Selective reduction of delta 6 and delta 5 desaturase activities but not delta 9 desaturase in micropigs chronically fed ethanol.

This study investigated the mechanism by which chronic ethanol feeding reduces arachidonate and other highly unsaturated fatty acids in pig liver phospholipids. Five micropigs were fed a diet providing 89 kcal/kg body wt for 12 mo, with ethanol and fat as 40 and 34% of energy, respectively. Five control pigs were pairfed corn starch instead of ethanol. The activities of delta 6 and delta 5 desaturases (expressed as microsomal conversion of precursor to product) in liver from ethanol-fed pigs were reduced to less than half that of controls, whereas the activity of delta 9 desaturase was unaffected in the ethanol group. delta 5 Desaturase activity showed positive correlation with the abundance of its products in liver total phospholipids and microsomes in the ethanol group, but not in the controls. Correlation between delta 6 desaturase activity and its products showed similar pattern to that of delta 5 desaturase, but did not reach statistical significance. No difference was observed between the two groups in coenzyme A concentration in the liver. These results suggest that the selective reduction of delta 6 and delta 5 desaturase activities, not the microsomal electron transport system, are directly responsible for the altered profile of liver phospholipids.

Capacity for moderate exercise in obese subjects after adaptation to a hypocaloric, ketogenic diet.

To study the capacity for moderate endurance exercise and change in metabolic fuel utilization during adaptation to a ketogenic diet, six moderately obese, untrained subjects were fed a eucaloric, balanced diet (base line) for 2 wk, followed by 6 wk of a protein-supplemented fast (PSF), which provided 1.2 g of protein/kg ideal body wt, supplemented with minerals and vitamins. The mean weight loss was 10.6 kg. The duration of treadmill exercise to subjective exhaustion was 80% of base line after 1 wk of the PSF, but increased to 155% after 6 wk. Despite adjusting up to base line, with a backpack, the subjects' exercise weight after 6 wk of dieting, the final exercise test was performed at a mean of 60% of maximum aerobic capacity, whereas the base-line level was 76%. Resting vastus lateralis glycogen content fell to 57% of base line after 1 wk of the PSF, but rose to 69% after 6 wk, at which time no decrement in muscle glycogen was measured after >4 h of uphill walking. The respiratory quotient (RQ) during steady-state exercise was 0.76 during base line, and fell progressively to 0.66 after 6 wk of the PSF. Blood glucose was well maintained during exercise in ketosis. The sum of acetoacetate and beta hydroxybutyrate rose from 3.28 to 5.03 mM during exercise after 6 wk of the PSF, explaining in part the low exercise RQ. The low RQ and the fact that blood glucose and muscle glycogen were maintained during exhausting exercise after 6 wk of a PSF suggest that prolonged ketosis results in an adaptation, after which lipid becomes the major metabolic fuel, and net carbohydrate utilization is markedly reduced during moderate but ultimately exhausting exercise.

Modification of fatty acid composition of membrane phospholipid in hepatocyte monolayer with n-3, n-6 and n-9 fatty acids and its relationship to triacylglycerol production.

The objective of these studies with rat hepatocytes in primary culture was to establish that: (a) membrane phospholipids would become enriched with the specific fatty acid supplemented to the media and (b) hepatocyte monolayer triacylglycerol synthetic rates were dependent on the type of fatty acid enrichment of the membrane phospholipids. Hepatocytes cultured in the absence of media lipid developed a phospholipid fatty acid composition which is indicative of an essential fatty acid deficiency. The extensive rise in 18:1(n - 9) content indicated that delta 9-desaturase was active. The fatty acid composition of phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol in the microsomal- and mitochondrial-enriched fractions was highly dependent upon the type of fatty acid supplemented to the medium. Incorporation of fatty acids into phospholipids was rapid, and a new steady-state in fatty acid composition was achieved within approx. 36 h. Changes in the fatty acid composition of these hepatocyte phospholipid subclasses resulting from media supplementation with 18:2/20:4(n-6) or 20:5(n-3) were similar, but not identical, to changes which occurred in vivo as a result of consuming diets rich in 18:2(n-6) or 20:5(n-3). Hepatocyte lipogenesis was highly dependent upon the type of fatty acid supplemented to the medium. Prior conditioning with 16:0 increased triacylglycerol synthesis and secretion. Secretion of triacylglycerol was reduced by polyenoic fatty acid enrichment with 20:5(n-3) greater than 20:4/18:2(n-6). The suppression of triacylglycerol synthesis by 20:5(n-3) was due to an increased (P less than 0.05) diacylglycerol specific activity, which indicates that 20:5(n-3) suppression of hepatic triacylglycerol production may be caused in part by the inhibition of diacylglycerol acyltransferase.

