Melatonin restores hepatic lipid metabolic homeostasis disrupted by blue light at night in high-fat diet-fed mice.

Artificial light at night (ALAN) is an emerging environmental pollutant that threatens public health. Recently, ALAN has been identified as a risk factor for obesity; however, the role of ALAN and its light wavelength in hepatic lipid metabolic homeostasis remains undetermined. We showed that chronic dim (~5 lx) ALAN (dLAN) exposure significantly promoted hepatic lipid accumulation in obese or diabetic mice, with the most severe effect of blue light and little effect of green or red light. These metabolic phenotypes were attributed to blue rather than green or red dLAN interfering with hepatic lipid metabolism, especially lipogenesis and lipolysis. Further studies found that blue dLAN disrupted hepatic lipogenesis and lipolysis processes by inhibiting hepatic REV-ERBs. Mechanistically, feeding behavior mediated the regulation of dLAN on hepatic REV-ERBs. In addition, different effects of light wavelengths at night on liver REV-ERBs depended on the activation of the corticosterone (CORT)/glucocorticoid receptor (GR) axis. Blue dLAN could activate the CORT/GR axis significantly while other wavelengths could not. Notably, we demonstrated that exogenous melatonin could effectively inhibit hepatic lipid accumulation and restore the hepatic GR/REV-ERBs axis disrupted by blue dLAN. These findings demonstrate that dLAN promotes hepatic lipid accumulation in mice via a short-wavelength-dependent manner, and exogenous melatonin is a potential therapeutic approach. This study strengthens the relationship between ALAN and hepatic lipid metabolism and provides insights into directing ambient light.

Lipophagy-Related Protein Perilipin-3 and Resistance of Prostate Cancer to Radiation Therapy.

PURPOSE: Radiation therapy is a principal treatment modality for localized and locally advanced prostate cancer (PCa). Metabolic alterations, including lipid metabolism, may reduce treatment efficacy, resulting in tumor relapse and poor therapeutic outcome. In the current study, we investigated the role of the lipophagy-related protein perilipin-3 (PLIN3) and the lysosomal acid lipase (LAL) in PCa response to radiation therapy. METHODS AND MATERIALS: We explored the in vitro and xenograft (in NOD SCID and R2G2 mice) response to radiation of either PLIN3-depleted or LAL-depleted hormone-refractory (DU145, PC3) and hormone-responsive (22Rv1) PCa cell lines. Moreover, we evaluated the clinical role of PLIN3 and LAL protein expression in a series of PCa tissue specimens from patients treated with radical radiation therapy. RESULTS: In vitro and in vivo experiments showed reduced proliferation and strong radiosensitization of all studied PCa cell lines upon PLIN3 depletion. In vivo experiments demonstrated the significantly augmented radiation therapy efficacy upon PLIN3 depletion, resulting in extensive tissue necrosis. Overexpression of PLIN3 in tissue specimens was correlated with an increased MIB1 proliferation index, increased autophagy flux, reduced response to radiation therapy, and poor prognosis. The effect of LAL depletion on radiation therapy was of lesser importance. CONCLUSIONS: Assessment of PLIN3 expression may identify subgroups of patients with PCa who are less responsive to radiation therapy and at high risk of relapse after irradiation. Whether radiation therapy efficacy may be enhanced by concurrent autophagy or PLIN3 inhibition in this subgroup of patients demands clinical evaluation.

Contribution of Lipid Oxidation and Ferroptosis to Radiotherapy Efficacy.

Radiotherapy promotes tumor cell death and senescence through the induction of oxidative damage. Recent work has highlighted the importance of lipid peroxidation for radiotherapy efficacy. Excessive lipid peroxidation can promote ferroptosis, a regulated form of cell death. In this review, we address the evidence supporting a role of ferroptosis in response to radiotherapy and discuss the molecular regulators that underlie this interaction. Finally, we postulate on the clinical implications for the intersection of ferroptosis and radiotherapy.

Deciphering Differential Life Stage Radioinduced Reproductive Decline in Caenorhabditis elegans through Lipid Analysis.

