Circadian alignment of feeding regulates lifespan extension by caloric restriction

Abstract Caloric restriction (CR) promotes longevity in several species. Classic CR protocols often lead to chronic cycles of 2h-feeding/22h-fasting, raising the question whether calories, fasting or time of day are causal. To address this, we tested an AL control group and five CR protocols with different timing and duration of feeding/fasting cycles. C57BL/6J male mice were subjected to 30% CR as one single meal a day at the beginning of the day or night (classical protocols with < 2h feeding, CR-day and CR-night), or smaller meals distributed for 12h (CR-day-12h and CR-night-12h), or evenly spread out throughout 24h (CR-spread) to abolish the otherwise daily feeding pattern adopted by nocturnal animals. We found that CR alone is sufficient to extend lifespan without fasting. However, the benefits are enhanced if feeding/fasting cycles are present and match their normal nocturnal activity. Circadian alignment of feeding with at least 12h fasting boosts CR-mediated increase on survival in mice, independently body weight. Aging leads to widespread upregulation of inflammation-related genes and downregulation of metabolic pathways in liver from ad lib fed mice; whereas CR at night ameliorates these aging-related changes and preserves circadian oscillations in gene expression. Overall, our results demonstrate that circadian interventions promote longevity and provide a novel perspective for elucidating mechanisms of aging.

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Anti-Obesity and Anti-Adipogenic Effects of Chitosan Oligosaccharide (GO2KA1) in SD Rats and in 3T3-L1 Preadipocytes Models

Molecules ◽

10.3390/molecules26020331 ◽

2021 ◽

Vol 26 (2) ◽

pp. 331

Author(s):

Jung-Yun Lee ◽

Tae Yang Kim ◽

Hanna Kang ◽

Jungbae Oh ◽

Joo Woong Park ◽

...

Keyword(s):

Gene Expression ◽

Body Weight ◽

Density Lipoprotein ◽

Treated Group ◽

Control Group ◽

Chitosan Oligosaccharide ◽

Sd Rats ◽

Adipogenic Gene

Excess body weight is a major risk factor for type 2 diabetes (T2D) and associated metabolic complications, and weight loss has been shown to improve glycemic control and decrease morbidity and mortality in T2D patients. Weight-loss strategies using dietary interventions produce a significant decrease in diabetes-related metabolic disturbance. We have previously reported that the supplementation of low molecular chitosan oligosaccharide (GO2KA1) significantly inhibited blood glucose levels in both animals and humans. However, the effect of GO2KA1 on obesity still remains unclear. The aim of the study was to evaluate the anti-obesity effect of GO2KA1 on lipid accumulation and adipogenic gene expression using 3T3-L1 adipocytes in vitro and plasma lipid profiles using a Sprague-Dawley (SD) rat model. Murine 3T3-L1 preadipocytes were stimulated to differentiate under the adipogenic stimulation in the presence and absence of varying concentrations of GO2KA1. Adipocyte differentiation was confirmed by Oil Red O staining of lipids and the expression of adipogenic gene expression. Compared to control group, the cells treated with GO2KA1 significantly decreased in intracellular lipid accumulation with concomitant decreases in the expression of key transcription factors, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (CEBP/α). Consistently, the mRNA expression of downstream adipogenic target genes such as fatty acid binding protein 4 (FABP4), fatty acid synthase (FAS), were significantly lower in the GO2KA1-treated group than in the control group. In vivo, male SD rats were fed a high fat diet (HFD) for 6 weeks to induced obesity, followed by oral administration of GO2KA1 at 0.1 g/kg/body weight or vehicle control in HFD. We assessed body weight, food intake, plasma lipids, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) for liver function, and serum level of adiponectin, a marker for obesity-mediated metabolic syndrome. Compared to control group GO2KA1 significantly suppressed body weight gain (185.8 ± 8.8 g vs. 211.6 ± 20.1 g, p < 0.05) with no significant difference in food intake. The serum total cholesterol, triglyceride, and low-density lipoprotein (LDL) levels were significantly lower in the GO2KA1-treated group than in the control group, whereas the high-density lipoprotein (HDL) level was higher in the GO2KA1 group. The GO2KA1-treated group also showed a significant reduction in ALT and AST levels compared to the control. Moreover, serum adiponectin levels were significantly 1.5-folder higher than the control group. These in vivo and in vitro findings suggest that dietary supplementation of GO2KA1 may prevent diet-induced weight gain and the anti-obesity effect is mediated in part by inhibiting adipogenesis and increasing adiponectin level.

