Publications by authors named "Oren Froy"

83 Publications

REV-ERBα alters circadian rhythms by modulating mTOR signaling.

Mol Cell Endocrinol 2021 02 5;521:111108. Epub 2020 Dec 5.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 76100, Israel. Electronic address:

REV-ERBα is a nuclear receptor that inhibits Bmal1 transcription as part of the circadian clock molecular mechanism. Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell and whole-body energy homeostasis, that serves as an important link between metabolism and circadian clock, in part, by regulating BMAL1 activity. While the connection of REV-ERBα to the circadian clock molecular mechanism is well characterized, the interaction between mTORC1, REV-ERBα and the circadian clock machinery is not very clear. We used leucine and rapamycin to modulate mTORC1 activation and evaluate this effect on circadian rhythms. In the liver, mTORC1 was inhibited by leucine. REV-ERBα overexpression activated the mTORC1 signaling pathway via transcription inhibition of mTORC1 inhibitor, Tsc1, antagonizing the effect of leucine, while its silencing downregulated mTORC1 signaling. Activation of mTORC1 led to increased BMAL1 phosphorylation. Activation as well as inhibition of mTORC1 led to altered circadian rhythms in mouse muscle. Inhibition of liver mTORC1 by leucine or rapamycin led to low-amplitude circadian rhythms. In summary, our study shows that leucine inhibits liver mTORC1 pathway leading to dampened circadian rhythms. REV-ERBα activates the mTORC1 pathway, leading to phosphorylation of the clock protein BMAL1.
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http://dx.doi.org/10.1016/j.mce.2020.111108DOI Listing
February 2021

Development of Criteria for a Positive Front-of-Package Food Labeling: The Israeli Case.

Nutrients 2020 Jun 23;12(6). Epub 2020 Jun 23.

Nutrition Division, Ministry of Health, Jerusalem 9101002, Israel.

Efforts to shape the food environment are aimed at reducing diet-related co-morbidities. Front-of-package labeling (FOPL) may support the consumers to make an informed decision at the point of purchase and encourage industry to reformulate food products. The Israeli Ministry of Health (MOH) implemented a unique FOPL system, using two colors: A mandatory warning (red) label alongside a voluntary positive (green) label. An independent Scientific Committee, from academia, the healthcare system, and MOH was appointed to determine the core principles for the positive FOPL. The criteria were based on the Mediterranean diet principles, with adjustments to the Israeli dietary habits, focusing on the health advantages of the food and considering its processing level. The food products eligible for positive FOPL are foods in their natural form or with added spices or herbs, or those that underwent minimal processing, with no food additives. Based on population consumption data, 19.8% of food products were eligible for positive FOPL; of them, 54% were fruits and vegetables, 20% dairy, and 14% grains. An evaluation plan is needed to assess the degree of acceptance of the positive FOPL by the industry, retailers, and the public, and its impact on food consumption and on public health.
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http://dx.doi.org/10.3390/nu12061875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353345PMC
June 2020

REV-ERBα activates the mTOR signalling pathway and promotes myotubes differentiation.

Biol Cell 2020 Aug 7;112(8):213-221. Epub 2020 May 7.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 76100, Israel.

Background Information: Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell and whole-body energy homoeostasis. REV-ERBα is a nuclear receptor that plays an important role in metabolism. While mTORC1 activation is necessary for muscle differentiation, the role of REV-ERBα is less clear.

Results: We studied the effect of REV-ERBα overexpression and silencing as well as mTORC1 activation and inhibition on the differentiation of C2C12 myoblasts to myotubes. mTOR, myogenin and REV-ERBα were induced during differentiation of myoblasts into myotubes. REV-ERBα was found to activate mTORC1 during the differentiation process even in the absence of the differentiation medium. This activation was presumably through the downregulation of the expression of TSC1, an mTORC1 inhibitor.

Conclusion: Herein we show that REV-ERBα promotes myoblasts differentiation via the activation of the mTORC1 signalling pathway.

Significance: REV-ERBα modulation can activate mTORC1 signalling and promote myoblasts differentiation.
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http://dx.doi.org/10.1111/boc.201900091DOI Listing
August 2020

Response to Comment on Jakubowicz et al. Reduction in Glycated Hemoglobin and Daily Insulin Dose Alongside Circadian Clock Upregulation in Patients With Type 2 Diabetes Consuming a Three-Meal Diet: A Randomized Clinical Trial. Diabetes Care 2019;42:2171-2180.

Authors:
Oren Froy

Diabetes Care 2020 01;43(1):e13-e14

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel

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http://dx.doi.org/10.2337/dci19-0061DOI Listing
January 2020

Non-obesogenic doses of palmitate disrupt circadian metabolism in adipocytes.

Adipocyte 2019 12;8(1):392-400

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.

Saturated fatty acids, such as palmitate, lead to circadian disruption. We aimed at studying the effect of low doses of palmitate on circadian metabolism and to decipher the mechanism by which fatty acids convey their effect in adipocytes. Mice were fed non-obesogenic doses of palm or olive oil and adipocytes were treated with palmitate and oleate. Cultured adipocytes treated with oleate showed increased AMPK activity and induced the expression of mitochondrial genes indicating increased fatty acid oxidation, while palmitate increased ACC activity and induced the expression of lipogenic genes, indicating increased fatty acid synthesis. Low doses of palmitate were sufficient to alter circadian rhythms, due to changes in the expression and/or activity of key metabolic proteins including GSK3β and AKT. Palmitate-induced AKT and GSK3β activation led to the phosphorylation of BMAL1 that resulted in low levels as well as high amplitude of circadian clock expression. In adipocytes, the detrimental metabolic alteration of palmitate manifests itself early on even at non-obesogenic levels. This is accompanied by modulating BMAL1 expression and phosphorylation levels, which lead to dampened clock gene expression.
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http://dx.doi.org/10.1080/21623945.2019.1698791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948973PMC
December 2019

Serotonin Prevents Differentiation of Brown Adipocytes by Interfering with Their Clock.

Obesity (Silver Spring) 2019 12 1;27(12):2018-2024. Epub 2019 Nov 1.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.