Normal cardiac rhythm during hypocaloric diets of varying carbohydrate content.

Cardiac arrhythmias have been implicated in the deaths of 17 morbidly obese individuals subsisting on a collagen hydrolysate preparation ("liquid protein") during a modified fasting regimen for weight loss. Serious cardiac arrhythmias have been noted in three of six subjects studied prospectively within 28 days of starting a similar regimen, which used an inadequate protein source and was nearly devoid of all essential minerals. A comparative study of three 28-day weight loss diets of varying carbohydrate, protein, and energy content (450 to 820 kcal/day) but employing protein of good quality and adequate in micronutrients did not disclose substantial diet-related arrhythmias in five subjects on each of the three diets. The incidence of arrhythmia seen with liquid protein diets is not likely to be related to the absolute energy or carbohydrate content of the modified fasting regimen itself.

Exercise during and after very-low-calorie dieting.

Neither diet nor exercise are effective as single modes of intervention in the treatment of obesity. Although it is logical that they be combined in the context of multidisciplinary treatment, restrictions in calorie or protein intakes while dieting may impair short-term or long-term function. The limited evidence available indicates that properly constituted very-low-calorie diets can effectively preserve physical function across major weight loss, but long-term preservation of this weight loss is strongly influenced by postdiet exercise habits. In summary, counseling on and initiation of safe and effective exercise practices during dietary treatment of obesity are appropriate, but the ultimate goal should be to direct the patient towards lifelong exercise behaviors that will contribute to sustained weight maintenance.

Fetal growth and fetal lung phospholipid content in rats fed safflower oil, menhaden oil, or hydrogenated coconut oil.

The objective was to determine if dietary fish oil decreased the degree of fatty acid saturation in rat lung phosphatidylcholine (PC). A diet containing 12% of its energy as fat was fed for 3 wk to growing male Sprague-Dawley rats (trial I) or to pregnant rats for days 8-21 of gestation (trial II). The dietary fat treatments in trial I were safflower oil (SO), menhaden oil (MO), or hydrogenated coconut oil (HCO) and in trial II were SO, MO, HCO, or SO-MO (75%:25%). Polyunsaturated fatty acids reduced (p less than 0.05) hepatic fatty acid synthetase (MO greater than SO) in growing rats but the dietary lipids had no effect on lung palmitate content. Maternal consumption of MO vs SO reduced (p less than 0.05) fetal body weight and lung weight but not lung:body wt ratio. Dietary MO and SO-MO increased (p less than 0.05) disaturated PC content of fetal lungs. The fetal lung data indicate that maternal ingestion of fish oil improve fetal lung maturation.

Obesity and weight loss alter serum polyunsaturated lipids in humans.

