Regulation of body weight and thermogenesis in seasonally acclimatized Brandt's voles (Microtus brandti)

Seasonal changes in an animal's morphology, physiology, and behavior are considered to be an adaptive strategy for survival and reproductive success. In the present study, we examined body weight and several behavioral, physiological, hormonal, and biochemical markers in seasonally acclimatized Brandt's voles (Microtus brandti) to test our hypothesis that Brandt's voles can decrease energy intake associated with decrease in body weight, body fat content, serum leptin level, and increasing thermogenesis in winter conditions. We found that the body weight of Brandt's voles was lowest in winter (December to February) and highest in spring and early summer (May to June). This seasonal variation in body weight was associated with changes in other markers examined. For example, the winter decrease in body weight was accompanied by increased energy intake and enhanced nonshivering thermogenesis (NST) as well as by decreased body fat mass and reduced levels of circulating leptin. Further, circulating levels of leptin were positively correlated with body weight and body fat mass, and negatively correlated with energy intake and uncoupling protein 1 contents. Together, these data do not support our hypothesis and suggest that leptin may be involved in this process and serve as a starvation signal in Brandt's voles.     

Seasonal regulations of energetics, serum concentrations of leptin, and uncoupling protein 1 content of brown adipose tissue in root voles (Microtus oeconomus) from the Qinghai-Tibetan plateau

Survival of small mammals in winter requires proper adjustments in physiology, behavior and morphology. The present study was designed to examine the changes in serum leptin concentration and the molecular basis of thermogenesis in seasonally acclimatized root voles (Microtus oeconomus) from the Qinghai-Tibetan plateau. In January root voles had lower body mass and body fat mass coupled with higher nonshivering thermogenesis (NST) capacity. Consistently, cytochrome c oxidase activity and mitochondrial uncoupling protein-1 (UCP1) protein contents in brown adipose tissues were higher in January as compared to that in July. Circulating level of serum leptin was significantly lower in winter and higher in July. Correlation analysis showed that serum leptin levels were positively related with body mass and body fat mass while negatively correlated with UCP1 protein contents. Together, these data provided further evidence for our previous findings that root voles from the Qinghai-Tibetan plateau mainly depend on higher NST coupled with lower body mass to enhance winter survival. Further, fat deposition was significantly mobilized in cold winter and leptin was potentially involved in the regulation of body mass and thermogenesis in root voles. Serum leptin might act as a starvation signal in winter and satiety signal in summer.     

Photoperiodic regulation in energy intake, thermogenesis and body mass in root voles (Microtus oeconomus)

The present study was designed to examine whether photoperiod alone was effective to induce seasonal regulations in physiology in root voles (Microtus oeconomus) from the Qinghai-Tibetan plateau noted for its extreme cold environment. Root voles were randomly assigned into either long photoperiod (LD; 16L:8D) or short photoperiod (SD; 8L:16D) for 4 weeks at constant temperature (20 degrees C). At the end of acclimation, SD voles showed lower body mass and body fat coupled with higher energy intake than LD voles. SD greatly enhanced thermogenic capacities in root voles, as indicated by elevated basal metabolic rate (BMR), nonshivering thermogenesis (NST), mitochondrial protein content and uncoupling protein-1 (UCP1) content in brown adipose tissue (BAT). Although no variations in serum leptin levels were found between SD and LD voles, serum leptin levels were positively correlated with body mass and body fat mass, and negatively correlated with energy intake and UCP1 content in BAT, respectively. To summarize, SD alone is effective in inducing higher thermogenic capacities and energy intake coupled with lower body mass and body fat mass in root voles. Leptin is potentially involved in the photoperiod induced body mass regulation and thermogenesis in root voles.     

Energy metabolism, thermogenesis and body mass regulation in Brandt's voles (Lasiopodomys brandtii) during cold acclimation and rewarming

Environmental cues play important roles in the regulation of an animal's physiology and behavior. The purpose of the present study was to test the hypothesis that ambient temperature was a cue to induce adjustments in body mass, energy intake and thermogenic capacity, associated with changes in serum leptin levels in Brandt's voles (Lasiopodomys brandtii). We found that Brandt's voles increased resting metabolic rate (RMR) and energy intake and kept body mass stable when exposed to the cold while showed a significant increase in body mass after rewarming. The increase in body mass after rewarming was associated with the higher energy intake compared with control. Uncoupling protein 1 (UCP1) content in brown adipose tissue (BAT) increased in the cold and reversed after rewarming. Serum leptin levels decreased in the cold while increased after rewarming, associated with the opposite changes in energy intake. Further, serum leptin levels were positively correlated with body mass and body fat mass. Together, these data supported our hypothesis that ambient temperature was a cue to induce changes in body mass and metabolism. Serum leptin, as a starvation signal in the cold and satiety signal in rewarming, was involved in the processes of thermogenesis and body mass regulation in Brandt's voles.     