Objective: Serotonin was shown to interfere with the differentiation of brown adipocytes. In addition, clock components inhibit brown adipogenesis through direct transcriptional control of key components of the transforming growth factor β pathway. The aim of this study was to investigate whether serotonin abrogates brown adipogenesis by affecting clock functionality.

Methods: Nondifferentiated and differentiated HIB1B brown adipocytes were treated with serotonin, and their clock expression and functionality and differentiation state were examined.

Results: Nondifferentiated HIB1B brown adipocytes treated with serotonin showed increased brown adipocyte markers alongside increased brain-muscle Arnt-like protein 1 (Bmal1) and RAR related orphan receptor A (Rora) but decreased nuclear receptor Rev-erbα mRNA levels. BMAL1 overexpression together with serotonin led to significantly lower brown adipocyte markers. Serotonin in the differentiation cocktail led to reduced brown adipocyte markers as well as clock gene expression. After differentiation, serotonin treatment significantly decreased brown adipocyte markers and reduced BMAL1 and RORα but increased REV-ERBα protein levels. Addition of serotonin to the differentiation medium or addition after differentiation reduced activity of calcium/calmodulin-dependent protein kinase type II subunit gamma, which interferes with circadian locomoter output cycles protein kaput (CLOCK):BMAL1 dimerization and transactivation.

Conclusions: Clock expression is required at the early stages of differentiation to brown adipocytes, and serotonin interferes with this process by modulating clock functionality. Serotonin interferes with clock functionality by reducing the levels of the active form of calcium/calmodulin-dependent protein kinase type II subunit gamma.
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http://dx.doi.org/10.1002/oby.22606DOI Listing
December 2019

Reduction in Glycated Hemoglobin and Daily Insulin Dose Alongside Circadian Clock Upregulation in Patients With Type 2 Diabetes Consuming a Three-Meal Diet: A Randomized Clinical Trial.

Diabetes Care 2019 12 23;42(12):2171-2180. Epub 2019 Sep 23.

Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel

Objective: In type 2 diabetes, insulin resistance and progressive β-cell failure require treatment with high insulin doses, leading to weight gain. Our aim was to study whether a three-meal diet (3Mdiet) with a carbohydrate-rich breakfast may upregulate clock gene expression and, as a result, allow dose reduction of insulin, leading to weight loss and better glycemic control compared with an isocaloric six-meal diet (6Mdiet).

Research Design And Methods: Twenty-eight volunteers with diabetes (BMI 32.4 ± 5.2 kg/m and HbA 8.1 ± 1.1% [64.5 ± 11.9 mmol/mol]) were randomly assigned to 3Mdiet or 6Mdiet. Body weight, glycemic control, continuous glucose monitoring (CGM), appetite, and clock gene expression were assessed at baseline, after 2 weeks, and after 12 weeks.

Results: 3Mdiet, but not 6Mdiet, led to a significant weight loss (-5.4 ± 0.9 kg) ( < 0.01) and decreased HbA (-12 mmol/mol [-1.2%]) ( < 0.0001) after 12 weeks. Fasting glucose and daily and nocturnal glucose levels were significantly lower on the 3Mdiet. CGM showed a significant decrease in the time spent in hyperglycemia only on the 3Mdiet. Total daily insulin dose was significantly reduced by 26 ± 7 units only on the 3Mdiet. There was a significant decrease in the hunger and cravings only in the 3Mdiet group. Clock genes exhibited oscillation, increased expression, and higher amplitude on the 3Mdiet compared with the 6Mdiet.

Conclusions: A 3Mdiet, in contrast to an isocaloric 6Mdiet, leads to weight loss and significant reduction in HbA, appetite, and overall glycemia, with a decrease in daily insulin. Upregulation of clock genes seen in this diet intervention could contribute to the improved glucose metabolism.
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http://dx.doi.org/10.2337/dc19-1142DOI Listing
December 2019

Clock Gene Disruption Is an Initial Manifestation of Inflammatory Bowel Diseases.

Clin Gastroenterol Hepatol 2020 01 10;18(1):115-122.e1. Epub 2019 Apr 10.

Institute of Biochemistry, Food Science and Nutrition, the Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel. Electronic address:

Background & Aims: Sleep disruption modifies the immune system and can trigger flares of inflammatory bowel diseases (IBD). Changes in expression of clock genes have been reported in patients with IBD. We investigated whether a change in the circadian clock is an early event in development of IBD.

Methods: We performed a prospective study of patients younger than 21 years old who underwent diagnostic endoscopies at the pediatric and adult gastroenterology units at the Tel Aviv Sourasky Medical Center from August 2016 through August 2017. Questionnaires were completed by 32 patients with IBD (8-21 years old) and 18 healthy individuals (controls) that provided data on demographics, sleep, disease activity scores. We also obtained data on endoscopic scores, anthropometric parameters, blood level of C-reactive protein (CRP), and fecal level of calprotectin. Peripheral blood and intestinal mucosa samples were analyzed for expression levels of clock gene (CLOCK, BMAL1, CRY1, CRY2, PER1, and PER2).

Results: Levels of CRP and fecal calprotectin were significantly higher in patients with IBD compared with controls (P<.05). Expression levels of clock genes (CLOCK, CRY1, CRY2, PER1, and PER2) were significantly lower in inflamed intestinal mucosa from patients compared with intestinal mucosa from controls (P<.05). Expression levels of all clock genes except for PER2, were also significantly lower in non-inflamed intestinal mucosal tissues from patients compared with controls (P<.05). Expression levels of clock genes (CLOCK, BMAL1, CRY1, CRY2, PER1 and PER2) were lower in white blood cells from patients with IBD compared with controls. This reduction was greater in white blood cells from patients with ulcerative colitis than in patients with Crohn's disease.

Conclusion: Young, newly diagnosed, untreated patients with IBD have reduced expression of clock genes in inflamed and non-inflamed intestinal mucosal samples, and also in blood cells, compared with healthy individuals. Alterations in expression of clock genes might be an early event in IBD pathogenesis. ClinicalTrials.gov Identifier: NCT03662646.
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http://dx.doi.org/10.1016/j.cgh.2019.04.013DOI Listing
January 2020

Non-obesogenic doses of fatty acids modulate the functionality of the circadian clock in the liver.