Serum omega 6 (n-6) fatty acids were assessed in 12 obese women during an outpatient very-low-calorie diet (VLCD). Ten subjects (S10) achieved a mean weight loss of 17 kg over 3-5 mo (initial weight-for-height 157%). Serum was obtained before (baseline) and monthly during the VLCD and from five of them (S5) after 2-3 mo of weight stability (refed) at 21 kg of loss. At baseline for S10, the serum phospholipid (PL) 20:4 omega 6 was 9.16 wt% and differed from normal (12.81 wt%) by P less than 0.0001, but cholesterol ester (CE) 20:4 omega 6 did not differ from normal. During 3 mo of VLCD, the S10 serum PL and CE 18:2 omega 6 fell (P less than 0.005 and 0.0001, respectively). Serum PL 20:4 omega 6 rose to normal during VLCD months 1-3 (P less than 0.01) while the serum CE 20:4 omega 6 rose above normal (P less than 0.0002). During the VLCD, S5 results paralleled S10. However when refed, S5 PL and CE 18:2 omega 6 and 20:4 omega 6 all reverted to baseline (PL 20:4 omega 6 below normal, P less than 0.001). Serum PL 20:4 omega 6 is low in moderate obesity, corrects to normal during a VLCD, but regresses to the predict abnormality after weight loss.

The transient hypercholesterolemia of major weight loss.

Serum lipoproteins, body composition, and adipose cholesterol contents of six obese women were studied during and after major weight loss by very-low-calorie diets (VLCDs). Subjects started at 168 +/- 11% of ideal body weight, lost 30.3 +/- 3.7 kg in 5-7 mo, followed by 2+ mo in weight maintenance. Serum cholesterol fell from a prediet (baseline) value of 5.49 +/- 0.32 to 3.62 +/- 0.31 mmol/L (P less than 0.01) after 1-2 mo of VLCDs (nadir), after which it rose to 5.95 +/- 0.36 mmol/L (peak, P less than 0.01 compared with nadir and baseline) as weight loss continued. With weight maintenance, serum cholesterol fell to 4.92 +/- 0.34 mmol/L (P less than 0.05 compared with peak). Adipose cholesterol content did not change in peripheral (arm and leg) biopsy sites but rose significantly in abdominal adipose tissue with weight loss. We conclude that major weight loss was associated with a late rise in serum cholesterol, possibly from mobilization of adipose cholesterol stores, which resolved when weight loss ceased.

Liver fatty acid composition correlates with body fat and sex in a multigenic mouse model of obesity.

To determine whether there is altered liver lipid-fraction fatty acid distribution in a multigenic obese mouse model, we examined livers from eight lean (0.2-4.2% carcass fat), seven intermediate (5.7-13.8%), and five obese (20.2-48.7%) backcross progeny [(C57BL/6J x Mus spretus) x C57BL/6J] aged 2-3 mo. Thirteen males and seven females were fed a nonpurified stock diet. Liver lipid fractions were separated and fatty acids quantitated by thin-layer and gas chromatography. There was a significant effect of obesity on 18:2 omega 6 in liver phospholipids (PL), cholesteryl esters, and triglycerides. PL 18:2 omega 6 was negatively correlated with carcass fat (r = -0.74, P < 0.001); 20:3 omega 6 was elevated in PL with increased obesity (P < 0.0001), and was correlated with carcass fat (r = 0.92, P < 0.0001); and 20:4 omega 6 in PL did not differ with obesity status. PL 20:3 omega 6 and 20:4 omega 6 were lower in males (P < 0.01 and 0.02, respectively) than in females. We conclude that obesity and sex affect distribution of omega 6 essential fatty acids in mouse liver lipid fractions.

Reduced arachidonate in serum phospholipids and cholesteryl esters associated with vegetarian diets in humans.

Lipid fractions such as phospholipids (PLs), cholesteryl esters (CEs), and free fatty acids (FFAs) represent source pools for eicosanoid synthesis. To determine whether dietary habits affect the enrichment of 20:4n-6 in these precursor pools, we studied humans with partial or complete arachidonate restriction resulting from chronic avoidance of animal fat and tissue. Fasting serum was obtained from omnivorous control subjects (Omni, n = 100), semivegetarians (Semiveg, n = 16), and vegetarians (Veg, n = 25). PLs, CEs, FFAs, and triglyceride (TG) fatty acids were quantitated by thin-layer and gas chromatography. Serum 20:4n-6 was lower in the PL fraction in both Veg (p less than 0.01) and Semiveg groups (p less than 0.05) than in the Omni group and lower in the CE fraction in the Veg group (p less than 0.05). Serum 18:2n-6 did not differ between groups for any serum lipid fraction. 18:3n-3 was elevated in PLs and CEs of both Veg (p less than 0.05 and 0.01) and Semiveg groups (p less than 0.05 and 0.01) compared with the Omni group but did not result in differences in 20:5n-3 in PLs or CEs between diet groups. The lower concentration of 20:4n-6 in serum PLs and CEs of the Veg group indicates that dietary arachidonic acid enriches its circulating pool in humans; however, 20:5n-3 is not similarly responsive to dietary restriction.

