2005

Ann Nutr Metab. 2005 Mar-Apr;49(2):77-82.
Effects of intermittent fasting on serum lipid levels, coagulation status and plasma homocysteine levels.
Aksungar FB, Eren A, Ure S, Teskin O, Ates G.
Department of Biochemistry, School of Medicine, Maltepe University, Istanbul, Turkey.

BACKGROUND: During Ramadan, Muslims fast during the daylight hours for a month. The duration of restricted food and beverage intake is approximately 12 h/day which makes Ramadan a unique model of intermittent fasting. Many physiological and psychological changes are observed during Ramadan that are probably due to the changes in eating and sleeping patterns. METHODS: Serum total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), prothrombin time, activated partial thromboplastin time (aPTT), plasma fibrinogen, D-dimer and homocysteine levels were measured in 24 healthy fasting volunteers (12 females, 12 males) aged 21-35 years. Venous blood samples were taken 1 week before Ramadan, on the 21st day of Ramadan and 20 days after Ramadan. RESULTS: No significant changes were observed on serum total cholesterol, triglycerides and LDL levels. HDL levels were significantly elevated during Ramadan (p < 0.001) and 20 days after Ramadan (p < 0.05). Prothrombin time, aPTT, fibrinogen and D-dimer levels were in the physiologic limits in all samples but D-dimer levels were significantly low at the end of Ramadan in comparison to pre- and post-fasting levels (p < 0.001). Homocysteine levels, being still in reference ranges, were low during Ramadan (p < 0.05) and reached the pre-fasting levels after Ramadan. CONCLUSION: Our results demonstrate that intermittent fasting led to some beneficial changes in serum HDL and plasma homocysteine levels, and the coagulation status. These changes may be due to omitting at least one meal when the body was particularly metabolically active and possibly had a low blood viscosity level at the same time. We conclude that intermittent fasting may have beneficial effects on hemostatic risk markers for cardiovascular diseases. Copyright (c) 2005 S. Karger AG, Basel.

Mech Ageing Dev. 2005 May 10.
Membrane alteration as a basis of aging and the protective effects of calorie restriction.
Yu BP.
Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

As has been experimentally determined, oxidative modification to biological systems can be extensive, although the identification and stochiometric relation of the reactive species that cause these alterations have not been fully elucidated. In this review, arguments are presented to support the notion that the combined effects of membrane lipid peroxidation and its by-products, reactive aldehydes are likely responsible for membrane-associated functional declines during aging. As evidence for a systemic response to overall oxidative stress, the molecular inflammation hypothesis of aging is discussed by considering that the activation of inflammatory genes act as a bridge linking normal aging to pathological processes.

Nat Rev Mol Cell Biol. 2005 Apr;6(4):298-305.
Calorie restriction, SIRT1 and metabolism: understanding longevity.
Bordone L, Guarente L.
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing.

Int J Obes Relat Metab Disord. 2005 Apr 19.
Antiobese and hypolipidemic effects of platycodin saponins in diet-induced obese rats: evidences for lipase inhibition and calorie intake restriction.
Zhao HL, Sim JS, Shim SH, Ha YW, Kang SS, Kim YS.
1Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Korea.

OBJECTIVE:: To investigate how and to what extent platycodin saponin (PS) from Platycodi Radix exerts a favorable influence on obesity and hyperlipidemia. DESIGN:: Sprague-Dawley rats were fed with a high fat (HF) diet for 4 weeks and then the animals were treated with 35 or 70 mg/kg of PS for another 4 weeks. Changes in body weight and daily calorie intake were measured regularly during the experimental period and the degree of linear correlation for the above two variables was further analyzed. The in vitro lipase inhibition of each PS compound and the in vivo fecal lipid excretion were examined in hope of revealing their relationship. The concentrations of hepatic triglyceride and cholesterol in serum. RESULTS:: The body weight reduction (13+/-4% vs HF control, P<0.05) by PS administration was highly correlated to the food intake restriction (Pearson's linear coefficient r=0.752, P<0.005). The in vitro inhibition of lipase by each isolated compound and mixture of PS were virtually identical. Consequently, the fecal TG excretion was increased by 2.1-3.2 folds depending on the dose of PS. The serum TG and LDL-cholesterol concentrations were decreased without noticeable changes in HDL-cholesterol levels. Concomitantly, the contents of the hepatic TG, cholesterol, and the liver surface fat pads were decreased in ubiquity, but no noticeable biochemical abnormalities or histological tissue damages were observed. CONCLUSIONS:: The administration of PS produced profound effects on the control of obesity and lipid metabolism, which resulted in LDL-cholesterol reduction. PS also caused a remarkable reduction in calorie intake, which was highly correlated to the body weight loss. These results suggest that PS has a greater role in antiobesity, hypolipidemia, and liver protection than previously thought. Hence, PS could be a potential therapeutic alternative in the treatment of obesity and hyperlipidemia.International Journal of Obesity advance online publication, 19 April 2005; doi:10.1038/sj.ijo.0802948.