Wildlife is chronically exposed to various sources of ionizing radiations, both environmental or anthropic, due to nuclear energy use, which can induce several defects in organisms. In invertebrates, reproduction, which directly impacts population dynamics, has been found to be the most radiosensitive endpoint. Understanding the underlying molecular pathways inducing this reproduction decrease can help in predicting the effects at larger scales (i.e., population). In this study, we used a life stage dependent approach in order to better understand the molecular determinants of reproduction decrease in the roundworm C. elegans. Worms were chronically exposed to 50 mGy·h-1 external gamma ionizing radiations throughout different developmental periods (namely embryogenesis, gametogenesis, and full development). Then, in addition to reproduction parameters, we performed a wide analysis of lipids (different class and fatty acid via FAMES), which are both important signaling molecules for reproduction and molecular targets of oxidative stress. Our results showed that reproductive defects are life stage dependent, that lipids are differently misregulated according to the considered exposure (e.g., upon embryogenesis and full development) and do not fully explain radiation induced reproductive defects. Finally, our results enable us to propose a conceptual model of lipid signaling after radiation stress in which both the soma and the germline participate.

Associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation.

The space radiation environment consists of multiple species of charged particles, including 28Si ions, that may impact brain function during and following missions. To develop biomarkers of the space radiation response, BALB/c and C3H female and male mice and their F2 hybrid progeny were irradiated with 28Si ions (350 MeV/n, 0.2 Gy) and tested for behavioral and cognitive performance 1, 6, and 12 months following irradiation. The plasma of the mice was collected for analysis of miRNA levels. Select pertinent brain regions were dissected for lipidomic analyses and analyses of levels of select biomarkers shown to be sensitive to effects of space radiation in previous studies. There were associations between lipids in select brain regions, plasma miRNA, and cognitive measures and behavioral following 28Si ion irradiation. Different but overlapping sets of miRNAs in plasma were found to be associated with cognitive measures and behavioral in sham and irradiated mice at the three time points. The radiation condition revealed pathways involved in neurodegenerative conditions and cancers. Levels of the dendritic marker MAP2 in the cortex were higher in irradiated than sham-irradiated mice at middle age, which might be part of a compensatory response. Relationships were also revealed with CD68 in miRNAs in an anatomical distinct fashion, suggesting that distinct miRNAs modulate neuroinflammation in different brain regions. The associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation could be used for the development of biomarker of the space radiation response.

Proteomics and lipidomics reveal the protective mechanism of dietary n-3 PUFA supplementation for photoaging.

Chronic ultraviolet radiation exposure could induce photoaging, and even carcinogenesis. Dietary omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation has proved to alleviate photoaging and cutaneous carcinoma. Although the exact mechanism remains poorly elucidated, accumulated evidence suggests that the alleviation effect of n-3 PUFA for photoaging is a multifactorial procession characterized by different pathways. Here, we performed a whole-genome proteomics and lipidomics analyses using a self-constructed photoaging mouse model with n-3 PUFA or n-6 PUFA supplementation. Significant alleviation of photoaging was observed, and a total of 88 differentially expressed proteins and 152 differentially expressed lipids were identified in mice with n-3 PUFA supplementation. We found that n-3 PUFA may alleviate photoaging by upregulating Hmmr (hyaluronic acid receptor) expression, which can decrease Mmp9 expression, reducing collagen degradation. As most proteins were associated with lipogenesis and lipid metabolism, we further analyzed the lipidomics data, finding that most triglycerides (93%) showed a significant increase in the n-3 PUFA supplementation group. Our proteomics and lipidomics results indicate that the protective mechanism of n-3 PUFA for photoaging is complicated. Furthermore, the effect of elevated triglycerides by n-3 PUFA supplementation in counteracting skin photoaging cannot be ignored, which will become a new prime target in anti-photoaging.

Late Health Effects of Partial Body Irradiation Injury in a Minipig Model Are Associated with Changes in Systemic and Cardiac IGF-1 Signaling.