Cell Mol Life Sci 2019 May 29;76(9):1795-1806. Epub 2019 Jan 29.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, 76100, Rehovot, Israel.

Saturated fatty acids, such as palmitate, lead to circadian disruption in cell culture. Moreover, information regarding the effects of unsaturated fatty acids on circadian parameters is scarce. We aimed at studying the effects of low doses of saturated as well as unsaturated fatty acids on circadian metabolism in vivo and at deciphering the mechanism by which fatty acids convey their effect. Mice were fed non-obesogenic doses of palm or olive oil and hepatocytes were treated with palmitate and oleate. Mice fed non-obesogenic doses of palm oil showed increased signaling towards fatty acid synthesis, while olive oil increased signaling towards fatty acid oxidation. Low doses of palmitate and oleate were sufficient to alter circadian rhythms, due to changes in the expression and/or activity of key metabolic proteins. Palmitate, but not oleate, counteracted the reduction in lipid accumulation and BMAL1-induced expression of mitochondrial genes involved in fatty acid oxidation. Palmitate was also found to interfere with the transcriptional activity of CLOCK:BMAL1 by preventing BMAL1 deacetylation and activation. In addition, palmitate, but not oleate, reduced PER2-mediated transcriptional activation and increased REV-ERBα-mediated transcriptional inhibition of Bmal1. The inhibition of PER2-mediated transcriptional activation by palmitate was achieved by interfering with PER2 nuclear translocation. Indeed, PER2 reduced fat accumulation in hepatocytes and this reduction was prevented by palmitate. Herein, we show that the detrimental metabolic alteration seen with high doses of palmitate manifests itself early on even with non-obesogenic levels. This is achieved by modulating BMAL1 at several levels abrogating its activity and expression.
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http://dx.doi.org/10.1007/s00018-019-03023-6DOI Listing
May 2019

The Circadian Clock Drives Mast Cell Functions in Allergic Reactions.

Front Immunol 2018 6;9:1526. Epub 2018 Jul 6.

Institute for Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.

Allergic diseases are known to vary in the severity of their symptoms throughout the day/night cycle. This rhythmicity is also observed in mast cell function and responsiveness. Mast cells are key effector cells of allergic reactions and release cytokines, chemokines, and important inflammatory mediators such as histamine, which have been shown to display diurnal variation. Recent research clarified that mast cells are controlled by their internal clock-which is regulated by a specific set of clock genes-as well as external factors such as light sensed by the suprachiasmatic nuclei, hormonal status, or diet. Here, we give an overview of the connections between circadian clock, mast cells, and allergic disease. Further work aimed at studying the role of chronotherapy/chronomedicine should take into account this rhythmic nature of not only mast cells but also the immune responses generated by mast cell signaling.
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http://dx.doi.org/10.3389/fimmu.2018.01526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043637PMC
July 2018

The Circadian Clock in White and Brown Adipose Tissue: Mechanistic, Endocrine, and Clinical Aspects.

Endocr Rev 2018 06;39(3):261-273

Department of Physiology, University of Murcia, Murcia, Spain.

Obesity is a major risk factor for the development of illnesses, such as insulin resistance and hypertension, and has become a serious public health problem. Mammals have developed a circadian clock located in the hypothalamic suprachiasmatic nuclei (SCN) that responds to the environmental light-dark cycle. Clocks similar to the one located in the SCN are found in peripheral tissues, such as the kidney, liver, and adipose tissue. The circadian clock regulates metabolism and energy homeostasis in peripheral tissues by mediating activity and/or expression of key metabolic enzymes and transport systems. Knockouts or mutations in clock genes that lead to disruption of cellular rhythmicity have provided evidence to the tight link between the circadian clock and metabolism. In addition, key proteins play a dual role in regulating the core clock mechanism, as well as adipose tissue metabolism, and link circadian rhythms with lipogenesis and lipolysis. Adipose tissues are distinguished as white, brown, and beige (or brite), each with unique metabolic characteristics. Recently, the role of the circadian clock in regulating the differentiation into the different adipose tissues has been investigated. In this review, the role of clock proteins and the downstream signaling pathways in white, brown, and brite adipose tissue function and differentiation will be reviewed. In addition, chronodisruption and metabolic disorders and clinical aspects of circadian adiposity will be addressed.
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http://dx.doi.org/10.1210/er.2017-00193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456924PMC
June 2018

High-energy breakfast based on whey protein reduces body weight, postprandial glycemia and HbA in Type 2 diabetes.

J Nutr Biochem 2017 11 21;49:1-7. Epub 2017 Jul 21.

Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel. Electronic address:

Acute studies show that addition of whey protein at breakfast has a glucose-lowering effect through increased incretin and insulin secretion. However, whether this is a long-term effect in Type 2 diabetes is unknown. Fifty-six Type 2 diabetes participants aged 58.9±4.5 years, BMI 32.1±0.9 kg/m and HbA 7.8±0.1% (61.6±0.79 mmol/mol) were randomized to one of 3 isocaloric diets with similar lunch and dinner, but different breakfast: 1) 42 g total protein, 28 g whey (WBdiet, n=19); 2) 42 g various protein sources (PBdiet, n=19); or 3) high-carbohydrate breakfast, 17 g protein from various sources (CBdiet, n=18). Body weight and HbA were examined after 12 weeks. All participants underwent three all-day meal challenges for postprandial glycemia, insulin, C-peptide, intact glucagon-like peptide 1 (iGLP-1), ghrelin and hunger and satiety scores. Overall postprandial AUC was reduced by 12% in PBdiet and by 19% in WBdiet, compared with CBdiet (P<.0001). Compared with PBdiet and CBdiet, WBdiet led to a greater postprandial overall AUC for insulin, C-peptide, iGLP-1 and satiety scores, while postprandial overall AUC for ghrelin and hunger scores were reduced (P<.0001). After 12 weeks, HbA was reduced after WBdiet by 0.89±0.05% (11.5±0.6 mmol/mol), after PBdiet by 0.6±0.04% (7.1±0.31 mmol/mol) and after CBdiet by 0.36±0.04% (2.9±0.31 mmol/mol) (P<.0001). Furthermore, the participants on WBdiet lost 7.6±0.3 kg, PBdiet 6.1±0.3 kg and CBdiet 3.5±0.3 kg (P<.0001). Whey protein-based breakfast is an important adjuvant in the management of Type 2 diabetes.
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http://dx.doi.org/10.1016/j.jnutbio.2017.07.005DOI Listing
November 2017

Influences of Breakfast on Clock Gene Expression and Postprandial Glycemia in Healthy Individuals and Individuals With Diabetes: A Randomized Clinical Trial.

