Oren Froy

Metabolism and Circadian Rhythms—Implications for Obesity

Obesity has become a serious public health problem and a major risk factor for the development of illnesses, such as insulin resistance and hypertension. Human homeostatic systems have adapted to daily changes in light and dark in a way that the body anticipates the sleep and activity periods. Mammals have developed an endogenous circadian clock located in the suprachiasmatic nuclei of the anterior hypothalamus that responds to the environmental light-dark cycle. Similar clocks have been found in peripheral tissues, such as the liver, intestine, and adipose tissue, regulating cellular and physiological functions. The circadian clock has been reported to regulate metabolism and energy homeostasis in the liver and other peripheral tissues. This is achieved by mediating the expression and/or activity of certain metabolic enzymes and transport systems. In return, key metabolic enzymes and transcription activators interact with and affect the core clock mechanism. In addition, the core clock mechanism has been shown to be linked with lipogenic and adipogenic pathways. Animals with mutations in clock genes that disrupt cellular rhythmicity have provided evidence for the relationship between the circadian clock and metabolic homeostasis. In addition, clinical studies in shift workers and obese patients accentuate the link between the circadian clock and metabolism. This review will focus on the interconnection between the circadian clock and metabolism, with implications for obesity and how the circadian clock is influenced by hormones, nutrients, and timed meals.

The relationship between nutrition and circadian rhythms in mammals.

The master clock located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus regulates circadian rhythms in mammals. The clock is an intracellular, transcriptional mechanism sharing the same molecular components in SCN neurons and in peripheral cells, such as the liver, intestine, and retina. The circadian clock controls food processing and energy homeostasis by regulating the expression and/or activity of enzymes involved in cholesterol, amino acid, lipid, glycogen, and glucose metabolism. In addition, many hormones involved in metabolism, such as insulin, glucagon, adiponectin, corticosterone, leptin, and ghrelin, exhibit circadian oscillation. Furthermore, disruption of circadian rhythms is involved in the development of cancer, metabolic syndrome, and obesity. Metabolism and food intake also feed back to influence the biological clock. Calorie restriction (CR) entrains the SCN clock, whereas timed meals entrain peripheral oscillators. Furthermore, the cellular redox state, dictated by food metabolism, and several nutrients, such as glucose, ethanol, adenosine, caffeine, thiamine, and retinoic acid, can phase-shift circadian rhythms. In conclusion, there is a large body of evidence that links feeding regimens, food components, and the biological clock.

High Caloric intake at breakfast vs. dinner differentially influences weight loss of overweight and obese women

Few studies examined the association between time‐of‐day of nutrient intake and the metabolic syndrome. Our goal was to compare a weight loss diet with high caloric intake during breakfast to an isocaloric diet with high caloric intake at dinner.

The two CRYs of the butterfly

(Current Biology 15, R953–R954; December 6, 2005)The authors wish to correct an omission in this Correspondence. Dr. Adriana D. Briscoe should be a coauthor for this paper, because she was the first to disclose to us the existence of a mammalian-like cryptochrome (CRY2) in Anopheles and other insects, a discovery that led directly to our searching and finding the monarch butterfly CRY2 in the EST library. Her name and address should be as above.

Timed high-fat diet resets circadian metabolism and prevents obesity

Disruption of circadian rhythms leads to obesity and metabolic disorders. Timed restricted feeding (RF) provides a time cue and resets the circadian clock, leading to better health. In contrast, a high‐fat (HF) diet leads to disrupted circadian expression of metabolic factors and obesity. We tested whether long‐term (18 wk) clock resetting by RF can attenuate the disruptive effects of diet‐induced obesity. Analyses included liver clock gene expression, locomotor activity, blood glucose, metabolic markers, lipids, and hormones around the circadian cycle for a more accurate assessment. Compared with mice fed the HF diet ad libitum, the timed HF diet restored the expression phase of the clock genes Clock and Cry1 and phase‐advanced Per1, Per2, Cry2, Bmal1, Rorα, and Rev‐erbα. Although timed HF‐diet‐fed mice consumed the same amount of calories as ad libitum low‐fat diet‐fed mice, they showed 12% reduced body weight, 21% reduced cholesterol levels, and 1.4‐fold increased insulin sensitivity. Compared with the HF diet ad libitum, the timed HF diet led to 18% lower body weight, 30% decreased cholesterol levels, 10% reduced TNF‐α levels, and 3.7‐fold improved insulin sensitivity. Timed HF‐diet‐fed mice exhibited a better satiated and less stressed phenotype of 25% lower ghrelin and 53% lower corticosterone levels compared with mice fed the timed low‐fat diet. Taken together, our findings suggest that timing can prevent obesity and rectify the harmful effects of a HF diet.—Sherman, H., Genzer, Y., Cohen, R., Chapnik, N., Madar, Z., Froy, O. Timed high‐fat diet resets circadian metabolism and prevents obesity. FASEB J. 26, 3493–3502 (2012). www.fasebj.org

Biochemical and metabolic mechanisms by which dietary whey protein may combat obesity and Type 2 diabetes