Clinical, epidemiological, and experimental evidence demonstrate non-cancer, cardiovascular, and endocrine effects of ionizing radiation exposure including growth hormone deficiency, obesity, metabolic syndrome, diabetes, and hyperinsulinemia. Insulin-like growth factor-1 (IGF-1) signaling perturbations are implicated in development of cardiovascular disease and metabolic syndrome. The minipig is an emerging model for studying radiation effects given its high analogy to human anatomy and physiology. Here we use a minipig model to study late health effects of radiation by exposing male Göttingen minipigs to 1.9-2.0 Gy X-rays (lower limb tibias spared). Animals were monitored for 120 days following irradiation and blood counts, body weight, heart rate, clinical chemistry parameters, and circulating biomarkers were assessed longitudinally. Collagen deposition, histolopathology, IGF-1 signaling, and mRNA sequencing were evaluated in tissues. Our findings indicate a single exposure induced histopathological changes, attenuated circulating IGF-1, and disrupted cardiac IGF-1 signaling. Electrolytes, lipid profiles, liver and kidney markers, and heart rate and rhythm were also affected. In the heart, collagen deposition was significantly increased and transforming growth factor beta-1 (TGF-beta-1) was induced following irradiation; collagen deposition and fibrosis were also observed in the kidney of irradiated animals. Our findings show Göttingen minipigs are a suitable large animal model to study long-term effects of radiation exposure and radiation-induced inhibition of IGF-1 signaling may play a role in development of late organ injuries.

Targeted peripheral focused ultrasound stimulation attenuates obesity-induced metabolic and inflammatory dysfunctions.

Obesity, a growing health concern, is associated with an increased risk of morbidity and mortality. Chronic low-grade inflammation is implicated in obesity-driven metabolic complications. Peripheral focused ultrasound stimulation (pFUS) is an emerging non-invasive technology that modulates inflammation. Here, we reasoned that focused ultrasound stimulation of the liver may alleviate obesity-related inflammation and other comorbidities. After 8 weeks on a high-fat high-carbohydrate "Western" diet, C57BL/6J mice were subjected to either sham stimulation or focused ultrasound stimulation at the porta hepatis. Daily liver-focused ultrasound stimulation for 8 weeks significantly decreased body weight, circulating lipids and mitigated dysregulation of adipokines. In addition, liver-focused ultrasound stimulation significantly reduced hepatic cytokine levels and leukocyte infiltration. Our findings demonstrate the efficacy of hepatic focused ultrasound for alleviating obesity and obesity-associated complications in mice. These findings suggest a previously unrecognized potential of hepatic focused ultrasound as a possible novel noninvasive approach in the context of obesity.

Isolation and characterization of Lipomyces starkeyi mutants with greatly increased lipid productivity following UV irradiation.

The oleaginous yeast Lipomyces starkeyi is an intriguing lipid producer that can produce triacylglycerol (TAG), a feedstock for biodiesel production. We previously reported that the L. starkeyi mutant E15 with high levels of TAG production compared with the wild-type was efficiently obtained using Percoll density gradient centrifugation. However, considering its use for biodiesel production, it is necessary to further improve the lipid productivity of the mutant. In this study, we aimed to obtain mutants with better lipid productivity than E15, evaluate its lipid productivity, and analyze lipid synthesis-related gene expression in the wild-type and mutant strains. The mutants E15-11, E15-15, and E15-25 exhibiting higher lipid productivity than E15 were efficiently isolated from cells exposed to ultraviolet light using Percoll density gradient centrifugation. They exhibited approximately 4.5-fold higher lipid productivity than the wild-type on day 3. The obtained mutants did not exhibit significantly different fatty acid profiles than the wild-type and E15 mutant strains. E15-11, E15-15, and E15-25 exhibited higher expression of acyl-CoA synthesis- and Kennedy pathway-related genes than the wild-type and E15 mutant strains. Activation of the pentose phosphate pathway, which supplies NADPH, was also observed. These results suggested that the increased expression of acyl-CoA synthesis- and Kennedy pathway-related genes plays a vital role in lipid productivity in the oleaginous yeast L. starkeyi.