Diabetes Care 2017 11 22;40(11):1573-1579. Epub 2017 Aug 22.

Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel

Objective: The circadian clock regulates glucose metabolism by mediating the activity of metabolic enzymes, hormones, and transport systems. Breakfast skipping and night eating have been associated with high HbA and postprandial hyperglycemia after lunch and dinner. Our aim was to explore the acute effect of breakfast consumption or omission on glucose homeostasis and clock gene expression in healthy individuals and individuals with type 2 diabetes.

Research Design And Methods: In a crossover design, 18 healthy volunteers and 18 volunteers with 14.5 ± 1.5 years diabetes, BMI 30.7 ± 1.1 kg/m, and HbA 7.6 ± 0.1% (59.6 ± 0.8 mmol/mol) were randomly assigned to a test day with breakfast and lunch (YesB) and a test day with only lunch (NoB). Postprandial clock and clock-controlled gene expression, plasma glucose, insulin, intact glucagon-like peptide 1 (iGLP-1), and dipeptidyl peptidase IV (DPP-IV) plasma activity were assessed after breakfast and lunch.

Results: In healthy individuals, the expression level of , , , and was lower ( < 0.05) but was higher ( < 0.05) after breakfast. In contrast, in individuals with type 2 diabetes, , , and only slightly, but significantly, decreased and increased ( < 0.05) after breakfast. In healthy individuals, the expression level of , , and was higher ( < 0.05) after lunch on YesB day, whereas the other clock genes remained unchanged. In individuals with type 2 diabetes, , , , , and increased ( < 0.05) after lunch on the YesB day. Omission of breakfast altered clock and metabolic gene expression in both healthy and individuals with type 2 diabetes.

Conclusions: Breakfast consumption acutely affects clock and clock-controlled gene expression leading to normal oscillation. Breakfast skipping adversely affects clock and clock-controlled gene expression and is correlated with increased postprandial glycemic response in both healthy individuals and individuals with diabetes.
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http://dx.doi.org/10.2337/dc16-2753DOI Listing
November 2017

Effect of brain-derived neurotrophic factor (BDNF) on hepatocyte metabolism.

Int J Biochem Cell Biol 2017 07 5;88:69-74. Epub 2017 May 5.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Electronic address:

Brain-derived neurotrophic factor (BDNF) plays crucial roles in the development, maintenance, plasticity and homeostasis of the central and peripheral nervous systems. Perturbing BDNF signaling in mouse brain results in hyperphagia, obesity, hyperinsulinemia and hyperglycemia. Currently, little is known whether BDNF affects liver tissue directly. Our aim was to determine the metabolic signaling pathways activated after BDNF treatment in hepatocytes. Unlike its effect in the brain, BDNF did not lead to activation of the liver AKT pathway. However, AMP protein activated kinase (AMPK) was ∼3 times more active and fatty acid synthase (FAS) ∼2-fold less active, suggesting increased fatty acid oxidation and reduced fatty acid synthesis. In addition, cAMP response element binding protein (CREB) was ∼3.5-fold less active together with its output the gluconeogenic transcript phosphoenolpyruvate carboxykinase (Pepck), suggesting reduced gluconeogenesis. The levels of glycogen synthase kinase 3b (GSK3b) was ∼3-fold higher suggesting increased glycogen synthesis. In parallel, the expression levels of the clock genes Bmal1 and Cry1, whose protein products play also a metabolic role, were ∼2-fold increased and decreased, respectively. In conclusion, BDNF binding to hepatocytes leads to activation of catabolic pathways, such as fatty acid oxidation. In parallel gluconeogenesis is inhibited, while glycogen storage is triggered. This metabolic state mimics that of after breakfast, in which the liver continues to oxidize fat, stops gluconeogenesis and replenishes glycogen stores.
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http://dx.doi.org/10.1016/j.biocel.2017.05.008DOI Listing
July 2017

Relationship between FGF21 and UCP1 levels under time-restricted feeding and high-fat diet.

J Nutr Biochem 2017 02 2;40:116-121. Epub 2016 Nov 2.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Electronic address:

Fibroblast growth factor 21 (FGF21) exhibits a circadian oscillation, and its induction is critical during fasting. When secreted by liver and skeletal muscle, FGF21 enhances thermogenic activity in brown adipose tissue (BAT) by utilizing uncoupling protein 1 (UCP1) to dissipate energy as heat. Recently, it has been reported that UCP1 is not required for FGF21-mediated reduction in body weight or improvements in glucose homeostasis. As the relationship between FGF21 and UCP1 induction in tissues other than BAT is less clear, we tested the effect of restricted feeding (RF) and high dietary fat on FGF21 circadian expression and its correlation with UCP1 expression in liver and white adipose tissue (WAT). High dietary fat disrupted Fgf21 mRNA circadian oscillation but increased its levels in WAT. RF led to increased liver FGF21 protein levels, whereas those of UCP1 decreased. In contrast, WAT FGF21 protein levels increased under high-fat diet, whereas those of UCP1 decreased under RF. In summary, FGF21 exhibits circadian oscillation, which is disrupted with increased dietary fat. The relationship between FGF21 and UCP1 levels depends on the tissue and the cellular energy status.
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http://dx.doi.org/10.1016/j.jnutbio.2016.10.017DOI Listing
February 2017

Differential effect of fructose on fat metabolism and clock gene expression in hepatocytes vs. myotubes.