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Lipolysis defect in white adipose tissue and rapid weight regain

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00542.2018 ◽

2019 ◽

Vol 317 (2) ◽

pp. E185-E193 ◽

Cited By ~ 1

Author(s):

Michal Kasher-Meron ◽

Dou Y. Youn ◽

Haihong Zong ◽

Jeffery E. Pessin

Keyword(s):

Weight Loss ◽

Body Weight ◽

Adipose Tissue ◽

Caloric Restriction ◽

White Adipose Tissue ◽

Weight Regain ◽

Serine Phosphorylation ◽

Lean Body Weight ◽

Control Group ◽

Short Period

Weight regain after weight loss is a well-described phenomenon in both humans and animal models of obesity. Reduced energy expenditure and increased caloric intake are considered the main drivers of weight regain. We hypothesized that adipose tissue with obesity memory (OM) has a tissue-autonomous lipolytic defect, allowing for increased efficiency of lipid storage. We utilized a mouse model of diet-induced obesity, which was subjected to 60% caloric restriction to achieve lean body weight, followed by a short period of high-fat diet (HFD) rechallenge. Age-matched lean mice fed HFD for the first time were used as the control group. Upon rechallenge with HFD, mice with OM had higher respiratory exchange ratios than lean mice with no OM despite comparable body weight, suggesting higher utilization of glucose over fatty acid oxidation. White adipose tissue explants with OM had comparable lipolytic response after caloric restriction; however, reduced functional lipolytic response to norepinephrine was noted as early as 5 days after rechallenge with HFD and was accompanied by reduction in hormone-sensitive lipase serine phosphorylation. The relative lipolytic defect was associated with increased expression of inflammatory genes and a decrease in adrenergic receptor genes, most notably Adrb3. Taken together, white adipose tissue of lean mice with OM shows increased sensitization to HFD compared with white adipose tissue with no OM, rendering it resistant to catecholamine-induced lipolysis. This relative lipolytic defect is tissue-autonomous and could play a role in the rapid weight regain observed after weight loss.

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Effect of neonatal hyperthyroidism on GH gene expression reprogramming and physiological repercussions in rat adulthood

Journal of Endocrinology ◽

10.1677/joe.1.06371 ◽

2006 ◽

Vol 190 (2) ◽

pp. 407-414 ◽

Cited By ~ 7

Author(s):

Kely de Picoli Souza ◽

Francemilson Goulart da Silva ◽

Maria Tereza Nunes

Keyword(s):

Gene Expression ◽

Body Weight ◽

Adult Life ◽

Control Group ◽

Postnatal Life ◽

Mrna Levels ◽

Mineral Density ◽

Thyroid State ◽

Gh Gene ◽

Neonatal Hyperthyroidism

The neonatal period (NP) is a critical phase of the development in which the expression pattern of most genes is established. Thyroid hormones (TH) play a key role in this process and, alterations in its availability in the NP may lead to different patterns of gene expression, which might reflect in the permanent expression of several genes in the adulthood. GH gene expression in the pituitary is greatly dependent on TH in the early postnatal life; thus, modifications of thyroid state in NP might lead to alterations in GH gene expression as well as to physiological repercussions in the adult life. This study aimed to investigate this possibility by means of the induction of a neonatal hyperthyroidism in rats (4 μg of 3,5,3′-triiodo-l-thyronine (T3)/100 g body weight, s.c.) for 5, 15 or 30 days, and further evaluation of GH gene expression, as well as its physiological consequences in adult rats subjected to a transient hyperthyroidism in the first 30 days of life. GH mRNA level was shown to be increased in T3-treated rats for 5 days; when the treatment was extended to 15 or 30 days, the GH mRNA levels were similar to the control group. Moreover, rats treated with T3 for 30 days and killed when 90 days old, i.e., 60 days at the end of the T3 treatment, showed decreased GH mRNA content, body weight, bone mineral density, and lean body mass. In conclusion: (1) T3 effects on GH gene expression depend on the period of life in which the hyperthyroidism is set and on the length of T3 treatment in the NP and (2) transient neonatal hyperthyroidism leads to a lower GH mRNA expression in adult life accompanied by physiological repercussions indicative of GH deficiency.

