Hyperglycemia plays a major role in the development of diabetic macrovascular complications, including atherosclerosis and restenosis, which are responsible for the most of disability and mortality in diabetic patients. Osteopontin (OPN) is an important factor involved in atherogenesis, and hyperglycemia enhances the transcriptional activity of FoxO1 which is closely association with insulin resistance and diabetes. Here, we showed that plasma OPN levels were significantly elevated in type 2 diabetic patients and positively correlated with glycated albumin (GA). The more atherosclerotic lesions were observed in the aorta of diabetic ApoE−/− mice analyzed by Sudan IV staining. High glucose increased both the mRNA and protein expression levels of OPN and inhibited the phosphorylation of FoxO1 in RAW 264.7 cells. Overexpression of WT or constitutively active mutant FoxO1 promoted the expression levels of OPN, while the dominant-negative mutant FoxO1 decreased slightly the expression of OPN. Conversely, knockdown of FoxO1 reduced the expression of OPN. Luciferase reporter assay revealed that high glucose and overexpression of FoxO1 enhanced the activities of the OPN promoter region nt −1918 ~ −713. Furthermore, the interactions between FoxO1 and the OPN promoter were confirmed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). Our results suggest that high glucose upregulates OPN expression via FoxO1 activation, which would play a critical role in the development of diabetic atherogenesis.
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Qiongge Zhang, Chaoqun Wang, Yehua Tang, Qiangqiang Zhu, Yongcheng Li, Haiyan Chen, Yi Bao, Song Xue, Liangliang Sun, Wei Tang, Xiangfang Chen, Yongquan Shi, Lefeng Qu, Bin Lu and Jiaoyang Zheng
Monisha Rajasekaran, Ok-Joo Sul, Eun-Kyung Choi, Ji-Eun Kim, Jae-Hee Suh and Hye-Seon Choi
Obesity is strongly associated with chronic inflammation for which adipose tissue macrophages play a critical role. The objective of this study is to identify monocyte chemoattractant protein-1 (MCP-1, CCL2) as a key player governing M1–M2 macrophage polarization and energy balance. We evaluated body weight, fat mass, adipocyte size and energy expenditure as well as core body temperature of Ccl2 knockout mice compared with wild-type mice. Adipose tissues, differentiated adipocyte and bone marrow-derived macrophages were assessed by qPCR, Western blot analysis and histochemistry. MCP-1 deficiency augmented energy expenditure by promoting browning in white adipose tissue and brown adipose tissue activity via increasing the expressions of Ucp1, Prdm16, Tnfrsf9, Ppargc1a, Nrf1 and Th and mitochondrial DNA copy number. MCP-1 abrogation promoted M2 polarization which is characterized by increased expression of Arg1, Chil3, Il10 and Klf4 whereas it decreased M1 polarization by decreased p65 nuclear translocation and attenuated expression of Itgax, Tnf and Nos2, leading to increased browning of adipocytes. Enhanced M2 polarization and attenuated M1 polarization in the absence of MCP-1 are independent. Collectively, our results suggest that the action of MCP-1 in macrophages modulates energy expenditure by impairing browning in adipose tissue.
Sivaporn Sivasinprasasn, Siripong Palee, Kenneth Chattipakorn, Thidarat Jaiwongkum, Nattayaporn Apaijai, Wasana Pratchayasakul, Siriporn C Chattipakorn and Nipon Chattipakorn
Myocardial damage and mitochondrial dysfunction caused by cardiac ischemia-reperfusion (I/R) injury are intensified by endogenous estrogen deprivation. Although N-acetylcysteine (NAC) exerted cardioprotective effects, its benefits when used in combination with hormone therapy are unknown. We tested the hypothesis that a combination of NAC with low-dose estrogen improves cardiometabolic function and protects cardiac mitochondria against I/R injury, to a similar extent to regular-dose estrogen treatment, in estrogen-deprived rats. Female Wistar rats had a bilateral ovariectomy (OVX) or sham operation. Twelve weeks after the operation, OVX rats were treated with regular-dose estrogen (E; 50 µg/kg/day), low-dose estrogen (e; 25 µg/kg/day), NAC (N; 100 mg/kg/day) or combined low-dose estradiol with NAC (eN) for 4 weeks (n = 6/group). Metabolic parameters, echocardiography, heart rate variability and then cardiac I/R protocol involving 30-min coronary artery ligation, followed by 120-min reperfusion, were performed. OVX rats had increased body weight, visceral fat, fasting plasma glucose, HOMA-IR index, triglycerides, cholesterol and LDL levels (P < 0.05 vs sham). Only OVX-E and OVX-eN had a similarly improved HOMA-IR index. LVEF was increased in all treatment groups, but HRV was restored only by OVX-E and OVX-eN. After I/R, myocardial infarct size was decreased in both OVX-E and OVX-eN groups. OVX-E and OVX-eN rats similarly had a reduced mitochondrial ROS level and increased mitochondrial membrane potential in the ischemic myocardium. In conclusion, combined NAC with low-dose estrogen and regular-dose estrogen therapy similarly improve cardiometabolic function, prevent cardiac mitochondrial dysfunction and reduces the infarct size in estrogen-deprived rats with cardiac I/R injury.