Int J Biochem Cell Biol 2016 08 27;77(Pt A):35-40. Epub 2016 May 27.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Electronic address:

In the liver, fructose bypasses the main rate-limiting step of glycolysis at the level of phosphofructokinase, allowing it to act as an unregulated substrate for de novo lipogenesis. It has been reported that consumption of large amounts of fructose increases de novo lipogenesis in the liver. However, the effect of fructose on ectopic deposition of muscle fat has been under dispute. Our aim was to study the effect of fructose on levels of genes and proteins involved in fatty acid oxidation and synthesis in hepatocytes vs. muscle cells. In addition, as fat accumulation leads to disruption of daily rhythms, we tested the effect of fructose treatment on clock gene expression. AML-12 hepatocytes and C2C12 myotubes were treated with fructose or glucose for 2 consecutive 24-h cycles and harvested every 6h. In contrast to glucose, fructose disrupted clock gene rhythms in hepatocytes, but in myotubes, it led to more robust rhythms. Fructose led to low levels of phosphorylated AMP-activated protein kinase (pAMPK) and high levels of LIPIN1 in hepatocytes compared with glucose. In contrast, fructose led to high pAMPK and low LIPIN1 and microsomal triacylglycerol transfer protein (MTTP) levels in myotubes compared with glucose. Analysis of fat content revealed that fructose led to less fat accumulation in myotubes compared to hepatocytes. In summary, fructose shifts metabolism towards fatty acid synthesis and clock disruption in hepatocytes, but not in myotubes.
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http://dx.doi.org/10.1016/j.biocel.2016.05.019DOI Listing
August 2016

Effect of dietary fat and the circadian clock on the expression of brain-derived neurotrophic factor (BDNF).

Mol Cell Endocrinol 2016 07 22;430:49-55. Epub 2016 Apr 22.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Electronic address:

Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain and its decreased levels are associated with the development of obesity and neurodegeneration. Our aim was to test the effect of dietary fat, its timing and the circadian clock on the expression of BDNF and associated signaling pathways in mouse brain and liver. Bdnf mRNA oscillated robustly in brain and liver, but with a 12-h shift between the tissues. Brain and liver Bdnf mRNA showed a 12-h phase shift when fed ketogenic diet (KD) compared with high-fat diet (HFD) or low-fat diet (LFD). Brain or liver Bdnf mRNA did not show the typical phase advance usually seen under time-restricted feeding (RF). Clock knockdown in HT-4 hippocampal neurons led to 86% up-regulation of Bdnf mRNA, whereas it led to 60% down-regulation in AML-12 hepatocytes. Dietary fat in mice or cultured hepatocytes and hippocampal neurons led to increased Bdnf mRNA expression. At the protein level, HFD increased the ratio of the mature BDNF protein (mBDNF) to its precursor (proBDNF). In the liver, RF under LFD or HFD reduced the mBDNF/proBDNF ratio. In the brain, the two signaling pathways related to BDNF, mTOR and AMPK, showed reduced and increased levels, respectively, under timed HFD. In the liver, the reverse was achieved. In summary, Bdnf expression is mediated by the circadian clock and dietary fat. Although RF does not affect its expression phase, in the brain, when combined with high-fat diet, it leads to a unique metabolic state in which AMPK is activated, mTOR is down-regulated and the levels of mBDNF are high.
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http://dx.doi.org/10.1016/j.mce.2016.04.015DOI Listing
July 2016

Metabolic effect of fluvoxamine in mouse peripheral tissues.

Mol Cell Endocrinol 2016 Mar 12;424:12-22. Epub 2016 Jan 12.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 76100, Israel. Electronic address:

Serotonin leads to reduced food intake and satiety. Disrupted circadian rhythms lead to hyperphagia and obesity. The serotonergic and circadian systems are intertwined, as the central brain clock receives direct serotonergic innervation and, in turn, makes polysynaptic output back to serotonergic nuclei. Our objective was to test the hypothesis that peripherally serotonin alters circadian rhythms leading to a shift towards fat synthesis and weight gain. We studied the effect of serotonin and fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), on the circadian clock and metabolic gene and protein expression in mouse liver, muscle and white adipose tissue (WAT) and cell culture. We found that serotonin and/or the SSRI fluvoxamine led to fat accumulation in mouse liver and hepatocytes by shifting metabolism towards fatty acid synthesis mainly through low average levels of phosphorylated acetyl CoA carboxylase (pACC) and phosphorylated protein phosphatase 2A (pPP2A). This shift towards fat synthesis was also observed in adipose tissue. Muscle cells were only slightly affected metabolically by serotonin or fluvoxamine. In conclusion, although centrally it leads to increased satiety, in peripheral tissues, such as the liver and WAT, serotonin induces fat accumulation.
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http://dx.doi.org/10.1016/j.mce.2016.01.009DOI Listing
March 2016

Serotonin suppresses food anticipatory activity and synchronizes the food-entrainable oscillator during time-restricted feeding.

Behav Brain Res 2016 Jan 20;297:150-4. Epub 2015 Oct 20.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Electronic address:

The serotonergic and circadian systems are intertwined as serotonin modulates the response of the central brain suprachiasmatic nuclei (SCN) clock to light. Time-restricted feeding (RF) is characterized by increased food anticipatory activity (FAA) and controlled by the food-entrainable oscillator (FEO) rather than the SCN. Our objective was to test whether serotonin affects the FEO. Mice were treated with the selective serotonin reuptake inhibitor (SSRI) fluvoxamine (FLX) or the tryptophan hydroxylase inhibitor parachlorophenylalanine (PCPA) and locomotor activity under ad libitum feeding, RF and different lighting conditions was monitored. Under AL, FLX administration did not affect 24-h locomotor activity, while mice treated with PCPA exhibited increased activity. RF-FLX-treated mice showed less FAA 2h before food availability (ZT2-ZT4) compared to RF- or RF-PCPA-fed mice. Under DD, RF-PCPA-treated mice displayed increased activity, as was seen under LD conditions. Surprisingly, RF-PCPA-treated mice showed free running in the FAA component. These results emphasize the role of serotonin in SCN-mediated activity inhibition and FEO entrainment and activity.
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http://dx.doi.org/10.1016/j.bbr.2015.10.019DOI Listing
January 2016

Ketogenic diet delays the phase of circadian rhythms and does not affect AMP-activated protein kinase (AMPK) in mouse liver.