Reduced tissue arachidonic acid concentration with chronic ethanol feeding in miniature pigs.

The effect of ethanol feeding on the essential fatty acid content of tissues has been contradictory. To define the effect, we analyzed fatty acid profiles in various tissues from five miniature pigs fed daily 105 kJ basal diet/kg body wt and 146 kJ ethanol/kg body wt, and also five control pigs pair-fed the same amount of basal diet but with corn starch substituted for ethanol. After 12 mo, biopsy samples were taken, and tissue fatty acid profiles were analyzed. In the phospholipid fraction from the ethanol group there was a uniform decrease in arachidonic acid (AA) and an increase in oleic acid in liver, serum, and muscle. AA was consistently decreased in the triglyceride fractions of liver, serum and subcutaneous adipose of the ethanol group. Possible explanations for this general reduction in tissue AA with ethanol feeding include decreased activities of delta 6 and delta 5 desaturases, and a displacement of AA from lipid fractions by other fatty acids.

Human subcutaneous adipose tissue shows site-specific differences in fatty acid composition.

Adipose tissue was obtained from six women undergoing liposuction twice at 6-mo intervals. Samples obtained bilaterally from abdomen, inner thigh, and outer thigh had fatty acids quantified by gas chromatography. There were no important differences between sides or over time. The saturates 14:0, 16:0, 18:0, and 20:0 were higher in abdominal adipose than in outer thigh (P < 0.002 for all); 16:1 and 18:1 omega 9 were lower in abdomen vs outer thigh (P < 0.01), whereas 18:1 omega 7 and 20:1 omega 9 were unchanged. Polyunsaturates 18:2 omega 6, 20:3 omega 6, and 20:4 omega 6 were higher in outer thigh than in abdomen (P < 0.06), and inner thigh values were intermediate. These changes in fatty acid composition resulted in lower mean triglyceride melting points from abdomen to inner thigh to outer thigh, and suggest that temperature may influence the selection process determining the variation in adipose fatty acid composition with anatomical location. Because the site-specific differences included essential fatty acids, selective uptake as well as potential differences in in situ fatty acid modification are indicated.

Self-help weight loss versus a structured commercial program after 26 weeks: a randomized controlled study.

PURPOSE: There have been few randomized controlled trials of commercial weight-loss programs. This ongoing study compares the effects of a self-help program and a commercial program on weight loss and other measures of obesity in overweight and obese men and women. SUBJECTS AND METHODS: We report the results of the first 26 weeks of a multicenter, randomized, 2-year study of 423 subjects who had a body mass index of 27 to 40 kg/m(2). Subjects were randomly assigned to either a self-help program, consisting of two 20-minute sessions with a nutritionist and provision of printed materials and other self-help resources, or to attendance at meetings of a commercial program (Weight Watchers). Outcome measures were changes in body weight, body mass index, waist circumference, and body fat. Changes in serum homocysteine levels were measured in a subsample of participants during the first 12 weeks. RESULTS: After 26 weeks, subjects in the commercial program, as compared with those in the self-help program, had greater decreases in body weight [mean (+/- SD) -4.8+/-5.6 vs -1.4+/-4.7 kg] and body mass index (-1.7+/-1.9 vs -0.5+/-1.6 kg/m(2), both P<0.001) in intention-to-treat analyses. Among subjects measured at week 26, mean waist circumference (-4.3+/-10.5 vs -0.7+/-12.7 cm) and fat mass (-3.8 +/-7.0 vs -1.5+/-7.6 kg, both P<0.05) also decreased more among subjects in the commercial program. Mean serum homocysteine levels improved in the commercial program compared with self-help (-0.5+/-1.3 vs 0.9+/-1.8 microM, P<0.05). CONCLUSIONS: A structured commercial weight-loss program is more likely to be effective for managing moderately overweight patients than brief counseling and self-help.