M J Vazquez, I Velasco and M Tena-Sempere
Puberty is driven by sophisticated neuroendocrine networks that timely activate the brain centers governing the reproductive axis. The timing of puberty is genetically determined; yet, puberty is also sensitive to numerous internal and external cues, among which metabolic/nutritional signals are especially prominent. Compelling epidemiological evidence suggests that alterations of the age of puberty are becoming more frequent; the underlying mechanisms remain largely unknown, but the escalating prevalence of obesity and other metabolic/feeding disorders is possibly a major contributing factor. This phenomenon may have clinical implications, since alterations in pubertal timing have been associated to adverse health outcomes, including higher risk of earlier all-cause mortality. This urges for a better understanding of the neurohormonal basis of normal puberty and its deviations. Compelling evidence has recently documented the master role of hypothalamic neurons producing kisspeptins, encoded by Kiss1, in the neuroendocrine pathways controlling puberty. Kiss1 neurons seemingly participate in transmitting the regulatory actions of metabolic cues on pubertal maturation. Key cellular metabolic sensors, as the mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK) and the fuel-sensing deacetylase, SIRT1, have been recently shown to participate also in the metabolic modulation of puberty. Recently, we have documented that AMPK and SIRT1 operate as major molecular effectors for the metabolic control of Kiss1 neurons and, thereby, puberty onset. Alterations of these molecular pathways may contribute to the perturbation of pubertal timing linked to conditions of metabolic stress in humans, such as subnutrition or obesity and might become druggable targets for better management of pubertal disorders.
Alia H Sukkar, Aaron M Lett, Gary Frost and Edward S Chambers
Short-chain fatty acids (SCFAs) are metabolites produced from the fermentation of dietary fibre by the gut microbiota. High-fibre diets have been associated with lower weight gain and a number of reports have therefore investigated if these positive effects of a dietary fibre on body weight can be replicated through the direct administration of SCFAs. Many of these studies have reported that SCFAs can prevent or attenuate long-term body weight gain by increasing energy expenditure through increased lipid oxidation. The aim of the present review is to therefore evaluate the current evidence for an effect of SCFAs on whole-body energy expenditure and to assess the potential underlying mechanisms. The available data highlights that SCFAs can exert multiple effects at various organ and tissue sites that would cumulatively raise energy expenditure via a promotion of lipid oxidation. In conclusion, the present review proposes that dietary interventions and other therapies that augment gut-derived SCFAs and systemic availability may present an effective strategy to improve long-term energy balance and body weight management.
Raul Riquelme, Freddy Ruz, Artur Mayerhofer and Hernán E Lara
An increase in the sympathetic tone in the rat ovary induces a polycystic ovary (PCOS-like) phenotype. No information exists about its impact on fertility. In contrast, increased follicular development and improved fertility in rats were found after pharmacological inhibition of acetylcholinesterase, which increased intraovarian acetylcholine (ACh). Now, we studied the impact of sympathetic stress, followed by a recovery period without stress, on the cholinergic and noradrenergic systems of the rat ovary and on fertility. To activate ovarian sympathetic nerves, female Sprague–Dawley rats were exposed to cold stress (4°C/3 h day for 28 days; first period), followed by a 28-day period without cold stress (second period). No changes in estrous cyclicity during the first period was found. At the end of this period, ovarian levels of NA and ACh were increased. Morphometric analysis showed lower numbers of secondary and antral follicles, enhanced follicular atresia and fewer corpora lutea. Plasma progesterone was lower and testosterone was higher than that in controls. At end of the second period, ovarian ACh levels had returned to control levels, but NA levels remained elevated. The second period was also characterized by the presence of cystic follicles in the ovary, by elevated plasma testosterone and estradiol levels, while progesterone levels were decreased. Estrous cyclicity and ovulation during that period were irregular and fertility decreased. Thus, cold stress initially activated both ovarian noradrenergic and cholinergic system. After stress, the ovary did not fully recover and activation of the noradrenergic system persisted and correlated with cystic ovarian morphology and decreased fertility.
