Physical inactivity is a pandemic that contributes to several chronic diseases and poses a significant burden on health care systems worldwide. The search for effective strategies to combat sedentary behavior has led to an intensification of the research efforts to unravel the biological substrate controlling activity. A wide body of preclinical evidence makes a strong case for sex steroids regulating physical activity in both genders, albeit the mechanisms implicated remain unclear. The beneficial effects of androgens on muscle as well as on other peripheral functions might play a role in favoring adaptation to exercise. Alternatively or in addition, sex steroids could act on specific brain circuitries to boost physical activity. This review critically discusses the evidence supporting a role for androgens and estrogens stimulating male physical activity, with special emphasis on the possible role of peripheral and/or central mechanisms. Finally, the potential translation of these findings to humans is briefly discussed.
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Ferran Jardí, Michaël R Laurent, Vanessa Dubois, Nari Kim, Rougin Khalil, Brigitte Decallonne, Dirk Vanderschueren and Frank Claessens
Michael E Symonds, Peter Aldiss, Neele Dellschaft, James Law, Hernan P Fainberg, Mark Pope, Harold Sacks and Helen Budge
Although brown adipose tissue (BAT) is one of the smallest organs in the body, it has the potential to have a substantial impact on both heat production as well as fat and carbohydrate metabolism. This is most apparent at birth, which is characterised with the rapid appearance and activation of the BAT specific mitochondrial uncoupling protein (UCP)1 in many large mammals. The amount of brown fat then gradually declines with age, an adaptation that can be modulated by the thermal environment. Given the increased incidence of maternal obesity and its potential transmission to the mother’s offspring, increasing BAT activity in the mother could be one mechanism to prevent this cycle. To date, however, all rodent studies investigating maternal obesity have been conducted at standard laboratory temperature (21°C), which represents an appreciable cold challenge. This could also explain why offspring weight is rarely increased, suggesting that future studies would benefit from being conducted at thermoneutrality (~28°C). It is also becoming apparent that each fat depot has a unique transcriptome and show different developmental pattern, which is not readily apparent macroscopically. These differences could contribute to the retention of UCP1 within the supraclavicular fat depot, the most active depot in adult humans, increasing heat production following a meal. Despite the rapid increase in publications on BAT over the past decade, the extent to which modifications in diet and/or environment can be utilised to promote its activity in the mother and/or her offspring remains to be established.
Maik Pietzner, Tim Kacprowski and Nele Friedrich
OMICs subsume different physiological layers including the genome, transcriptome, proteome and metabolome. Recent advances in analytical techniques allow for the exhaustive determination of biomolecules in all OMICs levels from less invasive human specimens such as blood and urine. Investigating OMICs in deeply characterized population-based or experimental studies has led to seminal improvement of our understanding of genetic determinants of thyroid function, identified putative thyroid hormone target genes and thyroid hormone-induced shifts in the plasma protein and metabolite content. Consequently, plasma biomolecules have been suggested as surrogates of tissue-specific action of thyroid hormones. This review provides a brief introduction to OMICs in thyroid research with a particular focus on metabolomics studies in humans elucidating the important role of thyroid hormones for whole body metabolism in adults.
Bishnu Adhikari, Prabhat Khanal and Mette Olaf Nielsen
To evaluate the long-term impacts of early-life nutritional manipulations on glucagon secretion and hepatic signalling, thirty-six twin-pregnant ewes during their last trimester were exposed to NORM (fulfilling 100% of daily energy/protein requirements), HIGH (fulfilling 150/110% of daily energy/protein requirements) or LOW (50% of NORM) diets. Twin lambs were assigned after birth to a moderate (CONV) or high-carbohydrate high-fat (HCHF) diet until 6 months. Then, responses in plasma glucagon concentrations and glucagon ratios relative to previously reported values for insulin, glucose and lactate were determined after intravenous bolus injections of glucose or propionate (fed and 2-day fasting state). Hepatic mRNA expressions of glucagon receptor (GCGR), glucose-6-phosphatase (G6PC), phosphoenolpyruvate carboxykinase (PEPCK) and fructose 1,6-biphosphatase (FBP) were also determined in a sub group of autopsied lambs. Expression of GCGR and all three enzymes were supressed by prenatal LOW compared to NORM (except PEPCK) and HIGH (except FBP) nutrition. The postnatal HCHF diet reduced plasma glucagon responses to propionate and hepatic mRNA expression of all genes. In response to propionate, insulin/glucagon ratio was decreased (fasted state), but lactate/glucagon and glucose/glucagon increased in HCHF compared to CONV lambs. In conclusion, prenatal undernutrition and postnatal overnutrition had similar long-term implications and reduced hepatic glucagon signalling. Glucagon secretory responses to propionate were, however, not related to the prenatal nutrition history, but negatively affected by the postnatal obesogenic diet. The pancreatic α-cell compared to β-cells may thus be less sensitive towards late gestation malnutrition, whereas hepatic glucagon signalling appears to be a target of prenatal programming.