Comparative Study of the Effects of Light Controlled Germination Conditions on Saponarin Content in Barley Sprouts and Lipid Accumulation Suppression in HepG2 Hepatocyte and 3T3-L1 Adipocyte Cells Using Barley Sprout Extracts.

Barley sprouts (BS) contain physiologically active substances and promote various positive physiological functions in the human body. The levels of the physiologically active substances in plants depend on their growth conditions. In this study, BS were germinated using differently colored LED lights and different nutrient supplements. Overall, there were 238 varied BS samples analyzed for their total polyphenol and flavonoid contents. Principal component analysis (PCA) was performed to determine the relationship between the germinated samples and their total polyphenol and flavonoid contents, and those with high levels were further analyzed for their saponarin content. Based on the PCA plot, the optimal conditions for metabolite production were blue light with 0.1% boric acid supplementation. In vitro experiments using the ethanol extract from the BS cultured in blue light showed that the extract significantly inhibited the total lipid accumulation in 3T3-L1 adipocytes and the lipid droplets in HepG2 hepatocytes. These findings suggest that specific and controlled light source and nutrient conditions for BS growth could increase the production of secondary metabolites associated with inhibited fat accumulation in adipocytes and hepatocytes.

Photobiomodulation reduces hepatic lipogenesis and enhances insulin sensitivity through activation of CaMKKß/AMPK signaling pathway.

Photobiomodulation (PBM) could improve systemic blood glucose and insulin resistance in diet-induced diabetic mice. A few possible molecular mechanisms for the beneficial effects of PBM on diabetes have been proposed, but there is still an urgent need to explore the underlying mechanisms that support the application of PBM in the treatment of diabetes. Our study aimed to evaluate the effects of PBM on lipid metabolism in the liver of high-fat diet (HFD)-induced mice and explore the potential mechanisms of PBM on obesity and type 2 diabetes. Here, we administered PBM therapy (wavelength: 635 nm, energy density: 8 J/cm2) daily for eight weeks to HFD-induced mice. We detected that eight-week daily administration of PBM ameliorated HFD-induced gain weight, hyperlipidemia, and hyperglycemia, but also protected against diet-induced hepatic steatosis and insulin resistance. Furthermore, PBM increased AMP-activated protein kinase (AMPK) activation, lowered nuclear translocation of sterol regulatory element binding protein 1 (SREBP1), decreased aberrant lipogenesis, and enhanced insulin sensitive in HFD-induced mice livers. We also observed that Ca2+/calmodulin-dependent protein kinase kinase ß (CaMKKß) activation was responsible for AMPK activation in insulin-resistant HepG2 cells exposed to PBM. In summary, PBM at 635 nm and 8 J/cm2 improved hepatic lipid metabolism and inhibited the development of HFD-induced obesity and type 2 diabetes. Moreover, increased intracellular Ca2+ content and CaMKKß-dependent AMPK activation were possible molecular mechanisms underlying the PBM-induced improvement on obesity and type 2 diabetes.

PPARα mediates night neon light-induced weight gain: role of lipid homeostasis.

Rationale: Light pollution leads to high risk of obesity but the underlying mechanism is not known except for the influence of altered circadian rhythm. Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism, but its role in circadian-related obesity is not clear. Methods: Wild-type (WT) and Ppara-null (KO) mice on a high-fat diet (HFD) were treated with neon light at night for 6 weeks. Body weights were recorded and diet consumption measured. The hypothalamus, liver, adipose and serum were collected for mechanism experimentation. Results: WT mice on a HFD and exposed to night neon light gained about 19% body weight more than the WT control mice without light exposure and KO control mice on a HFD and exposed to night neon light. The increase in adipose tissue weight and adipocyte size led to the differences in body weights. Biochemical analysis suggested increased hepatic lipid accumulated and increased transport of lipid from the liver to peripheral tissues in the WT mice that gained weight under neon light exposure. Unlike KO mice, the expression of genes involved in lipid metabolism and the circadian factor circadian locomotor output cycles kaput (CLOCK) in both liver and adipose tissues were elevated in WT mice under neon light exposure. Conclusions: PPARα mediated weight gain of HFD-treated mice exposed to night neon light. More lipids were synthesized in the liver and transported to peripheral tissue leading to adaptive metabolism and lipid deposition in the adipose tissue. These data revealed an important mechanism of obesity induced by artificial light pollution where PPARα was implicated.