Effects of aerobic exercise on energy expenditure and nitrogen balance during very low calorie dieting.

Aerobic exercise in addition to severe caloric restriction was studied for its effects on resting energy expenditure (REE), weight loss, and lean tissue preservation in adult women. A formula diet providing 1.5 g protein and 0.5 g carbohydrate (CHO) per kilogram of ideal body weight daily (mean intake 720 kcal/d) was given to 12 overweight inpatients for 4 to 5 weeks. Six subjects remained sedentary (group 1), while the other six subjects (group 2) performed supervised endurance exercise (a total of 27 hours at 50% of maximal oxygen uptake (VO2max) over 4 weeks). Lean tissue preservation was excellent in both groups and was unaffected by the group 2 exercise regimen. Weight loss over 4 weeks in the two groups did not differ (group 1, 6.9 +/- 0.7 kg; group 2, 6.5 +/- 0.7 kg). The VO2max was not increased after 4 weeks of exercise compared with controls. The resting oxygen consumption (rVO2) of both groups declined 10% (P less than .001) in the first seven days of dieting. Thereafter the rVO2 in group 1 remained stable, but a further 17% reduction occurred in group 2 (P less than .03) by the third week of exercise. The free triiodothyronine (fT3) concentration also fell more in group 2 (P less than .05), suggesting a relationship between fT3 and energy expenditure during severe caloric restriction. The ergometer exercise for up to two hours daily was well tolerated. The absence of either a training effect or accelerated weight loss in group 2 may be due to the limited duration (4 weeks) or intensity of the exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

The body composition and lipid metabolic effects of long-term ethanol feeding during a high omega 6 polyunsaturated fatty acid diet in micropigs.

Our previous research with miniature pigs has shown that long-term ethanol feeding with a low-fat diet decreases arachidonic acid (20:4 omega 6) levels in multiple tissues, but we did not find significant liver pathology. In this study, we investigated the effect of ethanol feeding with high dietary linoleic acid (18:2 omega 6) on tissue fatty acid (FA) profiles and body composition. Five Yucatan micropigs were fed 370 kJ (89 kcal)/kg body weight of a diet containing ethanol and fat as 40% and 34% of energy, respectively; five control pigs were pair-fed corn starch in place of ethanol. Corn oil, 61% 18:2 omega 6, supplied most of the dietary fat. Liver biopsies were performed at baseline (n = 2 per group) and at three other time points (n = 5 per group). Phospholipid (PL) FA levels were measured by thin-layer and gas chromatography. Body composition was analyzed by underwater weighing of carcasses. Body composition analysis demonstrated a marked reduction of carcass fat in the ethanol group, but no significant reduction of carcass lean weight after 12 months. In liver PLs, the ethanol group showed decreased 20:4 omega 6 and docosahexaenoic acid (22:6 omega 3) after 1 month. While the decreased 20:4 omega 6 remained constant after 1 month, 22:6 omega 3 showed a progressive decrease up to 12-months, resulting in a continuous decrease of the omega 3/omega 6 FA ratio. This slowly progressive decrease in the omega 3/omega 6 ratio in liver PLs with ethanol feeding may have enhanced the inflammatory response in the liver, contributing to liver pathology. Body composition results indicate marked wasting of energy in the ethanol group.

Abnormal polyunsaturated lipid metabolism in the obese Zucker rat, with partial metabolic correction by gamma-linolenic acid administration.