2004

Obes Res. 2004 Nov;12 Suppl 2:115S-23S.
Cardiovascular and hormonal aspects of very-low-carbohydrate ketogenic diets.
Volek JS, Sharman MJ.
Hman Performance Laboratory, Department of Kinesiology, University of Connecticut, Storrs, CT 06269-1110, USA.

In recent years, restriction of carbohydrate intake for weight loss has become widespread. Our research group began studying physiological responses to very-low-carbohydrate ketogenic diets (VLCKDs) in the late 1990s because we felt there was a significant void in the literature and limited understanding of metabolic responses to VLCKDs. This launched us into a line of research examining the physiological effects of VLCKDs. In this paper, we briefly overview nine studies we have published on isoenergetic and hypoenergetic VLCKDs in men and women. These studies have focused on blood lipid responses to VLCKDs, but we have also addressed changes in body weight, body composition, and hormones. Compared with low-fat diets, short-term VLCKDs consistently result in improvements in fat loss, fasting and postprandial triacylglycerols, high-density lipoprotein-cholesterol, the distribution of low-density lipoprotein-cholesterol subclasses, and insulin resistance. These are the key metabolic abnormalities of metabolic syndrome, a problem of epidemic proportions in the United States. There is substantial variability in total cholesterol and low-density lipoprotein-cholesterol responses to VLCKD. The factors responsible for this variability are not known, and studies designed to identify methods to predict blood lipid responses to VLCKD and other dietary approaches represent critical areas for nutrition researchers. Further research is warranted to validate the physiological effects of VLCKD over longer periods of time, including studies that modify the quality of macronutrients (i.e., the type of fat and protein) and the interaction with other interventions (e.g., exercise, dietary supplements, drugs).

2003

Epilepsia. 2003 Jun;44(6):752-60.
Calorie restriction and ketogenic diet diminish neuronal excitability in rat dentate gyrus in vivo.
Bough KJ, Schwartzkroin PA, Rho JM.
Emory University School of Medicine, Department of Pharmacology, Rollins Research Center, Atlanta, GA 30322, USA.

PURPOSE: The ketogenic diet (KD) is an effective treatment for intractable epilepsy. However, little is known about its underlying mechanisms. METHODS: In this study, in vivo extracellular field responses to angular bundle stimulation were recorded in the dentate gyrus of Sprague-Dawley rats fed one of three diets: ketogenic calorie-restricted (KCR), normal calorie-restricted (NCR), or normal ad libitum (NAL). Input/output curves and paired-pulse relations were used to assess network excitability. A maximal dentate activation (MDA) protocol was used to measure electrographic seizure threshold and duration. RESULTS: Animals fed calorie-restricted (CR) diets exhibited greater paired-pulse inhibition, an elevated MDA threshold, and an absence of spreading depression-like events compared with ad libitum-fed controls. In the MDA model of epileptogenesis, the rate of increase in electrographic seizure duration after repeated stimuli was markedly reduced in KCR-fed animals compared with NCR- and NAL-fed controls. CONCLUSIONS: These data suggest that CR, by itself, can be anticonvulsant, and treatment with a KCR diet may be both anticonvulsant and antiepileptogenic.

Epilepsy Res. 2003 Apr;54(1):41-52.
Calorie restriction of a high-carbohydrate diet elevates the threshold of PTZ-induced seizures to values equal to those seen with a ketogenic diet.
Eagles DA, Boyd SJ, Kotak A, Allan F.
Department of Biology, Georgetown University, Box 571229, Washington, DC 20057-1229, USA.