James C Needell, Madalyn N Brown and Danny Zipris
The etiopathogenesis of type 1 diabetes (T1D) remains poorly understood. We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced T1D to better understand the role of the innate immune system in the mechanism of virus-induced disease. We observed that infection with KRV results in cell influx into visceral adipose tissue soon following infection prior to insulitis and hyperglycemia. In sharp contrast, subcutaneous adipose tissue is free of cellular infiltration, whereas β cell inflammation and diabetes are observed beginning on day 14 post infection. Immunofluorescence studies further demonstrate that KRV triggers CD68+ macrophage recruitment and the expression of KRV transcripts and proinflammatory cytokines and chemokines in visceral adipose tissue. Adipocytes from naive rats cultured in the presence of KRV express virus transcripts and upregulate cytokine and chemokine gene expression. KRV induces apoptosis in visceral adipose tissue in vivo, which is reflected by positive TUNEL staining and the expression of cleaved caspase-3. Moreover, KRV leads to an oxidative stress response and downregulates the expression of adipokines and genes associated with mediating insulin signaling. Activation of innate immunity with Poly I:C in the absence of KRV leads to CD68+ macrophage recruitment to visceral adipose tissue and a decrease in adipokine expression detected 5 days following Poly (I:C) treatment. Finally, proof-of-principle studies show that brief anti-inflammatory steroid therapy suppresses visceral adipose tissue inflammation and protects from virus-induced disease. Our studies provide evidence raising the hypothesis that visceral adipose tissue inflammation and dysfunction may be involved in early mechanisms triggering β cell autoimmunity.
Sheng-Gao Tang, Xiao-Yu Liu, Ji-Ming Ye, Ting-Ting Hu, Ying-Ying Yang, Ting Han and Wen Tan
Diabetes-induced injury of myocardium, defined as diabetic cardiomyopathy (DCM), accounts for significant mortality and morbidity in diabetic population. Alleviation of DCM by a potent drug remains considerable interests in experimental and clinical researches because hypoglycemic drugs cannot effectively control this condition. Here, we explored the beneficial effects of isosteviol sodium (STVNa) on type 1 diabetes-induced DCM and the potential mechanisms involved. Male Wistar rats were induced to diabetes by injection of streptozotocin (STZ). One week later, diabetic rats were randomly grouped to receive STVNa (STZ/STVNa) or its vehicle (STZ). After 11 weeks of treatment or 11 weeks treatment following 4 weeks of removal of the treatment, the cardiac function and structure were evaluated and related mechanisms were investigated. In diabetic rats, oxidative stress, inflammation, blood glucose and plasma advanced glycation end products (AGEs) were significantly increased, whereas superoxide dismutase 2 (SOD-2) expression and activity were decreased. STVNa treatment inhibited cardiac hypertrophy, fibrosis and inflammation, showed similar ratio of heart to body weight and antioxidant capacities almost similar to the normal controls, which can be sustained at least 4 weeks. Moreover, STVNa inhibited diabetes-inducted stimulation of both extracellular signal-regulated kinase (ERK) and nuclear factor κB (NF-κB) signal pathways. However, blood glucose, plasma AGE and insulin levels were not altered by STVNa treatment. These results indicate that STVNa may be developed into a potent therapy for DCM. The mechanism underlying this therapeutic effect involves the suppression of oxidative stress and inflammation by inhibiting ERK and NF-κB without changing blood glucose or AGEs.