Below-normal proportions of phospholipid (PL) arachidonic acid (20:4 omega 6) have been reported in serum from obese humans and in liver from obese Zucker rats. This implies an abnormality of 20:4 omega 6 formation from linoleic acid (18:2 omega 6), possibly in the delta 6 desaturase step, or alternatively an abnormality in the catabolism or distribution of arachidonate. We previously speculated that a reduced proportion of 20:4 omega 6 in hepatic PL could contribute to the etiology of genetic obesity. Providing 18:3 omega 6 would bypass delta 6 desaturase and possibly normalize hepatic PL 20:4 omega 6. Therefore weanling Zucker rats were given free access to a defined diet (11% of energy as soy oil) and gavaged daily with 100 microL of either black currant oil concentrate ([BCO] 8% 18:2 omega 6 and 70% 18:3 omega 6) or soy oil ([Soy] 55% 18:2 omega 6 and < 0.1% 18:3 omega 6). Groups of eight lean and eight obese animals were randomized to receive Soy or BCO in a 2 x 2 design; 10 obese and 10 lean rats were fed a stock diet (nongavaged reference). All groups of lean rats had identical weight gain; food intake for Soy lean and BCO lean did not differ. The obese reference animals and Soy obese animals did not differ in weight gain. However, BCO obese animals ate less food (P < .06), gained less weight (P < .0001), and had lower percent body fat (P < .05) compared with the Soy obese animals. The fatty acid constituents from serum, liver, and adipose tissue showed marked differences between lean and obese animals. Hepatic PL 20:4 omega 6 was lower in Soy obese than in lean (P < .002), but was normalized by BCO gavage (diet effect, P < .007). The paucity of hepatic PL 20:4 omega 6 was not due to reduced desaturase activity, as the proportions of other desaturase products (20:3 omega 6, 20:3 omega 9, 20:5 omega 3) were significantly elevated in Soy obese rat liver and serum. Serum and hepatic cholesteryl ester 20:4 omega 6 levels were elevated in obese versus lean rats (P < .02 and P < .0001), indicating abnormal arachidonate distribution in the obese Zucker rat. Because BCO selectively reduced weight gain and percent body fat in obese Zucker rats, our results imply a role for abnormal omega 6 fatty acid metabolism in the etiology of Zucker obesity.(ABSTRACT TRUNCATED AT 400 WORDS)

Changes of serum leptin and endocrine and metabolic parameters after 7 days of energy restriction in men and women.

Circulating leptin decreases during fasting in rodents and humans; however, the mechanism of the decrease is unknown. The aim of this study was to examine the relationship between decrements of serum leptin concentrations and changes of hormonal (insulin and cortisol) and metabolic (glucose, ketones, and fatty acids) parameters involved in the metabolic adaptation to energy restriction in normal-weight humans. Because there are marked gender differences in circulating leptin, both men and women were studied. The body mass index (BMI), percent body fat (% body fat), and serum leptin, insulin, cortisol, glucose, beta-hydroxybutyrate,(BOHB), and nonesterified fatty acids (NEFA) were determined in 11 men and 13 women (age, 20 to 41 years; BMI, 21.2 to 26.8 kg/m2) before and during 7 days of energy restriction (-68% +/- 1% of daily energy requirements). Weight loss averaged about 4% in both men and women. Leptin in men was 3.7 +/- 0.5 and decreased to 2.1 +/- 0.4 ng/mL (percent change [%delta], -36% +/- 6.0%, P < .0005) during restriction. Concurrently, insulin decreased from 7.2 +/- 0.6 to 1.8 +/- 0.3 microU/mL (%delta, -74% +/- 4%, P < .0001). In contrast, leptin was higher in women before (16.2 +/- 1.9 ng/mL) and after (6.0 +/- 0.8 ng/mL) restriction and decreased more than in men (%delta, -61% +/- 4%, P < .02 v men), whereas the decrease of insulin in women was less than in men: 10.1 +/- 1.9 to 6.1 +/- 1.0 microU/mL (%delta, -31% +/- 9%, P < .0025; P < .0005 v men), perhaps because glucose decreased less in women than in men. Overall, the changes of leptin during fasting were independently correlated with the changes of glucose (r = .53, P < .007), NEFA (r = .53, P < .01), and BOHB (r = .65, P < .001). In addition, the change of leptin correlated with a combined index of the parameters that reflect decreased glucose availability and increased lipolysis ([deltaglucose + deltainsulin + deltaNEFA]/3, r = .73, P < .0001) or a combined index of parameters that would be expected to limit glucose uptake by adipocytes ([deltaglucose + deltainsulin + deltacortisol]/3, r = .48, P < .02). We conclude that there are significant differences between men and women in the responses of leptin and insulin to energy restriction. Furthermore, decreases of circulating leptin during negative energy balance are related to changes of endocrine and metabolic parameters, suggesting that leptin secretion may be regulated by alterations of adipocyte glucose and lipid metabolism, ie, decreased glucose uptake and metabolism and increased lipolysis.