Leptin deficiency impairs adipogenesis and browning response in mouse mesenchymal progenitors

Although phenotypically different, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) are able to produce heat through non-shivering thermogenesis due to the presence of mitochondrial uncoupling protein 1 (UCP1). The appearance of thermogenically active beige adipocytes in iWAT is known as browning. Both brown and beige cells originate from mesenchymal stem cells (MSCs), and in culture conditions a browning response can be induced with hypothermia (i.e. 32 °C) during which nuclear leptin immunodetection was observed. The central role of leptin in regulating food intake and energy consumption is well recognised, but its importance in the browning process at the cellular level is unclear. Here, immunocytochemical analysis of MSC-derived adipocytes established nuclear localization of both leptin and leptin receptor suggesting an involvement of the leptin pathway in the browning response. In order to elucidate whether leptin modulates the expression of brown and beige adipocyte markers, BAT and iWAT samples from leptin-deficient (ob/ob) mice were analysed and exhibited reduced brown/beige marker expression compared to wild-type controls. When MSCs were isolated and differentiated into adipocytes, leptin deficiency was observed to induce a white phenotype, especially when incubated at 32 °C. These adaptations were accompanied with morphological signs of impaired adipogenic differentiation. Overall, our results indicate that leptin supports adipocyte browning and suggest a potential role for leptin in adipogenesis and browning.     

Effects of fasting and refeeding on body mass,thermogenesis and serum leptin in Brandt's voles (Lasiopodomys brandtii)

(1)

To investigate the effect of fasting and refeeding on the body mass, thermogenesis and serum leptin in Brandt's voles, the changes in body and body fat mass, resting metabolic rate (RMR), mitochondrial cytochrome c oxidase (COX) activity in liver and brown adipose tissue (BAT), uncoupling protein 1 (UCP1) content of BAT, serum leptin level and post-fasting food intake were monitored and measured.     

Phylogeography of field voles (Microtus agrestis) in Eurasia inferred from mitochondrial DNA sequences

In a distribution-wide phylogeographic survey of the field vole (Microtus agrestis), 75 specimens from 56 localities across Eurasia were examined for DNA sequence variation along the whole 1140 base pair (bp) mitochondrial (mt) cytochrome b gene. The species is subdivided into three main mtDNA phylogeographic groups - western, eastern and southern - with largely allopatric distributions. The western phylogeographical group is found in west and central Europe and spread most probably from a glacial refugium in the Carpathians. The eastern group covers a large range from Lithuania to central Asia, and probably originated from a southeast European source (e.g. the southern Urals or the Caucasus). The southern group occupies an area from Portugal to Hungary, with division into two distinct mtDNA sublineages that presumably derive from separate glacial refugia in the Iberian Peninsula. Molecular clock estimates suggest that the western and eastern field vole populations separated during the last glaciation, whereas the southern population dates back 0.5-0.9 Myr. High levels of mtDNA variation indicate relatively large population sizes and subdivisions within phylogeographic groups during the last glaciation. We report a possible new suture zone in east Europe.     

光周期和高脂食物对布氏田鼠能量代谢和产热的影响

为了研究光周期和高脂食物对小型哺乳动物能量代谢和产热的影响,将成年雌性布氏田鼠(Lasiopodomys brandtii)分别驯化于长光照低脂、高脂食物和短光照低脂、高脂食物,7周后测定动物的体重、能量摄入、产热、血清瘦素浓度以及褐色脂肪组织解偶联蛋白1(BAT-UCP1)含量等参数.结果发现:1)短光照抑制体重增长、降低体脂重量和血清瘦素水平,增加非颤抖性产热(NST)和UCP1含量;2)高脂食物使摄入能减少和消化率提高,但未显著影响体重、基础代谢率、NST、UCP1含量和血清瘦素;3)血清瘦素与摄入能不相关,但与体脂含量正相关.结果暗示:短光照下瘦素作用敏感性增加和产热能力增强,可能介导了抵抗高脂食物诱导的肥胖.在野外条件下草食性的布氏田鼠能通过能量代谢和产热的适应性调节避免体重的过度增长,有利于降低捕食风险,增强生存能力.同时布氏田鼠是研究食物诱导肥胖机理的一个好模型     