Mol Cell Endocrinol 2015 Dec 25;417:124-30. Epub 2015 Sep 25.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Electronic address:

Ketogenic diet (KD) is used for weight loss or to treat epilepsy. KD leads to liver AMP-activated protein kinase (AMPK) activation, which would be expected to inhibit gluconeogenesis. However, KD leads to increased hepatic glucose output. As AMPK and its active phosphorylated form (pAMPK) show circadian oscillation, this discrepancy could stem from wrong-time-of-day sampling. The effect of KD was tested on mouse clock gene expression, AMPK, mTOR, SIRT1 and locomotor activity for 2 months and compared to low-fat diet (LFD). KD led to 1.5-fold increased levels of blood glucose and insulin. Brain pAMPK/AMPK ratio was 40% higher under KD, whereas that in liver was not affected. KD led to 40% and 20% down-regulation of the ratio of pP70S6K/P70S6K, the downstream target of mTOR, in the brain and liver, respectively. SIRT1 levels were 40% higher in the brain, but 40% lower in the liver of KD-fed mice. Clock genes showed delayed rhythms under KD. In the brain of KD-fed mice, amplitudes of clock genes were down-regulated, whereas 6-fold up-regulation was found in the liver. The metabolic state under KD indicates reduced satiety in the brain and reduced anabolism alongside increased gluconeogenesis in the liver.
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http://dx.doi.org/10.1016/j.mce.2015.09.012DOI Listing
December 2015

Fasting until noon triggers increased postprandial hyperglycemia and impaired insulin response after lunch and dinner in individuals with type 2 diabetes: a randomized clinical trial.

Diabetes Care 2015 Oct 28;38(10):1820-6. Epub 2015 Jul 28.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel

Objective: Skipping breakfast has been consistently associated with high HbA1c and postprandial hyperglycemia (PPHG) in patients with type 2 diabetes. Our aim was to explore the effect of skipping breakfast on glycemia after a subsequent isocaloric (700 kcal) lunch and dinner.

Research Design And Methods: In a crossover design, 22 patients with diabetes with a mean diabetes duration of 8.4 ± 0.7 years, age 56.9 ± 1.0 years, BMI 28.2 ± 0.6 kg/m(2), and HbA1c 7.7 ± 0.1% (61 ± 0.8 mmol/mol) were randomly assigned to two test days: one day with breakfast, lunch, and dinner (YesB) and another with lunch and dinner but no breakfast (NoB). Postprandial plasma glucose, insulin, C-peptide, free fatty acids (FFA), glucagon, and intact glucagon-like peptide-1 (iGLP-1) were assessed.

Results: Compared with YesB, lunch area under the curves for 0-180 min (AUC0-180) for plasma glucose, FFA, and glucagon were 36.8, 41.1, and 14.8% higher, respectively, whereas the AUC0-180 for insulin and iGLP-1 were 17% and 19% lower, respectively, on the NoB day (P < 0.0001). Similarly, dinner AUC0-180 for glucose, FFA, and glucagon were 26.6, 29.6, and 11.5% higher, respectively, and AUC0-180 for insulin and iGLP-1 were 7.9% and 16.5% lower on the NoB day compared with the YesB day (P < 0.0001). Furthermore, insulin peak was delayed 30 min after lunch and dinner on the NoB day compared with the YesB day.

Conclusions: Skipping breakfast increases PPHG after lunch and dinner in association with lower iGLP-1 and impaired insulin response. This study shows a long-term influence of breakfast on glucose regulation that persists throughout the day. Breakfast consumption could be a successful strategy for reduction of PPHG in type 2 diabetes.
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http://dx.doi.org/10.2337/dc15-0761DOI Listing
October 2015

Concentrating carbohydrates before sleep improves feeding regulation and metabolic and inflammatory parameters in mice.

Mol Cell Endocrinol 2015 Oct 20;414:29-41. Epub 2015 Jul 20.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Electronic address:

New evidance highlights the importance of food timing. Recently, we showed that a low-calorie diet with carbohydrates eaten mostly at dinner changed diurnal hormone secretion and led to greater weight loss and improved metabolic status in obese people. Herein, we set out to test whether concentrated-carbohydrates diet (CCD), in which carbohydrates are fed only before sleep, leads to an improved metabolic status in mouse hypothalamus and peripheral tissues. Diet-induced obese mice were given concentrated or distributed carbohydrate diet for 6 weeks. Obese mice fed CCD ate 8.3% less, were 9.3% leaner and had 39.7% less fat mass. Leptin, ghrelin and adiponectin displayed altered secretion. In addition, these mice exhibited an improved biochemical and inflammatory status. In the hypothalamus, anorexigenic signals were up-regulated and orexigenic signals were down-regulated. In peripheral tissues, CCD promoted adiponectin signaling, repressed gluconeogenesis, enhanced lipid oxidation and lowered inflammation, thus ameliorating the major risk factors of obesity.
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http://dx.doi.org/10.1016/j.mce.2015.06.032DOI Listing
October 2015

High-energy breakfast with low-energy dinner decreases overall daily hyperglycaemia in type 2 diabetic patients: a randomised clinical trial.

Diabetologia 2015 May 1;58(5):912-9. Epub 2015 Mar 1.

Diabetes Unit, E. Wolfson Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Holon, 58100, Israel,

Aims/hypothesis: High-energy breakfast and reduced-energy dinner (Bdiet) significantly reduces postprandial glycaemia in obese non-diabetic individuals. Our objective was to test whether this meal schedule reduces postprandial hyperglycaemia (PPHG) in patients with type 2 diabetes by enhancing incretin and insulin levels when compared with high-energy dinner and reduced-energy breakfast (Ddiet).

