes), through vegetable cultivation (pesticides) and from containers for food storage and cooking (bisphenol A, phthalates and polybrominated diphenyl ethers). Due to the vital role of thyroid hormones during every stage of life, we review effects from the gestational period to adulthood, including evidence from in vitro studies, rodent models, human trials and epidemiological studies.

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Maria Jacoba Kruger, Maria Martha Conradie, Magda Conradie, and Mari van de Vyver

Obesity-associated inflammatory mechanisms play a key role in the pathogenesis of metabolic-related diseases. Failure of anti-inflammatory control mechanisms within adipose tissue and peripheral blood mononuclear cells (PBMCs) have been implicated in disease progression. This study investigated the efficacy of allogeneic adipose tissue-derived mesenchymal stem cells conditioned media (ADSC-CM) to counteract persistent inflammation by inducing an anti-inflammatory phenotype and cytokine response within PBMCs derived from patients with and without metabolic syndrome. Forty-six (n = 46) mixed ancestry females (18–45 years) were subdivided into (a) healthy lean (HL) (n = 10) (BMI <25 kg/m2), (b) overweight/obese (OW/OB) (BMI ≥25 kg/m2, <3 metabolic risk factors) (n = 22) and (c) metabolic syndrome (MetS) (visceral adiposity, ≥3 metabolic risk factors) (n = 14) groups. Body composition (DXA scan), metabolic (cholesterol, HDL, LDL, triglycerides, blood glucose) and inflammatory profiles (38-Plex cytokine panel) were determined. PBMCs were isolated from whole blood and treated ex vivo with either (i) autologous participant-derived serum, (ii) ADSCs-CM or (iii) a successive treatment regime. The activation status (CD11b+) and intracellular cytokine (IL6, IL10, TNFa) expression were determined in M1 (CD68+CD206−CD163−) and M2 (CD68+CD163+ CD206+) macrophage populations using flow cytometry. ADSC-CM treatment, promoted a M2 macrophage phenotype and induced IL10 expression, this was most pronounced in the OW/OB group. This response is likely mediated by multiple complementing factors within ADSC-CM, yet to be identified. This study is the first to demonstrate the therapeutic potential of ADSC-CM to restore the inflammatory balance in immune compromised obese individuals.

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Yujiro Yamanaka, Yoshiko Yamada, Ken-ichi Honma, and Sato Honma

Cryptochrome (Cry) 1 and 2 are essential for circadian rhythm generation, not only in the suprachiasmatic nucleus, the site of the mammalian master circadian clock, but also in peripheral organs throughout the body. CRY is also known as a repressor of arylalkylamine-N-acetyltransferase (Aanat) transcription; therefore, Cry deficiency is expected to induce constantly high pineal melatonin content. Nevertheless, we previously found that the content was consistently low in melatonin-proficient Cry1 and Cry2 double-deficient mice (Cry1 / /Cry2 / ) on C3H background. This study aims to clarify the mechanism underlying this discrepancy. In the Cry1 / /Cry2 / pineal, expression levels of Aanat and clock gene Per1 were consistently high with no circadian fluctuation on the first day in constant darkness, demonstrating that CRY acts in vivo as a repressor of the pineal circadian clock and AANAT. In contrast, the enzyme activity and protein levels of AANAT remained low throughout the day, supporting our previous observation of continuously low melatonin. Thus, effects of Cry deficiency on the responses of β-adrenergic receptors were examined in cultured pineal glands. Isoproterenol, a β-adrenergic stimulant, significantly increased melatonin content, although the increase was smaller in Cry1 / /Cry2 / than in WT mice, during both the day and night. However, the increase in cAMP in response to forskolin was similar in both genotypes, indicating that CRY deficiency does not affect the pathway downstream of the β-adrenergic receptor. These results suggest that a lack of circadian adrenergic input due to CRY deficiency decreases β-receptor activity and cAMP levels, resulting in consistently low AANAT levels despite abundant Aanat mRNA.