The purpose of this study was to evaluate the contributions of ketonemia, caloric restriction, and carbohydrates to seizure protection in rats fed selected diets. Male Sprague-Dawley rats were fed experimental diets of two basic types, one high in carbohydrates and restricted to 90, 65, or 50% of the normal daily caloric requirement and the other a normal rodent chow diet restricted to 90 or 65% of the daily caloric requirement. After consuming their respective diets for 20 days, animals were subjected to tail-vein infusion of pentylenetetrazole (PTZ) to determine seizure threshold, taken as the dose required to evoke the first clonic reaction. Seizure thresholds were compared to those of rats fed control diets of either normal rodent chow fed ad libitum or a standard high-fat (ketogenic) diet calorie-restricted to 90% of daily caloric requirement, all animals age- and weight-matched at the time of diet onset. All diets were balanced for vitamins and minerals and contained at least 10% protein (by weight). Seizure threshold and ketonemia were elevated in both experimental diets in approximate proportion to the degree of calorie restriction. Animals fed the most severely restricted high-carbohydrate diet (50%) had seizure thresholds equal to those fed the ketogenic diet but had significantly lower ketonemia.

2001

IUBMB Life. 2001 Apr;51(4):241-7
Ketone bodies, potential therapeutic uses.
Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF Jr.
Unit on Metabolic Control, LMMB/NIAAA, Rockville, Maryland, USA.

Ketosis, meaning elevation of D-beta-hydroxybutyrate (R-3hydroxybutyrate) and acetoacetate, has been central to starving man's survival by providing nonglucose substrate to his evolutionarily hypertrophied brain, sparing muscle from destruction for glucose synthesis. Surprisingly, D-beta-hydroxybutyrate (abbreviated "betaOHB") may also provide a more efficient source of energy for brain per unit oxygen, supported by the same phenomenon noted in the isolated working perfused rat heart and in sperm. It has also been shown to decrease cell death in two human neuronal cultures, one a model of Alzheimer's and the other of Parkinson's disease. These observations raise the possibility that a number of neurologic disorders, genetic and acquired, might benefit by ketosis. Other beneficial effects from betaOHB include an increased energy of ATP hydrolysis (deltaG') and its linked ionic gradients. This may be significant in drug-resistant epilepsy and in injury and anoxic states. The ability of betaOHB to oxidize co-enzyme Q and reduce NADP+ may also be important in decreasing free radical damage. Clinical maneuvers for increasing blood levels of betaOHB to 2-5 mmol may require synthetic esters or polymers of betaOHB taken orally, probably 100 to 150 g or more daily. This necessitates advances in food-science technology to provide at least enough orally acceptable synthetic material for animal and possibly subsequent clinical testing. The other major need is to bring the technology for the analysis of multiple metabolic "phenotypes" up to the level of sophistication of the instrumentation used, for example, in gene science or in structural biology. This technical strategy will be critical to the characterization of polygenic disorders by enhancing the knowledge gained from gene analysis and from the subsequent steps and modifications of the protein products themselves.

1999

J Nutr 1999 Nov;129(11):2005-8.
Fasting increases serum total cholesterol, LDL cholesterol and apolipoprotein B in healthy, nonobese humans.
Savendahl L; Underwood LE.
Department of Pediatrics, Division of Endocrinology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7220, USA.

Voluntary fasting is practiced by many humans in an attempt to lose body weight. Conflicting results have been published on the effects of food deprivation on serum lipids. To study the effect of acute starvation on serum lipids, 10 nonobese (93-124% of ideal body weight), healthy adults (6 men, 4 women, 21-38 y old) fasted (no energy) for 7 d. Fasting increased total serum cholesterol from 4.90 +/- 0.23 to 6.73 +/- 0.41 mmol/L (37.3 +/- 5.0%; P < 0.0001) and LDL cholesterol from 2.95 +/- 0.21 to 4.90 +/- 0.36 mmol/L (66.1 +/- 6. 6%; P < 0.0001). Serum apolipoprotein B (apo B) increased from 0.84 +/- 0.06 to 1.37 +/- 0.11 g/L (65.0 +/- 9.2%; P < 0.0001). The increases in serum cholesterol, LDL and apo B were associated with weight loss. Fasting did not affect serum concentrations of triacylglycerol and HDL cholesterol. Serum concentrations of insulin-like growth factor-I (IGF-I) decreased from 246 +/- 29 (prefast) to 87 +/- 10 microg/L after 1 wk of fasting (P < 0.0001). We conclude that, in nonobese subjects, fasting is accompanied by increases in serum cholesterol, LDL and apo B concentrations, whereas IGF-I levels are decreased.