Methods: In a randomised, open label, crossover design performed in a clinic setting, 18 individuals (aged 30-70 years with BMI 22-35 kg/m(2)) with type 2 diabetes (<10 years duration) treated with metformin and/or diet were given either Bdiet or Ddiet for 7 days. Participants were randomised by a person not involved in the study using a coin flip. Postprandial levels of plasma glucose, insulin, C-peptide and intact and total glucagon-like peptide-1 (iGLP-1 and tGLP-1) were assessed. The Bdiet included 2,946 kJ breakfast, 2,523 kJ lunch and 858 kJ dinner. The Ddiet comprised 858 kJ breakfast, 2,523 kJ lunch and 2,946 kJ dinner.

Results: Twenty-two individuals were randomised and 18 analysed. The AUC for glucose (AUCglucose) throughout the day was 20% lower, whereas AUCinsulin, AUCC-peptide and AUCtGLP-1 were 20% higher for the Bdiet than the Ddiet. Glucose AUC0-180min and its peak were both lower by 24%, whereas insulin AUC0-180min was 11% higher after the Bdiet than the Ddiet. This was accompanied by 30% higher tGLP-1 and 16% higher iGLP-1 levels. Despite the diets being isoenergetic, lunch resulted in lower glucose (by 21-25%) and higher insulin (by 23%) with the Bdiet vs Ddiet.

Conclusions/interpretation: High energy intake at breakfast is associated with significant reduction in overall PPHG in diabetic patients over the entire day. This dietary adjustment may have a therapeutic advantage for the achievement of optimal metabolic control and may have the potential for being preventive for cardiovascular and other complications of type 2 diabetes. Trial registration ClinicalTrials.gov NCT01977833 Funding No specific funding was received for the study.
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http://dx.doi.org/10.1007/s00125-015-3524-9DOI Listing
May 2015

IgE-dependent activation of human mast cells and fMLP-mediated activation of human eosinophils is controlled by the circadian clock.

Mol Immunol 2015 Mar 15;64(1):76-81. Epub 2014 Nov 15.

Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany. Electronic address:

Symptoms of allergic attacks frequently exhibit diurnal variations. Accordingly, we could recently demonstrate that mast cells and eosinophils - known as major effector cells of allergic diseases - showed an intact circadian clock. Here, we analyzed the role of the circadian clock in the functionality of mast cells and eosinophils. Human intestinal mast cells (hiMC) were isolated from intestinal mucosa; human eosinophils were isolated from peripheral blood. HiMC and eosinophils were synchronized by dexamethasone before stimulation every 4h around the circadian cycle by FcɛRI crosslinking or fMLP, respectively. Signaling molecule activation was examined using Western blot, mRNA expression by real-time RT-PCR, and mediator release by multiplex analysis. CXCL8 and CCL2 were expressed and released in a circadian manner by both hiMC and eosinophils in response to activation. Moreover, phosphorylation of ERK1/2, known to be involved in activation of hiMC and eosinophils, showed circadian rhythms in both cell types. Interestingly, all clock genes hPer1, hPer2, hCry1, hBmal1, and hClock were expressed in a similar circadian pattern in activated and unstimulated cells indicating that the local clock controls hiMC and eosinophils and subsequently allergic reactions but not vice versa.
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http://dx.doi.org/10.1016/j.molimm.2014.10.026DOI Listing
March 2015

The circadian clock machinery controls adiponectin expression.

Mol Cell Endocrinol 2015 Jan 24;399:284-7. Epub 2014 Oct 24.

Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel. Electronic address:

Adiponectin, an adipokine involved in glucose and lipid metabolism, exhibits a circadian manner of expression. Adiponectin expression is mediated by the helix-loop-helix transcription factor sterol regulatory element binding protein (SREBP)-1c. In this study, we tested whether the circadian clock helix-loop-helix transcription factors CLOCK and BMAL1 regulate adiponectin expression. We found that adiponectin expression is regulated by the clock through the circadian expression of its transcription factor peroxisome proliferator-activated receptor γ (PPARγ) and its co-activator PPARγ co-activator 1α (PGC1α) in mouse white adipose tissue and differentiated adipocytes. In addition, reconstitution of the core clock mechanism and siRNA experiments in cell culture suggest that the clock directly activates the adiponectin promoter and mediates its expression. In summary, adiponectin expression is regulated by the circadian clock and through the circadian expression of its transcription factor PPARγ and its co-activator PGC1α.
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http://dx.doi.org/10.1016/j.mce.2014.10.018DOI Listing
January 2015

Incretin, insulinotropic and glucose-lowering effects of whey protein pre-load in type 2 diabetes: a randomised clinical trial.

Diabetologia 2014 Sep 10;57(9):1807-11. Epub 2014 Jul 10.

Diabetes Unit, E. Wolfson Medical Center, Sackler Faculty of Medicine, Tel Aviv University, 62 Halochamim, 58100, Holon, Israel,

Aims/hypothesis: Since protein ingestion is known to stimulate the secretion of glucagon-like peptide-1 (GLP-1), we hypothesised that enhancing GLP-1 secretion to harness its insulinotropic/beta cell-stimulating activity with whey protein pre-load may have beneficial glucose-lowering effects in type 2 diabetes.

Methods: In a randomised, open-label crossover clinical trial, we studied 15 individuals with well-controlled type 2 diabetes who were not taking any medications except for sulfonylurea or metformin. These participants consumed, on two separate days, 50 g whey in 250 ml water or placebo (250 ml water) followed by a standardised high-glycaemic-index breakfast in a hospital setting. Participants were randomised using a coin flip. The primary endpoints of the study were plasma concentrations of glucose, intact GLP-1 and insulin during the 30 min following meal ingestion.

Results: In each group, 15 patients were analysed. The results showed that over the whole 180 min post-meal period, glucose levels were reduced by 28% after whey pre-load with a uniform reduction during both early and late phases. Insulin and C-peptide responses were both significantly higher (by 105% and 43%, respectively) with whey pre-load. Notably, the early insulin response was 96% higher after whey. Similarly, both total GLP-1 (tGLP-1) and intact GLP-1 (iGLP-1) levels were significantly higher (by 141% and 298%, respectively) with whey pre-load. Dipeptidyl peptidase 4 plasma activity did not display any significant difference after breakfast between the groups.

