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Shelley Gorman, Alexander N Larcombe, and Hayley E Christian

In this narrative review, we provide an overview of the role of physical activity as part of differing exposomes (our combined non-genetic exposures from conception onwards) and environmental influences on metabolic health. We discuss ‘beneficial’ exposomes (green/natural outdoor spaces, sun exposure, healthy diets and features of built environments) that could synergise with physical activity to prevent metabolic dysfunction, particularly that related to lifestyle diseases of obesity, type-2 diabetes and metabolic syndrome. Physical activity may also reduce the capacity of some adverse exposomes, specifically those with significant levels of air pollution, to contribute towards metabolic dysfunction. Other exposomes, such as those experienced during pandemics (including COVID-19), potentially limit opportunities for physical activity, and there may be unexpected combined effects of physical activity with other infections (e.g. adenovirus-36) on metabolic health. Finally, we discuss how environments could be better optimised to create exposomes that promote the health benefits of physical activity and likely future directions of this research field.

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Rachel A Davey, Michele Verity Clarke, Suzanne Golub, Patricia K Russell, and Jeffrey David Zajac

The physiological role of calcitonin, and its receptor, the CTR, has long been debated. We previously provided the first evidence for a physiological role of the CTR to limit maternal bone loss during lactation in mice by a direct action on osteocytes to inhibit osteocytic osteolysis. We now extend these findings to show that CTR gene expression is upregulated 2-3 fold in whole bone of control mice at the end of pregnancy (E18) and lactation (P21) compared to virgin controls. This was associated with an increase in osteoclast activity evidenced by increases in osteoclast surface/bone surface and Dcstamp gene expression. To investigate the mechanism by which the CTR inhibits osteocytic osteolysis, in vivo acidification of the osteocyte lacunae during lactation (P14 days) was assessed using a pH indicator dye. A lower pH was observed in the osteocyte lacunae of lactating Global-CTRKOs compared to controls and was associated with an increase in the gene expression of ATPase H+ transporting V0 subunit D2 (Atp6v0d2) in whole bone of Global-CTRKOs at the end of lacation (P21). To determine whether the CTR is required for the replacement of mineral within the lacunae post-lactation, lacunar area was determined 3 weeks post-weaning. Comparison of the largest 20% of lacunae by area did not differ between Global-CTRKOs and controls post-lactation. These results provide evidence for CTR activation to inhibit osteocytic osteolysis during lactation being mediated by regulating the acidity of the lacunae microenvironment, whilst the CTR is dispensable for replacement of bone mineral within lacunae by osteocytes post-lactation.

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Tanja Jene, Inigo Ruiz de Azua, Annika Hasch, Jennifer Klüpfel, Julia Deuster, Mirjam Maas, Cora H Nijboer, Beat Lutz, Marianne B Müller, and Michael van der Kooij

Stress has a major impact on the modulation of metabolism, as previously evidenced by hyperglycemia following chronic social defeat (CSD) stress in mice. Although CSD-triggered metabolic dysregulation might predispose to pre-diabetic conditions, insulin sensitivity remained intact, and obesity did not develop, when animals were fed with a standard diet (SD). Here, we investigated whether a nutritional challenge, a high fat diet (HFD), aggravates the metabolic phenotype, and whether there are particularly sensitive time windows for the negative consequences of HFD exposure. Chronically stressed male mice and controls (CTRL) were kept under (i) SD-conditions, (ii) with HFD commencing post-CSD, or (iii) provided with HFD lasting throughout, and after CSD. Under SD conditions, stress increased glucose levels early post-CSD. Both HFD regimens increased glucose levels in non-stressed mice, but not in stressed mice. Nonetheless, when HFD was provided after CSD, stressed mice did not differ from controls in long-term body weight gain, fat tissue mass and plasma insulin, and leptin levels. In contrast, when HFD was continuously available, stressed mice displayed reduced body weight gain, lowered plasma levels of insulin, and leptin, and reduced white adipose tissue weights as compared to their HFD-treated non-stressed controls. Interestingly, stress-induced adrenal hyperplasia and hypercortisolemia were observed in mice treated with SD and with HFD after CSD, but not in stressed mice exposed to a continuous HFD treatment. The present work demonstrates that CSD can reduce HFD-induced metabolic dysregulation. Hence, HFD during stress may act beneficially, as comfort food, by decreasing stress-induced metabolic demands.

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Wenjuan Liu, Harry Kevin Lau, Dong Ok Son, Tianru Jin, Yehong Yang, Zhaoyun Zhang, Yiming Li, Gerald J Prud’homme, and Qinghua Wang

γ-Aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent β-cell survival and function. In human β-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic β-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human β-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human β-cell counts and plasma human insulin levels. Importantly, the combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. The proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ β-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of α-Klotho, a protein with protective and stimulatory effects on β cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of β-cell proliferation and a decrease in apoptosis.