Effects of photoperiod on energy intake, thermogenesis and body mass in Eothenomys miletus in Hengduan Mountain region

The present study was designed to examine whether photoperiod alone was effective to induce seasonal changes in physiology in voles (Eothenomys.) from the Hengduan Mountain region. Eothenomys miletus were randomly assigned into either long photoperiod (LD; 16L: 8D) or short photoperiod (SD; 8L: 16D) for 4 weeks at constant temperature (25 °C). At the end of acclimation, SD voles showed lower body mass and body fat coupled with higher energy intake than LD voles. SD greatly enhanced the thermogenic capacity of E. miletus, as indicated by an elevated nonshivering thermogenesis (NST), mitochondrial protein in brown adipose tissue (BAT); basal metabolic rate (BMR) was also raised. Although no variations in serum leptin levels were found between SD and LD voles, serum leptin levels were positively correlated with body mass and body fat mass, and negatively correlated with energy intake and UCP1 content in BAT, respectively. To summarize, SD alone is effective in inducing higher thermogenic capacities and energy intake coupled with lower body mass and body fat mass in root voles. Leptin is potentially involved in the photoperiod induced body mass regulation and thermogenesis in E. miletus. Our study shows that SD alone is effective.     

Effects of photoperiod on energy budgets and thermogenesis in Mongolian gerbils (Meriones unguiculatus)

(1)

To investigate the role of photoperiod on the regulation of energy budgets and thermogenesis in Mongolian gerbils, body mass (BM), body fat mass (BFM), basal metabolic rate (BMR), nonshivering thermogenesis (NST), gross energy intake (GEI), mitochondrial cytochrome c oxidase (COX) activity and uncoupling protein1 (UCP1) content of brown adipose tissue (BAT), and serum tri-iodothyronine (T₃), thyroxine (T₄) and leptin levels were measured.     

FOXO1 associated with sensitivity to chemotherapy drugs and glial-mesenchymal transition in glioma

Mesenchymal subtype of glioblastoma (GBM), identified as one of four clinically relevant molecular subtypes, has worst prognosis because of its close relation with the malignant biological properties induced by glial-mesenchymal transition (GMT). However, the molecular mechanism of GMT and its characterized molecule of GBM have not been studied. Forkhead box protein O1 (FOXO1) is at a convergence point of receptor tyrosine kinase signaling as one of the three core pathways implicated in GBM. Our previous study indicated that the inactivation of FOXO1 involved in the inhibition of GMT is an independent prognosis factor of GBM. In this study, we will further confirm the role of FOXO1 in GMT through cytological experiments to clarify how FOXO1 regulates GMT and its clinical significance. We established virus-infected FOXO1 overexpression and FOXO1 knockdown cells of U373 MG and U251 mediated by lentivirus, based on the effect of which FOXO1-correlated-GMT experiments were performed in vitro and in vivo. Our data suggested that FOXO1 played a crucial role in resistance to TMZ, BCNU, and CDDP; migration and invasion; and stem cell properties of glioma cells. FOXO1 may serve as a targeted biomarker for prediction of sensitivity to chemotherapy drugs, metastasis, and prognosis, which provides a new idea for mesenchymal GBM treatment.     

Effect of Cheonggukjang supplementation upon hepatic acyl-CoA synthase, carnitine palmitoyltransferase I, acyl-CoA oxidase and uncoupling protein 2 mRNA levels in C57BL/6J mice fed with high fat diet

This study investigated the effect of Cheonggukjang on mRNA levels of hepatic acyl-CoA synthase (ACS), carnitine palmitoyltransferase I (CPT-I), acyl-CoA oxidase (ACO) and uncoupling protein 2 (UCP2), and on serum lipid profiles in C57BL/6J mice. Thirty male C57BL/6J mice were divided into three groups; normal diet (ND), high fat diet (HD) and high fat diet with 40% Cheonggukjang (HDC). Energy intake was significantly higher in the HDC group than in the ND and HD groups. The HDC group normalized in weight gain, epididymal and back fat (g/100 g) accumulation which are increased by high fat diet. Serum concentrations of triglyceride and total cholesterol in the HDC were significantly lower than those in the HD group. These results were confirmed by hepatic mRNA expression of enzymes and protein (ACS, CPT-1, ACO, UCP2) which is related with lipid metabolism by RT-PCR. Hepatic CPT-I, ACO and UCP2 mRNA expression was increased by Cheonggukjang supplementation. We demonstrated that Cheonggukjang supplement leads to increased mRNA expressions of enzymes and protein involved in fatty acid oxidation in liver, reduced accumulation of body fat and improvement of serum lipids in high fat diet fed mice.     