Conclusions/interpretation: In summary, consumption of whey protein shortly before a high-glycaemic-index breakfast increased the early prandial and late insulin secretion, augmented tGLP-1 and iGLP-1 responses and reduced postprandial glycaemia in type 2 diabetic patients. Whey protein may therefore represent a novel approach for enhancing glucose-lowering strategies in type 2 diabetes. Trial registration ClinicalTrials.gov NCT01571622 Funding The Israeli Ministry of Health and Milk Council funded the research.
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http://dx.doi.org/10.1007/s00125-014-3305-xDOI Listing
September 2014

Effect of metformin and lipid emulsion on the circadian gene expression in muscle cells.

Int J Biochem Cell Biol 2014 Aug 17;53:151-61. Epub 2014 May 17.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, PO Box 12, Rehovot 76100, Israel. Electronic address:

The circadian clock influences nearly all aspects of metabolism. However, little is known regarding the effect of the energy status on circadian rhythms. Our aim was to test the effect of two opposing energy situations, metformin and lipid emulsion (LE), on clock and metabolic circadian expression in differentiated C2C12 myotubes. Metformin treatment led to depleted ATP levels accompanied by elevated NADH levels, whereas LE treatment led to increased ATP and NAD(+) levels. Nevertheless, both LE and metformin treatments activated the AMP-activated protein kinase (AMPK) pathway. In contrast, the effect on circadian rhythms was completely different. LE led to disrupted clock and metabolic gene expression, whereas metformin led to mainly high-amplitude shifted rhythms. Combination of metformin and LE led to an antagonistic effect on circadian gene expression. Although metformin and LE have an opposing effect on circadian gene expression and on the cellular energy status, they both lead to AMPK activation.
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http://dx.doi.org/10.1016/j.biocel.2014.05.014DOI Listing
August 2014

Long-term commercial cow's milk consumption and its effects on metabolic parameters associated with obesity in young mice.

Mol Nutr Food Res 2014 May 23;58(5):1061-8. Epub 2013 Dec 23.

Robert H. Smith Faculty of Agriculture, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel.

Scope: Research has demonstrated that consumption of milk promotes weight loss and satiety, however conflicting evidence also exists. Therefore, we tested the effect of long-term milk consumption on body weight and metabolic parameters.

Methods And Results: Newly weaned mice received whole milk, low-fat milk, or water as control for 17 weeks and serum, liver, and white adipose tissue (WAT) were tested for parameters associated with obesity and diabetes. Our results show that low-fat milk leads to the same overall caloric intake and body weight as the control group. However, the whole-milk group consumed more calories and reached a higher body weight. In addition, in the low-fat milk group, cholesterol, HDL-cholesterol, triglycerides, leptin, ghrelin, insulin, corticosterone, and glucagon were not significantly different than the control group. In contrast, in the whole-milk group, cholesterol, HDL-cholesterol, triglycerides, and glucagon were high compared with the control group. Metabolism in both liver and WAT showed only slight differences between the milk groups. Whereas the whole-milk group showed reduced insulin signaling in WAT, the low-fat milk group exhibited increased insulin signaling.

Conclusion: Whole-milk consumption leads to increased body weight and caloric intake and reduced insulin signaling in WAT, as opposed to low-fat milk consumption.
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http://dx.doi.org/10.1002/mnfr.201300650DOI Listing
May 2014

AMPK-derived peptides reduce blood glucose levels but lead to fat retention in the liver of obese mice.

J Endocrinol 2014 Apr 7;221(1):89-99. Epub 2014 Mar 7.

Robert H. Smith Faculty of Agriculture, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem, Israel.

AMP-activated protein kinase (AMPK) is a regulator of energy balance at both the cellular and the whole-body levels. Direct activation of AMPK has been highlighted as a potential novel, and possibly safer, alternative to treat type II diabetes and obesity. In this study, we aimed to design and characterize novel peptides that mimic the αG region of the α2 AMPK catalytic domain to modulate its activity by inhibiting interactions between AMPK domains or other interacting proteins. The derived peptides were tested in vivo and in tissue culture. The computationally predicted structure of the free peptide with the addition of the myristoyl (Myr) or acetyl (Ac) moiety closely resembled the protein structure that it was designed to mimic. Myr-peptide and Ac-peptide activated AMPK in muscle cells and led to reduced adipose tissue weight, body weight, blood glucose levels, insulin levels, and insulin resistance index, as expected from AMPK activation. In addition, triglyceride, cholesterol, leptin, and adiponectin levels were also lower, suggesting increased adipose tissue breakdown, a result of AMPK activation. On the other hand, liver weight and liver lipid content increased due to fat retention. We could not find an elevated pAMPK:AMPK ratio in the liver in vivo or in hepatocytes ex vivo, suggesting that the peptide does not lead to AMPK activation in hepatocytes. The finding that an AMPK-derived peptide leads to the activation of AMPK in muscle cells and in adipose tissue and leads to reduced glucose levels in obese mice, but to fat accumulation in the liver, demonstrates the differential effect of AMPK modulation in various tissues.
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http://dx.doi.org/10.1530/JOE-13-0625DOI Listing
April 2014

Circadian aspects of energy metabolism and aging.

Authors:
Oren Froy

Ageing Res Rev 2013 Sep 25;12(4):931-40. Epub 2013 Sep 25.

Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Electronic address:

Life span extension has been a goal of research for several decades. Resetting circadian rhythms leads to well being and increased life span, while clock disruption is associated with increased morbidity accelerated aging. Increased longevity and improved health can be achieved by different feeding regimens that reset circadian rhythms and may lead to better synchrony in metabolism and physiology. This review focuses on the circadian aspects of energy metabolism and their relationship with aging in mammals.
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http://dx.doi.org/10.1016/j.arr.2013.09.002DOI Listing
September 2013