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Amanda K Mauro, Nauman Khurshid, Danielle M Berdahl, Amanda C Ampey, Daniel Adu, Dinesh M Shah, and Derek S Boeldt

Abstract

Endothelial dysfunction is a prominent feature of preeclampsia, a hypertensive disorder of pregnancy, and contributes to multiple symptoms characteristic of the syndrome. A myriad of growth factors and cytokines are dysregulated in preeclampsia as compared to normal pregnancy, however, a complete appreciation of the effect of changing concentrations of these factors on endothelial function is lacking. In this study, we evaluate the effect of a variety of growth factors and cytokines on Ca2+ signaling and monolayer integrity. We report that VEGF165, TNFα, EGF, and IL-1β either improve or inhibit Ca2+ signaling depending on dose, whereas TNFα and IL-1β reduce monolayer integrity and bFGF increases monolayer integrity. Additionally, to model the effects of combinations of growth factors and cytokines, we screened for Ca2+ signaling changes in response to 16 dose combinations of VEGF165 and TNFα together. This revealed an optimal combination capable of supporting pregnancy-adapted Ca2+ signaling, and that changes in either VEGF165 or TNFα dose would result in a shift toward suppressed function. This study shows in detail how growth factor or cytokine concentration effects endothelial cell function. Such data can be used to model how changing growth factor and cytokine levels in normal pregnancy may contribute to healthy endothelial function and in preeclampsia may promote endothelial dysfunction. The results of VEGF165 and TNFα combination treatments suggest that more complex growth factor and cytokine combination modeling may be important in order to more accurately understand the effects of circulating factors on the endothelial function.

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Ken Takao, Katsumi Iizuka, Yanyan Liu, Teruaki Sakurai, Sodai Kubota, Saki Kubota-Okamoto, Toshinori Imaizumi, Yoshihiro Takahashi, Yermek Rakhat, Satoko Komori, Tokuyuki Hirose, Kenta Nonomura, Takehiro Kato, Masami Mizuno, Testuya Suwa, Yukio Horikawa, Masakatsu Sone, and Daisuke Yabe

Carbohydrate response element binding protein (ChREBP) is critical in the regulation of fatty acid and triglyceride synthesis in the liver. Interestingly, Chrebp-/- mice show reduced levels of plasma cholesterol, which is critical for steroid hormone synthesis in adrenal glands. Furthermore, Chrebp mRNA expression was previously reported in human adrenal glands. Thus, it remains to be investigated whether ChREBP plays a role directly or indirectly in steroid hormone synthesis and release in adrenal glands. In the present study, we find that Chrebp mRNA is expressed in mouse adrenal glands and that ChREBP binds to carbohydrate response elements. Histological analysis of Chrebp-/- mice shows no adrenal hyperplasia and less oil red O staining compared with that in wild-type mice. In adrenal glands of Chrebp-/- mice, expression of Fasn and Scd1, two enzymes critical for fatty acid synthesis, was substantially lower and triglyceride content was reduced. Expression of Srebf2, a key transcription factor controlling synthesis and uptake of cholesterol and the target genes was upregulated, while cholesterol content was not significantly altered in the adrenal glands of Chrebp-/- mice. Adrenal corticosterone content and plasma adrenocorticotropic hormone and corticosterone levels were not significantly altered in Chrebp-/- mice. Consistently, expression of genes related to steroid hormone synthesis was not altered. Corticosterone secretion in response to two different stimuli, namely 24-h starvation and cosyntropin administration, were also not altered in Chrebp-/- mice. Taking these results together, corticosterone synthesis and release were not affected in Chrebp-/- mice despite reduced plasma cholesterol levels.

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Aarti D Rohira, David M Lonard, and Bert W O’Malley

Tissue parenchyma is the functional unit of an organ and all of the remaining cells within that organ collectively make up the tissue stroma. The stroma includes fibroblasts, endothelial cells, immune cells, and nerves. Interactions between stromal and epithelial cells are essential for tissue development and healing after injury. These interactions are governed by growth factors, inflammatory cytokines and hormone signaling cascades. The steroid receptor coactivator (SRC) family of proteins includes three transcriptional coactivators that facilitate the assembly of multi-protein complexes to induce gene expression in response to activation of many cellular transcription factor signaling cascades. They are ubiquitously expressed and are especially critical for the developmental function of steroid hormone responsive tissues. The SRCs are overexpressed in multiple cancers including breast, ovarian, prostate and endometrial cancers. In this review, we focus on the role of the SRCs in regulating the functions of stromal cell components responsible for angiogenesis, inflammation and cell differentiation.