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Identification of Adipocyte Genes Regulated by Caloric Intake

Endocrinology ◽

10.1210/endo.151.12.9993 ◽

2010 ◽

Vol 151 (12) ◽

pp. 5973-5973

Author(s):

Niclas Franck ◽

Anders Gummesson ◽

Margareta Jernås ◽

Camilla Glad ◽

Per-Arne Svensson ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Body Weight ◽

Protein Synthesis ◽

Caloric Restriction ◽

Healthy Subjects ◽

Caloric Intake ◽

Multiple Time ◽

Significance Level ◽

Obese Subjects

Context: Changes in energy intake have marked and rapid effects on metabolic functions, and some of these effects may be due to changes in adipocyte gene expression that precede alterations in body weight. Objective: The aim of the study was to identify adipocyte genes regulated by changes in caloric intake independent of alterations in body weight. Research Design and Methods: Obese subjects given a very low-caloric diet followed by gradual reintroduction of ordinary food and healthy subjects subjected to overfeeding were investigated. Adipose tissue biopsies were taken at multiple time-points, and gene expression was measured by DNA microarray. Genes regulated in the obese subjects undergoing caloric restriction followed by refeeding were identified using two-way ANOVA corrected with Bonferroni. From these, genes regulated by caloric restriction and oppositely during the weight-stable refeeding phase were identified in the obese subjects. The genes that were also regulated, in the same direction as the refeeding phase, in the healthy subjects after overfeeding were defined as being regulated by caloric intake. Results were confirmed using real-time PCR or immunoassay. Results: Using a significance level of P < 0.05 for all comparisons, 52 genes were down-regulated, and 50 were up-regulated by caloric restriction and regulated in the opposite direction by refeeding and overfeeding. Among these were genes involved in lipogenesis (ACLY, ACACA, FASN, SCD), control of protein synthesis (4EBP1, 4EBP2), β-oxidation (CPT1B), and insulin resistance (PEDF, SPARC). Conclusions: Metabolic genes involved in lipogenesis, protein synthesis, and insulin resistance are central in the transcriptional response of adipocytes to changes in caloric intake.

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Evaluation of the effective dose of amygdalin for the improvement of antioxidant gene expression and suppression of oxidative damage in mice

PeerJ ◽

10.7717/peerj.9232 ◽

2020 ◽

Vol 8 ◽

pp. e9232

Author(s):

Sarah Albogami ◽

Aziza Hassan ◽

Nibal Ahmed ◽

Alaa Alnefaie ◽

Afnan Alattas ◽

...

Keyword(s):

Gene Expression ◽

Lipid Peroxidation ◽

Superoxide Dismutase ◽

Body Weight ◽

High Dose ◽

Male Mice ◽

Antioxidant Gene ◽

Oxidative Balance ◽

Antioxidant Gene Expression ◽

Medium Dose

Background Little is known regarding the toxic and therapeutic doses of amygdalin. Treatment regimens and schedules can vary between humans and animal models, and there have been reports of cyanide toxicity due to amygdalin use. Objective The aim of this study was to evaluate the effect of different doses of amygdalin on antioxidant gene expression and suppression of oxidative damage in mice. Methods Forty adult male mice were divided randomly into four groups (n = 10) as follows and treated orally for two weeks: a control group treated with saline solution, a group treated with amygdalin at 200 mg/kg body weight, a group treated with amygdalin at 100 mg/kg body weight, and a group treated with amygdalin at 50 mg/kg body weight. Liver and testis samples were collected for gene expression, biochemical and histopathological analyses. Results The mice treated with medium-dose amygdalin (100 mg/kg) showed upregulated mRNA expression of glutathione peroxidase (P < 0.01) and superoxide dismutase (P < 0.05) and significantly decreased lipid peroxidation (P < 0.05) in hepatic and testicular tissues compared to those in the untreated groups (controls), with mild histopathological effects. The mice treated with high-dose of amygdalin (200 mg/kg) showed downregulated mRNA expression of glutathione peroxidase and superoxide dismutase (P < 0.01) and significantly increased lipid peroxidation (P < 0.05) in both hepatic and testicular tissues compared to those in the untreated groups (controls), with an apparent effect at the histopathological level. No effects were observed in the mice treated with low-dose amygdalin (50 mg/kg) at the gene, protein and histopathological level. Conclusion Low-and medium-dose amygdalin did not induce toxicity in the hepatic and testicular tissues of male mice, unlike high-dose amygdalin, which had a negative effect on oxidative balance in mice. Therefore, amygdalin at a moderate dose may improve oxidative balance in mice.