Prabhakara R Nagareddy, Sunil K Noothi, Michelle C Flynn and Andrew J Murphy
Platelets play a critical role in both the initiation and progression of atherosclerosis, and even more so in the ensuing atherothrombotic complications. Low-dose aspirin remains the mainstay of antiplatelet therapy in high-risk patients by reducing the risk of myocardial ischemia, stroke or death due to cardiovascular disease. However, antiplatelet therapies lose their efficacy in people with diabetes mellitus, increasing the risk of future atherothrombotic events. The molecular mechanisms that promote platelet hyperactivity remain unclear but could be due to glycation-induced conformational changes of platelet membranes resulting in impaired aspirin entry or less-efficient acetylation/compensatory increase in COX-2 expression in newborn platelets. Emerging evidence from our laboratory and elsewhere suggest that enhanced platelet turnover (thrombopoiesis), particularly the production of immature reticulated platelets from the bone marrow, could contribute to atherosclerotic complications. We have identified a major role for neutrophil-derived S100A8/A9, a damage-associated molecular pattern, in driving reticulated thrombopoiesis by directly interacting with its receptors on Kupffer cells in the liver. In this review, we discuss the role of hepatic inflammation in driving reticulated platelet production and suggest potential targets to control their production, improve efficacy of current antiplatelet therapies and reduce the risk of atherothrombotic complications.
Thomas Funck-Brentano, Karin H Nilsson, Robert Brommage, Petra Henning, Ulf H Lerner, Antti Koskela, Juha Tuukkanen, Martine Cohen-Solal, Sofia Movérare-Skrtic and Claes Ohlsson
WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.
Jie Miao, Yacir Benomar, Sarah Al Rifai, Ghislaine Poizat, Laure Riffault, Delphine Crépin and Mohammed Taouis
Autophagy is a non-selective degradation pathway induced in energy-deprived cells and in non-starved cells by participating in cellular inflammatory responses mainly through the elimination of injured and aged mitochondria that constitute an important source of reactive oxygen species. We have previously reported that resistin/TLR4 signaling pathway induces inflammation and insulin resistance in neuronal cell. However, the impact of resistin-induced inflammation on neuronal autophagy is unknown. In the present study, we hypothesized that resistin-induced neuroinflammation could be attributed, at least partially, to the impairment of autophagy pathways in neuronal cells. Our data show that resistin decreases neuronal autophagy as evidenced by the repression of the main autophagy markers in SH-SY5Y human neuroblastoma cell line. Furthermore, the silencing of TLR4 completely abolished these effects. Resistin also inhibits AMPK phosphorylation and increases that of Akt/mTOR contrasting with activated autophagy where AMPK phosphorylation is augmented and mTOR inhibited. In vivo, resistin treatment inhibits the mRNA expression of autophagy markers in the hypothalamus of WT mice but not in Tlr4−/− mice. In addition, resistin strongly diminished LC3 (a marker of autophagy) labeling in the arcuate nucleus of WT mice, and this effect is abolished in Tlr4−/− mice. Taken together, our findings clearly reveal resistin/TLR4 as a new regulatory pathway of neuronal autophagy.
Florencia Figueroa, Gisela Mendoza, Darío Cardozo, Fabián Mohamed, Liliana Oliveros and Myriam Forneris
Polycystic ovarian syndrome (PCOS) is a low-grade inflammatory disease characterized by hyperandrogenism and ovarian hyperinnervation. The aim of this work is to investigate whether in vivo bilateral superior ovarian nerve (SON) section in adult rats with estradiol valerate-induced PCOS (PCO rats) affects macrophage spleen cells (MФ) and modifies the steroidogenic ability of their secretions. Culture media of MФ from PCO rats and PCO rats with SON section (PCO-SON rats) were used to stimulate in vitro intact ovaries. Compared with macrophages PCO, macrophages from PCO-SON rats released less tumor necrosis factor-α and nitric oxide, expressed lower Bax and Nfkb mRNA and showed reduced TUNEL staining. Also, in PCO rats, the SON section decreased kisspeptin and nerve growth factor mRNA expressions, without changes in Trka receptor mRNA levels. Macrophage secretions from PCO-SON rats decreased androstenedione and stimulated progesterone release in PCO ovaries, compared to macrophage secretions from PCO rats. No changes were observed in ovarian estradiol response. These findings emphasize the importance of the SON in spleen MΦ, since its manipulation leads to secondary modifications of immunological and neural mediators, which might influence ovarian steroidogenesis. In PCO ovaries, the reduction of androstenedione and the improvement of progesterone release induced by PCO-SON MΦ secretion, might be beneficial considering the hormonal anomalies characteristic of PCOS. We present functional evidence that modulation of the immune-endocrine function by peripheral sympathetic nervous system might have implications for understanding the pathophysiology of PCOS.