Effects of light-emitting diodes (LEDs) on lipid production of the aerial microalga Coccomyxa sp. KGU-D001 under liquid- and aerial-phase conditions.

Algal biofuels are a promising alternative to fossil fuels, but their widespread use is hindered by problems with mass production. Light-emitting diodes (LEDs) with specific light wavelengths could be used as an energy source for algal growth and lipid synthesis. In this study, the effects of light source on the biomass and lipid production of the aerial microalga Coccomyxa sp. KGU-D001 were evaluated using LEDs. The integration of two-phase cultures, including growth and lipid production under the stress of nitrate depletion, was assessed for efficient lipid production under liquid- or aerial-phase conditions. Different wavelengths of light (blue, green, and red) were tested under liquid- and aerial-phase conditions. Under aerial-phase culture, the fatty acid contents in biofilm reached 320 mg g DWC-1 with the red LEDs. In view of these findings, we describe a one-step culture method for growth and lipid accumulation in algal biofilm under aerial-phase culture with red LED irradiation. When Coccomyxa biofilm was cultured on wet cotton wool with BBM in a petri dish under the red LED, it was able to grow and accumulate lipids under the aerial-phase condition. Based on the results of this study, a potential method for a continuous biodiesel production system is proposed.

Cannabidiol-Mediated Changes to the Phospholipid Profile of UVB-Irradiated Keratinocytes from Psoriatic Patients.

UVB phototherapy is treatment for psoriasis, which increases phospholipid oxidative modifications in the cell membrane of the skin. Therefore, we carried out lipidomic analysis on the keratinocytes of healthy individuals and patients with psoriasis irradiated with UVB and treated with cannabidiol (CBD), phytocannabinoid with antioxidant and anti-inflammatory properties. Our results showed that, in psoriatic keratinocytes phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidylserine (PS), and ether-linked phosphoethanolamine (PEo), were downregulated, while SM (d41:2) was upregulated. These changes were accompanied by an increase in negative zeta potential, which indicates translocation of PS to the outer layer of the membrane. CBD treatment of psoriatic keratinocytes led to downregulation of PC, PS, and upregulation of certain PEo and an SM species, SM (d42:2), and the zeta potential. However, UVB irradiation of psoriatic keratinocytes resulted in upregulation of PC, PC plasmalogens (PCp), PEo, and a decrease in the negative zeta potential. The exposure of UVB-irradiated cells to CBD led to a decrease in the level of SM (d42:2). Our results suggest that CBD induces pro-apoptotic mechanisms in psoriatic keratinocytes while simultaneously improving the antioxidant properties and preventing the loss of transepidermal water of keratinocytes of patients irradiated with UVB. Thus, CBD has potential therapeutic value in the treatment of psoriasis.

Gene Expression Profiles from Heart, Lung and Liver Samples of Total-Body-Irradiated Minipigs: Implications for Predicting Radiation-Induced Tissue Toxicity.