Age-related changes of serum mitochondrial uncoupling 1, rumen and rectal temperature in goats

Thermoregulatory processes are induced not only by exposure to cold or heat but also by a variety of physiological situations including age, fasting and food intake that result in changes in body temperature. The aim of the present study was to evaluate the differences in serum mitochondrial uncoupling protein 1 (UCP1), rumen temperature (T_RUMEN) and rectal temperature (T_RECTAL) values between adult and kids goats. Ten adult male Maltese goats aged 3–5 years old (Group A) and 30 male kids, raised for meat, were enrolled in this study. The kids were equally divided into 3 groups according to their age: Group B included kids aged 3 months, Group C included kids aged 4 months and Group D included kids aged 5 months. Blood samples and measurements of T_RUMEN and T_RECTAL were obtained from each animal. One-way repeated measures analysis of variance (ANOVA) was applied to evaluate the effect of age on the studied parameters. Statistically significant higher serum UCP1 levels (P<0.001) were found in Group A as compared to Groups B, C and D. Higher T_RUMEN values (P<0.001) were found in Group A than in Groups B, C and D, and in Group B than in Groups C and D. Group A showed lower T_RECTAL values (P<0.001) than Groups B, C and D. The Pearson's Correlation test was applied to assess significant relationship among studied parameters showing a statistically significant negative correlation between the values of T_RECTAL and serum UCP1 in all studied Groups (P<0.001). These results indicate that goats have good control of body temperature suggesting that further details about the thermogenic capacity and the function of UCP1 in kids and adult goats are worth exploring.     

Leptin regulates estrogen receptor gene expression in ATDC5 cells through the extracellular signal regulated kinase signaling pathway

Both estrogen and leptin play an important role in the regulation of physiological processes of endochondral bone formation in linear growth. Estrogen receptors (ERα and ERβ) are known as members of the superfamily of nuclear steroid hormone receptors and are detected in all zones of growth plate chondrocytes. They can be regulated in a ligand-independent manner. Whether leptin regulates ERs in the growth plate is still not clear. To explore this issue, chondrogenic ATDC5 cells were used in the present study. Messenger RNA and protein analyses were performed by quantitative PCR and Western blotting. We found that both ERα and ERβ were dynamically expressed during the ATDC5 cell differentiation for 21 days. Leptin (50 ng/ml) significantly upregulated ERα and ERβ mRNA and protein levels 48 h after leptin stimulation (P<0.05) at day 14. The up-regulation of ERα and ERβ mRNA by leptin was shown in a dose-dependent manner, but the most effective dose of leptin was different (100 and 1,000 ng/ml, respectively). Furthermore, we confirmed that leptin augmented the phosphorylation of ERK1/2 in a time-dependent manner. A maximum eightfold change was observed at 15 min. Finally, a specific ERK1/2 inhibitor, UO126, blocked leptin-induced ERs regulation in ATDC5 cells, indicating that ERK1/2 mediates, partly, the effects of leptin on ERs. These data demonstrate, for the first time, that leptin regulates the expression of ERs in growth plate chondrocytes via ERK signaling pathway, thereby suggesting a crosstalk between leptin and estrogen receptors in the regulation of bone formation.     