1995

Scand J Clin Lab Invest 1995 Jul;55(4):351-7.
Hypercholesterolaemia of prolonged fasting and cholesterol lowering of re-feeding in lean human subjects.
Thampy KG.
Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, Fort Wayne, USA.

Serum cholesterol and triglycerides were determined in 36 lean, healthy adults (mean body mass index = 24.3 +/- 0.4 kg m-2) during a period of fasting of 7-21 days. Fasting for 1 week resulted in significant elevation of serum cholesterol (mean increase 25%, range 0-68) and triglycerides (mean increase 24%). No correlation was observed between pre-fast cholesterol level and fasting-induced hypercholesterolaemia. Continued fasting for up to 21 days resulted in lowering of both cholesterol and triglycerides to pre-fast levels. One week of hypocaloric re-feeding resulted in significantly lower than pre-fast cholesterol (mean decrease 13%) and significantly higher than prefast triglycerides (mean increase 86%). The net change in serum cholesterol observed as a result of fasting and re-feeding correlated with prefast cholesterol (r = -0.6901, p = 0.0001). No significant change in the ratio of unesterified cholesterol to total cholesterol was observed during fasting. Fasting for 3 weeks followed by 1 week of hypocaloric re-feeding, however, resulted in a significant (p = 0.05) increase in this ratio from 0.27 +/- 0.0057 to 0.34 +/- 0.01. Fasting for 1 or 2 weeks followed by re-feeding also resulted in a similar increase in the ratio of unesterified cholesterol to total cholesterol. Cholesterol in the HDL fraction remained within normal range throughout the fasting and re-feeding period, with no significant changes between time points.

1994

Am J Physiol 1994 Feb;266(2 Pt 1):E179-85.
Regulation of hormone-sensitive lipase during fasting.
Sztalryd C; Kraemer FB.
Department of Medicine, Stanford University School of Medicine 94305.

Hormone-sensitive lipase (HSL) is the rate-limiting enzyme in lipolysis. The activity of HSL is thought to be primarily regulated by phosphorylation-dephosphorylation reactions. Although FFA levels are elevated during fasting, it has been difficult to demonstrate an increase in HSL activity with fasting. The current studies were undertaken to explore directly the regulation of HSL _expression in adipose tissue in the rat during fasting. Rats were fasted for periods up to 5 days and HSL activity, HSL immunoreactive protein, and HSL mRNA levels were measured both in intact epididymal adipose tissue and in isolated adipose cells. Fasting caused a progressive decline in total body weight and the weight of epididymal fat pads, whereas adipose cell size decreased approximately 50% after 2 days of fasting. Serum FFA levels approximately doubled within 1 day of fasting and remained elevated thereafter. Basal lipolysis, measured as glycerol release, did not increase until 2 days of fasting. HSL activity remained relatively unchanged until 3 days of fasting when it was increased twofold after 3-5 days of fasting. Likewise, HSL immunoreactive protein and HSL mRNA levels increased twofold after 3-5 days of fasting. Thus HSL activity appears to be regulated by pretranslational mechanisms during prolonged fasting. However, increases in FFA flux during short-term fasting appear to involve either post-translational control of HSL or the regulation of other enzymes.

Scand J Clin Lab Invest 1994 Jul;54(4):301-4.
Effect of 1-week fasting on some blood values in man.
Narvanen S; Frankberg-Lakkala H; Meurman JH.
Children's Hospital, Helsinki University Central Hospital, Finland.

Fifty-eight voluntary and healthy subjects (mean age 42.3 +/- 11.2 years) participated in 7-day supervised fasting trial during which only fruit and berry juices, tea and water were consumed. Venous blood was drawn before and after 1-week fasting and 3 months after the termination of the trial. The subjects' body weight and blood pressure values were also recorded. The results showed a statistically significant decrease in blood thrombocyte counts after 1-week fasting (p < 0.05), while a significant increase was observed in serum beta-hydroxybutyrate and alanine aminotransferase activities (p < 0.001). All other blood values, including glucose and creatinine, remained stable throughout the trial.

1990

Diabetes. 1990 Feb;39(2):234-40.
Metabolic effects of 1200-kcal diet in obese pregnant women with gestational diabetes.
Magee MS, Knopp RH, Benedetti TJ
Department of Medicine, University of Washington School of Medicine, Seattle .