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Yirui He, Cheng Zhang, Yong Luo, Jinhua Chen, Mengliu Yang, Ling Li, Harvest F Gu, Gangyi Yang, and Xianxiang Zhang

Bone morphogenetic proteins (BMPs) are secreted ligands that belong to the transforming growth factor-β (TGF-β) superfamily. BMP7 has been reported to play a role in reversing obesity and regulating appetite in the hypothalamus. Whether BMP9 plays a central role in regulating glucose metabolism and insulin sensitivity remains unclear. Here, we investigated the impact of central BMP9 signaling and possible route of transmission. We performed intracerebroventricular (ICV) surgery and injected adenovirus expressing BMP9 (Ad-BMP9) into the cerebral ventricle of mice. Metabolic analysis, hyperinsulinemic-euglycemic clamp test, and analysis of phosphatidylinositol 3, 4, 5- trisphosphate (PIP3) formation were then performed. Real-time PCR and western blotting were performed to detect gene expression and potential pathways involved. We found that hypothalamic BMP9 expression was downregulated in obese and insulin-resistant mice. Overexpression of BMP9 in the mediobasal hypothalamus reduced food intake, body weight, and blood glucose level, and elevated the energy expenditure in high-fat diet (HFD)-fed mice. Importantly, central treatment with BMP9 improved hepatic insulin resistance (IR) and inhibited hepatic glucose production in HFD-fed mice. ICV BMP9-induced increase in hepatic insulin sensitivity and related metabolic effects were blocked by ICV injection of rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) signaling. In addition, ICV BMP9 promoted the ability of insulin to activate the insulin receptor / phosphoinositide 3-kinase (PI3K) / Akt pathway in the hypothalamus. Thus, this study provides insights into the potential mechanism by which central BMP9 ameliorates hepatic glucose metabolism and IR via activating the mTOR/PI3K/Akt pathway in the hypothalamus.

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Michela Rossi, Giulia Battafarano, Viviana De Martino, Alfredo Scillitani, Salvatore Minisola, and Andrea Del Fattore

Bone remodelling is a complex mechanism regulated by osteoclasts and osteoblasts and perturbation of this process leads to the onset of diseases, which may be characterised by altered bone erosion or formation. In this review, we will describe some bone formation-related disorders as sclerosteosis, van Buchem disease, hypophosphatasia and Camurati–Engelmann disease. In the past decades, the research focused on these rare disorders offered the opportunity to understand important pathways regulating bone formation. Thus, the identification of the molecular defects behind the etiopathology of these diseases will open the way for new therapeutic approaches applicable also to the management of more common bone diseases including osteoporosis.

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Qiaoli Cui, Yijing Liao, Yaojing Jiang, Xiaohang Huang, Weihong Tao, Quanquan Zhou, Anna Shao, Ying Zhao, Jia Li, Anran Ma, Zhihong Wang, Li Zhang, Zunyuan Yang, Yinan Liang, Minglin Wu, Zhenyan Yang, Wen Zeng, and Qinghua Wang

Glucagon-like peptide 1 (GLP-1) is an insulinotropic hormone and plays an important role in regulating glucose homeostasis. GLP-1 has a short half-life (t1/2 < 2 min) due to degrading enzyme dipeptidyl peptidase-IV and rapid kidney clearance, which limits its clinical application as a therapeutic reagent. We demonstrated recently that supaglutide, a novel GLP-1 mimetic generated by recombinant fusion protein techniques, exerted hypoglycemic and β-cell trophic effects in type 2 diabetes db/db mice. In the present study, we examined supaglutide’s therapeutic efficacy and pharmacokinetics in diabetic rhesus monkeys. We found that a single subcutaneous injection of supaglutide of tested doses transiently and significantly reduced blood glucose levels in a dose-dependent fashion in the diabetic monkeys. During a 4-week intervention period, treatment of supaglutide of weekly dosing dose-dependently decreased fasting and random blood glucose levels. This was associated with significantly declined plasma fructosamine levels. The repeated administration of supaglutide remarkably also decreased body weight in a dose-dependent fashion accompanied by decreased food intake. Intravenous glucose tolerance test results showed that supaglutide improved glucose tolerance. The intervention also showed enhanced glucose-stimulated insulin secretion and improved lipid profile in diabetic rhesus monkeys. These results reveal that supaglutide exerts beneficial effects in regulating blood glucose and lipid homeostasis in diabetic rhesus monkeys.