Consumption of milk and dairy products has been associated with reduced risk of metabolic disorders and cardiovascular disease. Milk contains two primary sources of protein, casein (80%) and whey (20%). Recently, the beneficial physiological effects of whey protein on the control of food intake and glucose metabolism have been reported. Studies have shown an insulinotropic and glucose-lowering properties of whey protein in healthy and Type 2 diabetes subjects. Whey protein seems to induce these effects via bioactive peptides and amino acids generated during its gastrointestinal digestion. These amino acids and peptides stimulate the release of several gut hormones, such as cholecystokinin, peptide YY and the incretins gastric inhibitory peptide and glucagon-like peptide 1 that potentiate insulin secretion from β-cells and are associated with regulation of food intake. The bioactive peptides generated from whey protein may also serve as endogenous inhibitors of dipeptidyl peptidase-4 (DPP-4) in the proximal gut, preventing incretin degradation. Indeed, recently, DPP-4 inhibitors were identified in whey protein hydrolysates. This review will focus on the emerging properties of whey protein and its potential clinical application for obesity and Type 2 diabetes.

Connecting the navigational clock to sun compass input in monarch butterfly brain.

Migratory monarch butterflies (Danaus plexippus) use a time-compensated sun compass to navigate to their overwintering grounds in Mexico. Although polarized light is one of the celestial cues used for orientation, the spectral content (color) of that light has not been fully explored. We cloned the cDNAs of three visual pigment-encoding opsins (ultraviolet [UV], blue, and long wavelength) and found that all three are expressed uniformly in main retina. The photoreceptors of the polarization-specialized dorsal rim area, on the other hand, are monochromatic for the UV opsin. Behavioral studies support the importance of polarized UV light for flight orientation. Next, we used clock protein expression patterns to identify the location of a circadian clock in the dorsolateral protocerebrum of butterfly brain. To provide a link between the clock and the sun compass, we identified a CRYPTOCHROME-staining neural pathway that likely connects the circadian clock to polarized light input entering brain.

Microreview: Regulation of mammalian defensin expression by Toll‐like receptor‐dependent and independent signalling pathways

The immune system consists of innate and adaptive immune responses. The innate immune system confers non‐specific protection against a large number of pathogens, hence, serving as the first line of defence. The innate immune system utilizes Toll‐like receptors (TLRs) to recognize and bind pathogen‐associated molecular patterns (PAMPs). Binding of PAMPs leads to TLR activation, which, in turn, initiates MAPK‐ or NF‐κB‐dependent cascades that culminate in a proinflammatory response. This response involves the secretion of cytokines, chemokines and broad‐spectrum antibacterial substances, such as defensins. Increased defensin synthesis is also mediated by the activation of receptors other than TLRs, such as NOD2, IL‐17R and PAR‐2. This review summarizes the recently characterized signalling pathways leading to increased defensin synthesis as well as the pathway by which defensins activate TLRs on immature dendritic and memory T cells. Thus, not only do defensins eliminate pathogens, but they also recruit the adaptive immune system in instances of infection and/or inflammation.

High-Fat Diet Delays and Fasting Advances the Circadian Expression of Adiponectin Signaling Components in Mouse Liver

The circadian clock controls energy homeostasis by regulating circadian expression and/or activity of enzymes involved in metabolism. Disruption of circadian rhythms may lead to obesity and metabolic disorders. We tested whether the biological clock controls adiponectin signaling pathway in the liver and whether fasting and/or high-fat (HF) diet affects this control. Mice were fed low-fat or HF diet and fasted on the last day. The circadian expression of clock genes and components of adiponectin metabolic pathway in the liver was tested at the RNA, protein, or enzyme activity level. In addition, serum levels of glucose, adiponectin, and insulin were measured. Under low-fat diet, adiponectin signaling pathway components exhibited circadian rhythmicity. However, fasting and HF diet altered this circadian expression; fasting resulted in a phase advance, and HF diet caused a phase delay. In addition, adenosine monophosphate-activated protein kinase levels were high during fasting and low during HF diet. Changes in the phase and daily rhythm of clock genes and components of adiponectin signaling pathway as a result of HF diet may lead to obesity and may explain the disruption of other clock-controlled output systems, such as blood pressure and sleep/wake cycle, usually associated with metabolic disorders.

The Putative Bioactive Surface of Insect-selective Scorpion Excitatory Neurotoxins

Scorpion neurotoxins of the excitatory group show total specificity for insects and serve as invaluable probes for insect sodium channels. However, despite their significance and potential for application in insect-pest control, the structural basis for their bioactivity is still unknown. We isolated, characterized, and expressed an atypically long excitatory toxin, Bj-xtrIT, whose bioactive features resembled those of classical excitatory toxins, despite only 49% sequence identity. With the objective of clarifying the toxic site of this unique pharmacological group, Bj-xtrIT was employed in a genetic approach using point mutagenesis and biological and structural assays of the mutant products. A primary target for modification was the structurally unique C-terminal region. Sequential deletions of C-terminal residues suggested an inevitable significance of Ile73 and Ile74 for toxicity. Based on the bioactive role of the C-terminal region and a comparison of Bj-xtrIT with a Bj-xtrIT-based model of a classical excitatory toxin, AaHIT, a conserved surface comprising the C terminus is suggested to form the site of recognition with the sodium channel receptor.