Calorie restriction is widely used as a primary therapy for obese pregnant women with gestational diabetes. To better understand the metabolic consequences of marked calorie restriction, we performed a randomized prospective trial under metabolic ward conditions. Obese gestationally diabetic women were randomized to control (n = 5) and calorie-restricted (n = 7) groups. All patients consumed an approximately 2400-kcal/day diet during the 1st wk of the study, and at the end of the 1st wk, metabolic features of the two groups were statistically indistinguishable. During the 2nd wk, the control group continued to consume approximately 2400 kcal/day, whereas the calorie-restricted group consumed approximately 1200 kcal/day. Twenty-four-hour mean glucose levels remained unchanged in the control group (6.7 +/- 0.8 mM wk 1 vs. 6.8 +/- 0.8 mM wk 2), although they dropped dramatically in the calorie-restricted group (6.7 +/- 1.0 mM wk 1 vs. 5.4 +/- 0.5 mM wk 2, P less than 0.01). Fasting plasma insulin also declined in the calorie-restricted group (265 +/- 165 pM wk 1 vs. 145 +/- 130 pM wk 2), resulting in a significant change between groups (P less than 0.02). Surprisingly, fasting plasma glucose and glucose tolerance measured by the 3-h oral glucose tolerance test did not change within or between groups. Fasting levels of beta-hydroxybutyrate rose in the calorie-restricted group (290 +/- 240 microM wk 1 vs. 780 +/- 30 microM wk 2) but not in the control group (P less than 0.01). Finally, urine ketones increased significantly (P less than 0.02) in the calorie-restricted group, whereas they remained absent in the control group.(ABSTRACT TRUNCATED AT 250 WORDS).

Am J Clin Nutr. 1990 Feb;51(2):167-72.
Controlled trial of the metabolic effects of a very-low-calorie diet: short- and long-term effects.
Foster GD, Wadden TA, Feurer ID, Jennings AS, Stunkard AJ, Crosby LO, Ship J, Mullen JL.
University of Pennsylvania School of Medicine, Philadelphia.

Resting energy expenditure (REE), weight, and body composition were measured up to seven times in 13 obese women during a 24-wk study. Patients were randomly assigned to a very-low-calorie diet (VLCD, 500 kcal/d) or a balanced-deficit diet (BDD, 1200 kcal/d). After 8 wk of supplemented fasting, REE of the VLCD patients decreased by 17% whereas that of the BDD patients was virtually unchanged. REE of the VLCD patients increased during 12 subsequent weeks of realimentation such that differences in REE between the two groups were not statistically significant at week 24 (VLCD = -11%, BDD = -2%). Reductions in weight and fat-free mass (FFM) were 12.1% and 3.6% for the VLCD patients and 10.6% and 4.1% for the BDD patients, respectively. There were no significant differences between the groups in pre- to posttreatment changes in REE normalized to FFM. Results suggest that REE recovers partially after consumption of a VLCD. They also provide evidence of a possible metabolic advantage of weight loss by a more moderate restriction.

1986

Gerontol 1986 Sep;41(5):599-604.
Effects of fasting on ketone body concentrations in healthy men of different ages.
London ED; Margolin RA; Duara R; Holloway HW; Robertson-Tchabo EA; Cutler NR; Rapoport SI J.

This work was performed to assess age effects on fasting-induced hyperketonemia and to determine if measurement of cerebral glucose utilization by positron emission tomography after 6 to 8 hr of fasting is associated with hyperketonemia that could influence cerebral glucose metabolism. Acetoacetate and 3-hydroxybutyrate were assayed in venous blood from healthy men of various ages, subjected to an 18-hr fast. At 18 hr of fasting but not at 14 hr or earlier, 3-hydroxybutyrate concentrations were correlated significantly with age; concentrations of acetoacetate and 3-hydroxybutyrate were significantly higher than at earlier times in the fast, p less than or equal to .05, with elevations of 82% and 214% over baseline, respectively. Acetoacetate and 3-hydroxybutyrate concentrations were higher on the day when cerebral glucose utilization was determined than after a comparable fast at another time. The observed level of hyperketonemia, however, would not substantially influence cerebral glucose metabolism. The findings indicate that aging is associated with increased susceptibility to fasting-induced hyperketonemia.