In the event of a major accidental or intentional radiation exposure incident, the affected population could suffer from total- or partial-body exposures to ionizing radiation with acute exposure to organs that would produce life-threatening injury. Therefore, it is necessary to identify markers capable of predicting organ-specific damage so that appropriate directed or encompassing therapies can be applied. In the current work, gene expression changes in response to total-body irradiation (TBI) were identified in heart, lungs and liver tissue of Göttingen minipigs. Animals received 1.7, 1.9, 2.1 or 2.3 Gy TBI and were followed for 45 days. Organ samples were collected at the end of day 45 or sooner if the animal displayed morbidity necessitating euthanasia. Our findings indicate that different organs respond to TBI in a very specific and distinct manner. We also found that the liver was the most affected organ in terms of gene expression changes, and that lipid metabolic pathways were the most deregulated in the liver samples of non-survivors (survival time <45 days). We identified organ-specific gene expression signatures that accurately differentiated non-survivors from survivors and control animals, irrespective of dose and time postirradiation. At what point did these radiation-induced injury markers manifest and how this information could be used for applying intervention therapies are under investigation.

Chronic Occupational Exposure to Ionizing Radiation Induces Alterations in the Structure and Metabolism of the Heart: A Proteomic Analysis of Human Formalin-Fixed Paraffin-Embedded (FFPE) Cardiac Tissue.

Epidemiological studies on workers employed at the Mayak plutonium enrichment plant have demonstrated an association between external gamma ray exposure and an elevated risk of ischemic heart disease (IHD). In a previous study using fresh-frozen post mortem samples of the cardiac left ventricle of Mayak workers and non-irradiated controls, we observed radiation-induced alterations in the heart proteome, mainly downregulation of mitochondrial and structural proteins. As the control group available at that time was younger than the irradiated group, we could not exclude age as a confounding factor. To address this issue, we have now expanded our study to investigate additional samples using archival formalin-fixed paraffin-embedded (FFPE) tissue. Importantly, the control group studied here is older than the occupationally exposed (>500 mGy) group. Label-free quantitative proteomics analysis showed that proteins involved in the lipid metabolism, sirtuin signaling, mitochondrial function, cytoskeletal organization, and antioxidant defense were the most affected. A histopathological analysis elucidated large foci of fibrotic tissue, myocardial lipomatosis and lymphocytic infiltrations in the irradiated samples. These data highlight the suitability of FFPE material for proteomics analysis. The study confirms the previous results emphasizing the role of adverse metabolic changes in the radiation-associated IHD. Most importantly, it excludes age at the time of death as a confounding factor.

Crosstalk between sterol and neutral lipid metabolism in the alga Haematococcus pluvialis exposed to light stress.

The presence, biosynthesis and functional role of sterols in the green microalga Haematococcus pluvialis remain poorly understood. In this work we studied the effect of high-light (HL) stress on sterol synthesis in H. pluvialis UTEX 2505 cells. HL stress induced the synthesis of sterols in parallel with that of triacylglycerides (TAG), giving rise to the synthesis of cholesterol over that of phytosterols. Blockage of the carotenogenic 1-deoxy-D-xylulose 5-phosphate (MEP) pathway is shown to be involved in HL-induced sterol synthesis. In addition, high irradiance exposure induced MEP- and fatty acid (FA)-biosynthetic transcripts. The pharmacological inhibition of these pathways suggests a possible feedback regulation of sterol and FA homeostasis. Finally, both lipid classes proved crucial to the adequate photosynthetic performance of H. pluvialis grown under HL intensity stress. Our findings reveal new insights into H. pluvialis lipid metabolism that contribute to the development of value-added bioproducts from microalgae.

High light induces species specific changes in the membrane lipid composition of Chlorella.

Algae have evolved several mechanisms to adjust to changing environmental conditions. To separate from their surroundings, algal cell membranes form a hydrophobic barrier that is critical for life. Thus, it is important to maintain or adjust the physical and biochemical properties of cell membranes which are exposed to environmental factors. Especially glycerolipids of thylakoid membranes, the site of photosynthesis and photoprotection within chloroplasts, are affected by different light conditions. Since little is known about membrane lipid remodeling upon different light treatments, we examined light induced alterations in the glycerolipid composition of the two Chlorella species, C. vulgaris and C. sorokiniana, which differ strongly in their ability to cope with different light intensities. Lipidomic analysis and isotopic labeling experiments revealed differences in the composition of their galactolipid species, although both species likely utilize galactolipid precursors originated from the endoplasmic reticulum. However, in silico research of de novo sequenced genomes and ortholog mapping of proteins putatively involved in lipid metabolism showed largely conserved lipid biosynthesis pathways suggesting species specific lipid remodeling mechanisms, which possibly have an impact on the response to different light conditions.