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Complementary effects of coenzyme Q10 and Lepidium sativum supplementation on the reproductive function of mice: An experimental study

International Journal of Reproductive BioMedicine ◽

10.18502/ijrm.v19i7.9471 ◽

2021 ◽

Author(s):

Fatemeh Rahimi Asl ◽

Maryam Khosravi ◽

Ramin Hajikhani ◽

Jalal Solati ◽

Hossein Fahimi

Keyword(s):

Body Weight ◽

Luteinizing Hormone ◽

Coenzyme Q10 ◽

Follicle Stimulating Hormone ◽

Reproductive Function ◽

Serum Testosterone ◽

Lepidium Sativum ◽

Control Group ◽

Male Mice ◽

Weight Groups

Background: Coenzyme Q10 (CoQ10) and Lepidium sativum (LS) have therapeutic effects on infertility. Objective: To evaluate the combined effects of LS and CoQ10 on reproductive function in adult male NMRI mice. Materials and Methods: Eighty three-months-old male mice (35–40 gr) were divided into four groups (n = 10/each): control (treated with water), CoQ10-treated (200, 300, and 400 mg/kg/body weight), LS-treated (200, 400, 600 mg/kg/body weight), and co-treated (LS [600 mg/kg/body weight] + CoQ10 [200 mg/kg/body weight]) groups. Serum testosterone, luteinizing hormone, follicle-stimulating hormone, and gonadotropin realizing hormone (GnRH) levels were measured using ELISA method. The sperm quality was assessed using Sperm Class Analyzer® (SCA) CASA system and GnRH mRNA expression levels were evaluated by real-time polymerase chain reaction. Results: The number of sniffing and following behavior was significantly higher in LStreated (400 and 600 mg/ml/body weight) groups than the control group (p = 0.0007 and p = 0.0010, respectively). The number of mounting and coupling behaviors was significantly higher in the CoQ10 (300 and 400 mg/ml/body weight)-treated animals than the control group (p = 0.0170 and p = 0.0006, respectively). Co-treatment of CoQ10 (200 mg/ml/body weight) and LS (600 mg/ml/body weight) significantly increased all aspects of sexual behaviors as well as the levels of serum testosterone (p = 0.0011), luteinizing hormone (p = 0.0062), and follicle-stimulating hormone (p = 0.0001); sperm viability (p = 0.0300) and motility (p = 0.0010); and GnRH mRNA levels (p = 0.0016) compared to the control group. Conclusion: The coadministration of CoQ10 and LS significantly improves the activity of the hypothalamic-pituitary-gonadal axis and enhances the reproductive parameters in adult male mice. Key words: Lepidium sativum, Coenzyme Q10, Infertility, Male reproductive function.

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The Effects of Amoxicillin, Cefazolin, and Gentamicin Antibiotics on the Antioxidant System in Mouse Heart Tissues

Protein and Peptide Letters ◽

10.2174/0929866526666191112125949 ◽

2020 ◽

Vol 27 (7) ◽

pp. 614-622

Author(s):

Ahmet Savcı ◽

Enver Fehim Koçpınar ◽

Harun Budak ◽

Mehmet Çiftci ◽

Melda Şişecioğlu

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Free Radicals ◽

Enzyme Activities ◽

Control Group ◽

Mouse Heart ◽

Male Mice ◽

Expression Levels ◽

Improper Use ◽

Gene Expression Levels

Background: Free radicals lead to destruction in various organs of the organism. The improper use of antibiotics increases the formation of free radicals and causes oxidative stress. Objective: In this study, it was aimed to determine the effects of gentamicin, amoxicillin, and cefazolin antibiotics on the mouse heart. Methods: 20 male mice were divided into 4 groups (1st control, 2nd amoxicillin, 3rd cefazolin, and 4th gentamicin groups). The mice in the experimental groups were administered antibiotics intraperitoneally at a dose of 100 mg / kg for 6 days. The control group received normal saline in the same way. The gene expression levels and enzyme activities of SOD, CAT, GPx, GR, GST, and G6PD antioxidant enzymes were investigated. Results : GSH levels decreased in both the amoxicillin and cefazolin groups, while GR, CAT, and SOD enzyme activities increased. In the amoxicillin group, Gr, Gst, Cat, and Sod gene expression levels increased. Conclusion: As a result, it was concluded that amoxicillin and cefazolin caused oxidative stress in the heart, however, gentamicin did not cause any effects.