Masaki Nakano, Mika Ikegame, Junko Igarashi-Migitaka, Yusuke Maruyama, Nobuo Suzuki and Atsuhiko Hattori
Many studies have investigated the actions of melatonin on osteoblasts and osteoclasts. However, the underlying mechanisms, especially regarding osteocyte function, remain largely unknown. Therefore, this study aimed to clarify the underlying mechanisms of melatonin action on bone tissue via osteocyte function. Chick calvariae were employed as a model. In ovo injection of melatonin (5, 50 and 500 µg) dose-dependently decreased the mRNA expression levels of cathepsin K and matrix metalloproteinase 9 (MMP9) in chick calvariae without affecting the expression levels of receptor activator of NF-κB ligand or osteoprotegerin. Surprisingly enough, the expression of calcitonin mRNA in chick calvariae was significantly raised. After 3 days of in vitro treatment of melatonin (10−7 and 10−5 M) on newly hatched chick calvariae, both calcitonin mRNA expression in calvariae and the concentration of calcitonin in cultured medium were augmented in a dose-dependent manner, coincident with the decreased mRNA expression levels of cathepsin K and MMP9. Immunohistochemical analyses revealed expression of melatonin receptors and calcitonin by osteocytes buried in bone matrix. Moreover, the mRNA expression levels of melatonin receptors, calcitonin and sclerostin (a marker of osteocyte), were strongly and positively correlated. In conclusion, we demonstrated the expression of melatonin receptors and calcitonin expression in osteocytes for the first time and suggest a new mechanism underlying the suppressive effect of melatonin on osteoclasts via upregulation of calcitonin secretion by osteocytes.
Stephen G Hillier and Richard Lathe
The year 2019 marks the 80th anniversary of the 1939 Nobel Prize in Chemistry awarded to Leopold Ruzicka (1887–1976) for work on higher terpene molecular structures, including the first chemical synthesis of male sex hormones. Arguably his crowning achievement was the ‘biogenetic isoprene rule’, which helped to unravel the complexities of terpenoid biosynthesis. The rule declares terpenoids to be enzymatically cyclized products of substrate alkene chains containing a characteristic number of linear, head-to-tail condensed, C5 isoprene units. The number of repeat isoprene units dictates the type of terpene produced (i.e., 2, monoterpene; 3, sesquiterpene; 4, diterpene, etc.). In the case of triterpenes, six C5 isoprene units combine into C30 squalene, which is cyclized into one of the signature carbon skeletons from which myriad downstream triterpenoid structures are derived, including sterols and steroids. Ruzicka also had a keen interest in the origin of life, but the pivotal role of terpenoids has generally been overshadowed by nucleobases, amino acids, and sugars. To redress the balance, we provide a historical and evolutionary perspective. We address the potential abiotic generation of isoprene, the crucial role that polyprene terpenoids played in early membranes and cellular life, and emphasize that endocrinology from microbes to plants and vertebrates is firmly grounded on Ruzicka’s pivotal insights into the structure and function of terpenes. A harmonizing feature is that all known lifeforms (including bacteria) biosynthesize triterpenoid substances that are essential for cellular membrane formation and function, from which signaling molecules such as steroid hormones and cognate receptors are likely to have evolved.
Sean W Limesand, Kent L Thornburg and Jane E Harding
Jacqueline M Wallace
The competition for nutrients that arises when pregnancy coincides with continuing or incomplete growth in young adolescent girls increases the risk of preterm delivery and low birthweight with negative after-effects for mother and child extending beyond the perinatal period. Sheep paradigms involving nutritional management of weight and adiposity in young, biologically immature adolescents have allowed the consequences of differential maternal growth status to be explored. Although nutrient reserves at conception play a modest role, it is the dietary manipulation of the maternal growth trajectory thereafter which has the most negative impact on pregnancy outcome. Overnourishing adolescents to promote rapid maternal growth is particularly detrimental as placental growth, uteroplacental blood flows and fetal nutrient delivery are perturbed leading to a high incidence of fetal growth restriction and premature delivery of low birthweight lambs, whereas in undernourished adolescents further maternal growth is prevented, and depletion of the maternal body results in a small reduction in birthweight independent of placental size. Maternal and placental endocrine systems are differentially altered in both paradigms with downstream effects on fetal endocrine systems, organ development and body composition. Approaches to reverse these effects have been explored, predominantly targeting placental growth or function. After birth, growth-restricted offspring born to overnourished adolescents and fed to appetite have an altered metabolic phenotype which persists into adulthood, whereas offspring of undernourished adolescents are largely unaffected. This body of work using ovine paradigms has public health implications for nutritional advice offered to young adolescents before and during pregnancy, and their offspring thereafter.