Peripheral circadian rhythms in the liver and white adipose tissue of mice are attenuated by constant light and restored by time-restricted feeding.

Disturbance of circadian rhythms underlies various metabolic diseases. Constant light exposure (LL) is known to disrupt both central and peripheral circadian rhythms. Here, we attempted to determine whether the effects of LL are different between various peripheral tissues and whether time-restricted feeding restores the circadian rhythms especially in white adipose tissue (WAT). Six-week-old mice were subjected to three feeding regimes: ad libitum feeding under light/dark phase (LD), ad libitum feeding under LL cycle, and restricted feeding at night-time under LL cycle with a normal chow. After 3 weeks, we compared body weight, food intake, plasma levels of lipids and glucose, and the expression patterns of the clock genes and the genes involved in lipid metabolism in the liver and WAT. The mice kept under LL with or without time-restricted feeding were 5.2% heavier (p<0.001, n = 16) than the mice kept under LD even though the food intakes of the two groups were the same. Food intake occurred mostly in the dark phase. LL disrupted this pattern, causing disruptions in circadian rhythms of plasma levels of triglycerides (TG) and glucose. Time-restricted feeding partially restored the rhythms. LL eliminated the circadian rhythms of the expression of the clock genes as well as most of the genes involved in lipid metabolism in both liver and WAT. More notably, LL markedly decreased not only the amplitude but also the average levels of the expression of the genes in the liver, but not in the WAT, suggesting that transcription in the liver is sensitive to constant light exposure. Time-restricted feeding restored the circadian rhythms of most of the genes to various degrees in both liver and WAT. In conclusion, LL disrupted the peripheral circadian rhythms more severely in liver than in WAT. Time-restricted feeding restored the circadian rhythms in both tissues.

Dose threshold for radiation induced fetal programming in a mouse model at 4 months of age: Hepatic expression of genes and proteins involved in glucose metabolism and glucose uptake in brown adipose tissue.

Exposure to ionizing radiation contributing to negative health outcomes is a widespread concern. However, the impact of low dose and sub-lethal dose radiation (SLDR) exposures remain contentious, particularly in pregnant women who represent a vulnerable group. The fetal programming hypothesis states that an adverse in utero environment or stress during development of an embryo or fetus can result in permanent physiologic changes often resulting in progressive metabolic dysfunction with age. To assess changes in gene expression profiles of glucose/insulin signaling and lipid metabolism caused by radiation exposure in utero, pregnant C57Bl/6J mice were irradiated using a dose response ranging from low dose to SLDR and compared to a Sham-irradiated group. mRNA expression analysis in 16 week old offspring (n = 84) revealed that genes involved in metabolic function including glucose metabolism, insulin signaling and lipid metabolism were unaffected by prenatal radiation exposures up to 300 mGy. However, female offspring of dams exposed to 1000 mGy had upregulated expression of genes contributing to insulin resistance and gluconeogenesis. In a second cohort of mice, the effects of SLDR on fetal programming of hepatic SOCS3 and PEPCK protein expression were assessed. 4 month old female offspring of dams irradiated at 1000 mGy had: 1) increased liver weights, 2) increased hepatic expression of proteins involved in glucose metabolism and 3) increased 18F-fluorodeoxyglucose (FDG) uptake in interscapular brown adipose tissue (IBAT) measured by positron emission tomography (PET) (n = 25). The results of this study indicate that prenatal radiation exposure does not affect metabolic function up to 300 mGy and 1000 mGy may be a threshold dose for sex-specific alterations in glucose uptake and hepatic gene and protein expression of SOCS3, PEPCK, PPARGC1A and PPARGC1B. These findings suggest that SLDR doses alter glucose uptake in IBAT and hepatic gene and protein expression of offspring and these changes may progress with age.