The human metabolic response to chronic ketosis without caloric restriction: physical and biochemical adaptation.

To study the metabolic effects of ketosis without weight loss, nine lean men were fed a eucaloric balanced diet (EBD) for one week providing 35-50 kcal/kg/d, 1.75 g of protein per kilogram per day and the remaining kilocalories as two-thirds carbohydrate (CHO) and one-third fat. This was followed by four weeks of a eucaloric ketogenic diet (EKD)--isocaloric and isonitrogenous with the EBD but providing less than 20 g CHO daily. Both diets were appropriately supplemented with minerals and vitamins. Weight and whole-body potassium estimated by potassium-40 counting (40K) did not vary significantly during the five-week study. Nitrogen balance (N-Bal) was regained after one week of the EKD. The fasting blood glucose remained lower during the EKD than during the control diet (4.4 mmol/L at EBD, 4.1 mmol/L at EKD-4, P less than 0.01). The fasting whole-body glucose oxidation rate determined by a 13C-glucose primed constant infusion technique fell from 0.71 mg/kg/min during the control diet to 0.50 mg/kg/min (P less than 0.01) during the fourth week of the EKD. The mean serum cholesterol level rose (from 159 to 208 mg/dL) during the EKD, while triglycerides fell from 107 to 79 mg/dL. No disturbance of hepatic or renal function was noted at EKD-4. These findings indicate that the ketotic state induced by the EKD was well tolerated in lean subjects; nitrogen balance was regained after brief adaptation, serum lipids were not pathologically elevated, and blood glucose oxidation at rest was measurably reduced while the subjects remained euglycemic.

The human metabolic response to chronic ketosis without caloric restriction: preservation of submaximal exercise capability with reduced carbohydrate oxidation.

To study the effect of chronic ketosis on exercise performance in endurance-trained humans, five well-trained cyclists were fed a eucaloric balanced diet (EBD) for one week providing 35-50 kcal/kg/d, 1.75 g protein/kg/d and the remainder of kilocalories as two-thirds carbohydrate (CHO) and one-third fat. This was followed by four weeks of a eucaloric ketogenic diet (EKD), isocaloric and isonitrogenous with the EBD but providing less than 20 g CHO daily. Both diets were appropriately supplemented to meet the recommended daily allowances for vitamins and minerals. Pedal ergometer testing of maximal oxygen uptake (VO2max) was unchanged between the control week (EBD-1) and week 3 of the ketogenic diet (EKD-3). The mean ergometer endurance time for continuous exercise to exhaustion (ENDUR) at 62%-64% of VO2max was 147 minutes at EBD-1 and 151 minutes at EKD-4. The ENDUR steady-state RQ dropped from 0.83 to 0.72 (P less than 0.01) from EBD-1 to EKD-4. In agreement with this were a three-fold drop in glucose oxidation (from 15.1 to 5.1 mg/kg/min, P less than 0.05) and a four-fold reduction in muscle glycogen use (0.61 to 0.13 mmol/kg/min, P less than 0.01). Neither clinical nor biochemical evidence of hypoglycemia was observed during ENDUR at EKD-4. These results indicate that aerobic endurance exercise by well-trained cyclists was not compromised by four weeks of ketosis. This was accomplished by a dramatic physiologic adaptation that conserved limited carbohydrate stores (both glucose and muscle glycogen) and made fat the predominant muscle substrate at this submaximal power level.