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Ying Li, Fuzhe Ma, Huimin Li, Yuguo Song, Huan Zhang, Ziping Jiang, and Hao Wu

Impaired wound healing is a common complication among patients with diabetes mellitus (DM), resulting in high rates of disability and mortality. Recent findings highlighted the critical role of nuclear factor erythroid 2-related factor 2 (NRF2) – a master of cellular antioxidants scavenging excessive DM-induced free radicals – in accelerating diabetic wound healing. Dimethyl fumarate (DMF) is a potent NRF2 activator used for the treatment of multiple sclerosis. However, the effect of DMF on wound healing has not been determined. The present study investigated the effect of DMF on the diabetic and the non-diabetic wound healing in streptozotocin-induced diabetic mice and non-diabetic control mice. DMF activated NRF2 signaling under both conditions. Interestingly, DMF attenuated oxidative damage and inflammation and accelerated wound closure in diabetic mice. However, this effect was not observed in non-diabetic mice. Keratinocytes were treated with normal glucose (NG), high glucose (HG) or hydrogen peroxide (H2O2), in the presence or absence of DMF to assess the role of reactive oxygen species (ROS) – inducible in DM – in mediating DMF-induced protection. Both HG and H2O2 elevated ROS, oxidative damage and inflammation, the effects of which were similarly blunted by DMF. However, in spite of the activation of NRF2, DMF lost this capability under the NG condition. The findings of this study demonstrate that ROS activate the protective effect of DMF on the diabetic wound healing.

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Seisuke Sato, Hitomi Imachi, Jingya Lyu, Yumi Miyai, Kensaku Fukunaga, Tao Dong, Tomohiro Ibata, Toshihiro Kobayashi, Takuo Yoshimoto, Fumi Kikuchi, Kazuko Yonezaki, Nao Yamaji, Hisakazu Iwama, and Koji Murao

ATP-binding cassette transporter A1 (ABCA1), a 254-kD membrane protein, is a key regulator of lipid efflux from cells to apolipoproteins. ABCA1 in pancreatic β-cells influences insulin secretion and cholesterol homeostasis. Tumor necrosis factor (TNF)-α is a pleiotropic cytokine that elicits a wide spectrum of physiological events, including cell proliferation, differentiation and apoptosis and is also known to decrease glucose-dependent insulin secretion in pancreatic islets. In the present study, we examined the role of TNF-α on ABCA1 expression in rat pancreatic islets and INS-1 cells. ABCA1 protein levels decreased in response to rising concentrations of TNF-α in pancreatic islets. Real-time polymerase chain reaction analysis showed a significant decrease in ABCA1 mRNA expression. In parallel with its effect on endogenous ABCA1 mRNA levels, TNF-α suppressed the activity of a reporter construct containing the ABCA1 promoter. This effect was abrogated by BIRB796, but not by SB203580 or LY-294002. The constitutively active form of p38 mitogen-activated protein kinase (MAPK) γ suppressed ABCA1 promoter activity but not p38-MAPK (α, β), while a dominant-negative mutant of p38-MAPK γ blocked the effect of TNF-α on ABCA1 promoter activity. BIRB796 inhibited the increased cholesterol ester content induced by TNF-α. However, BIRB796 had no effect on either the decreased insulin content or the ABCA1 suppression caused by TNF-α in INS-1 cells. We checked the influence of TNF-α of insulin secretion and glucose-stimulated insulin secretion in rat pancreatic islet and INS-1 cell. TNF-α suppressed the insulin secretion and glucose-stimulated insulin secretion in both rat pancreatic islet and INS-1 cell. In summary, TNF-α suppressed the expression of endogenous ABCA1 and suppress the insulin secretion in pancreatic islets and INS-1 cells. These findings raise the possibility that TNF-α may affect insulin secretion by controlling ABCA1 expression.

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Meghan S Perkins, Renate Louw-du Toit, and Donita Africander

Although hormone therapy is widely used by millions of women to relieve symptoms of menopause, it has been associated with several side effects such as coronary heart disease, stroke and increased invasive breast cancer risk. These side effects have caused many women to seek alternatives to conventional hormone therapy, including the controversial custom-compounded bioidentical hormone therapy suggested to not increase breast cancer risk. Historically, estrogens and the estrogen receptor were considered the principal factors promoting breast cancer development and progression; however, a role for other members of the steroid receptor family in breast cancer pathogenesis is now evident, with emerging studies revealing an interplay between some steroid receptors. In this review, we discuss examples of hormone therapy used for the relief of menopausal symptoms, highlighting the distinction between conventional hormone therapy and custom-compounded bioidentical hormone therapy. Moreover, we highlight the fact that not all hormones have been evaluated for an association with increased breast cancer risk. We also summarize the current knowledge regarding the role of steroid receptors in mediating the carcinogenic effects of hormones used in menopausal hormone therapy, with special emphasis on the influence of the interplay or crosstalk between steroid receptors. Unraveling the intertwined nature of steroid hormone receptor signaling pathways in breast cancer biology is of utmost importance, considering that breast cancer is the most prevalent cancer among women worldwide. Moreover, understanding these mechanisms may reveal novel prevention or treatment options and lead to the development of new hormone therapies that do not cause increased breast cancer risk.