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Abstract P141: Cardiac TRH Partly Mediates Angiotensin II-induced Fibrotic and Hypertrophy Effects in "in vivo" and "in vitro" Models

Hypertension ◽

10.1161/hyp.66.suppl_1.p141 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Silvia I García ◽

Ludmila S Peres Diaz ◽

Maia Aisicovich ◽

Mariano L Schuman ◽

María S Landa

Keyword(s):

Gene Expression ◽

Body Weight ◽

Cardiac Hypertrophy ◽

Structural Changes ◽

In Vitro Models ◽

Heart Weight ◽

Saline Control ◽

Control Group

Cardiac TRH (cTRH) is overexpressed in the hypertrophied ventricle (LV) of the SHR. Additionally in vivo siRNA-TRH treatment induced downregulation of LV-TRH preventing cardiac hypertrophy and fibrosis demonstrating that TRH is involved in hypertrophic and fibrotic processes. Moreover, in a normal heart, the increase of LV TRH expression alone could induce structural changes where fibrosis and hypertrophy could be involved, independently of any other system alterations. Is well-known the cardiac hypertrophy/ fibrotic effects induced by AII, raising the question of whether specific LV cTRH inhibition might attenuates AII induced cardiac hypertrophy and fibrosis in mice. We challenged C57 mice with AII (osmotic pumps,14 days; 2 mg/kg) to induce cardiac hypertrophy vs saline. Groups were divided and , simultaneously to pump surgery, injected intracardiac with siRNA-TRH and siRNA-Con as its control. Body weight, water consume and SABP were measured daily. As expected, AII significantly increased SABP (p<0.05) in both groups treated , although cardiac hypertrophy (heart weight/body weight) was only evident in the group with the cardiac TRH system undamaged, suggesting that the cardiac TRH system function as a necessary mediator of the AII-induced hypertrophic effect. As hypothesized, we found an AII-induced increase of TRH (p<0.05) gene expression (real-t PCR) confirmed by immunofluorescence that was not observed in the group AII+siRNA-TRH demonstrating the specific siRNA treatment efficiency. Furthermore, AII significantly increase (p<0.05) BNP (hypertrophic marker), III collagen and TGFB (fibrosis markers) expressions only in the group with AII with the cardiac TRH system intact. On the contrary, the group with AII and the cTRH system inhibited, shows genes expressions similar to the saline control group. We confirmed these results by immunofluorescence. Similar fibrotic results were observed with NIH3T3 cell culture where we demonstrated that AII induced TRH gene expression (p<0.05) and its inhibition impedes AII-induced increase of TGFB and III/I collagens expressions telling us about the role of the cTRH in the AII fibrosis effects. Our results point out that the cardiac TRH is involved in the AII-induced hypertrophic and fibrotic effects.

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EFFECT OF CALORIC RESTRICTION AND RAPAMYCIN ON OVARIAN AGING IN MICE

Innovation in Aging ◽

10.1093/geroni/igz038.385 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S103-S103

Author(s):

Driele Garcia ◽

Tatiana Saccon ◽

Joao Rincon ◽

Jorgea Pradiee ◽

Rafael Mondadori ◽

...

Keyword(s):

Gene Expression ◽

Body Weight ◽

Caloric Restriction ◽

Primordial Follicle ◽

Tolerance Test ◽

Metabolic Effects ◽

Primordial Follicles ◽

Female Mice ◽

Insulin Tolerance ◽

Follicular Reserve

Abstract The ovarian follicular reserve of primordial follicle declines with aging in female mammals. Caloric restriction (CR) has been shown to increase the preservation of the ovarian follicular reserve. Likewise, rapamycin has similar effects to CR on the ovarian reserve. Therefore, the aim of our study was to evaluate the effects of rapamycin and CR on the metabolism and ovarian follicular reserve and gene expression in mice. Thirty-six female mice were used, and allocated into 3 groups: control, rapamycin (4mg/kg body weight every other day) and 30% CR. At 85 days of treatment, an insulin tolerance test (ITT) and glucose tolerance test (GTT) was performed. At 93 days ovaries were collected for analysis. CR females had lower body weight (P<0.05) and were more insulin sensitive (P=0.003), while rapamycin treated females did not change body weight (P>0.05) and were more resistant to insulin (P<0.05). Females from the CR and rapamycin groups had a twice higher number of primordial follicles (P=0.02 and 0.04) and half the number of primary, secondary and tertiary follicles (P<0.05). Both CR and rapamycin females had increased ovarian gene expression of Foxo3a mRNA (P<0.05). In conclusion, female mice from rapamycin and CR groups had an increased ovarian follicular reserve associated to higher expression of Foxo3a mRNA, despite divergent metabolic effects of the treatments.

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