Genistein stimulates fatty acid oxidation in a leptin receptor-independent manner through the JAK2-mediated phosphorylation and activation of AMPK in skeletal muscle

Obesity is a public health problem that contributes to the development of insulin resistance, which is associated with an excessive accumulation of lipids in skeletal muscle tissue. There is evidence that soy protein can decrease the ectopic accumulation of lipids and improves insulin sensitivity; however, it is unknown whether soy isoflavones, particularly genistein, can stimulate fatty acid oxidation in the skeletal muscle. Thus, we studied the mechanism by which genistein stimulates fatty acid oxidation in the skeletal muscle. We showed that genistein induced the expression of genes of fatty acid oxidation in the skeletal muscle of Zucker fa/fa rats and in leptin receptor (ObR)-silenced C2C12 myotubes through AMPK phosphorylation. Furthermore, the genistein-mediated AMPK phosphorylation occurred via JAK2, which was possibly activated through a mechanism that involved cAMP. Additionally, the genistein-mediated induction of fatty acid oxidation genes involved PGC1α and PPARδ. As a result, we observed that genistein increased fatty acid oxidation in both the control and silenced C2C12 myotubes, as well as a decrease in the RER in mice, suggesting that genistein can be used in strategies to decrease lipid accumulation in the skeletal muscle.     

The GS-X Pump in Plant, Yeast, and Animal Cells: Structure, Function, and Gene Expression

This review addresses the recent molecular identification of several members of the glutathione S-conjugate (GS-X) pump family, a new class of ATP-binding cassette (ABC) transporters responsible for the elimination and/or sequestration of pharmacologically and agronomically important compounds in mammalian, yeast and plant cells. The molecular structure and function of GS-X pumps encoded by MRP, cMOAT, YCF1. and AtMRP genes, have been conserved throughout molecular evolution. The physiologic function of GS-X pumps is closely related with cellular detoxification, oxidative stress, inflammation, and cancer drug resistance. Coordinated expression of GS-X pump genes, e.g., MRP1 and YCF1, and -glutamylcystaine synthetase, a rate-limiting enzyme of cellular glutathione (GSH) biosynthesis, has been frequently observed.     

Hypoxia-inducible factor 1 signalling,metabolism and its therapeutic potential in cardiovascular disease

Cardiovascular disease (CVD) accounts for the largest number of deaths worldwide, necessitating the development of novel treatments and prevention strategies. Given the huge energy demands placed on the heart, it is not surprising that changes in energy metabolism play a key role in the development of cardiac dysfunction in CVD. A reduction in oxygen delivery to the heart, hypoxia, is sensed and responded to by the hypoxia-inducible factor (HIF) and its family of proteins, by regulating the oxygen-dependent signalling cascade and subsequent response. Hypoxia is one of the main drivers of metabolic change in ischaemic disease and myocardial infarction, and we therefore suggest that HIF may be an attractive therapeutic target. In this review, we assess cardiac energy metabolism in health and disease, and how these can be regulated by HIF-1α activation. We then present an overview of research in the field of hypoxia-mimetic drugs recently developed in other treatment fields, which provide insight into the potential of systemic HIF-1α activation therapy for treating the heart.     

DNA methylation and histone deacetylation regulating insulin sensitivity due to chronic cold exposure

In this study, we investigated the causal relationship between chronic cold exposure and insulin resistance and the mechanisms of how DNA methylation and histone deacetylation regulate cold-reduced insulin resistance. 46 adult male mice from postnatal day 90–180 were randomly assigned to control group and cold-exposure group. Mice in cold-exposure group were placed at temperature from -1 to 4 °C for 30 days to mimic chronic cold environment. Then, fasting blood glucose, blood insulin level and insulin resistance index were measured with enzymatic methods. Immunofluorescent labeling was carried out to visualize the insulin receptor substrate 2 (IRS2), Obese receptor (Ob-R, a leptin receptor), voltage-dependent anion channel protein 1 (VDAC1), cytochrome C (cytC), 5-methylcytosine (5-mC) positive cells in hippocampal CA1 area. Furthermore, the expressions of some proteins mentioned above were detected with Western blot. The results showed: ① Chronic cold exposure could reduce the insulin resistance index (P < 0.01) and increase the number of IRS2 positive cells and Ob-R positive cells in hippocampus (P < 0.01). ② The expressions of mitochondrial energy-relative proteins, VDAC1 and cytC, were higher in cold-exposure group than in control group with both immunohistochemical staining and Western blot (P < 0.01). ③ Chronic cold exposure increased DNA methylation and histone deacetylation in the pyramidal cells of CA1 area and led to an increase in the expression of histone deacetylase 1 (HDAC1) and DNA methylation relative enzymes (P < 0.01). In conclusion, chronic cold exposure can improve insulin sensitivity, with the involvement of DNA methylation, histone deacetylation and the regulation of mitochondrial energy metabolism. These epigenetic modifications probably form the basic mechanism of cold-reduced insulin resistance.