Stephen D. Phinney

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.

Dietary carbohydrate restriction induces a unique metabolic state positively affecting atherogenic dyslipidemia, fatty acid partitioning, and metabolic syndrome.

Abnormal fatty acid metabolism and dyslipidemia play an intimate role in the pathogenesis of metabolic syndrome and cardiovascular diseases. The availability of glucose and insulin predominate as upstream regulatory elements that operate through a collection of transcription factors to partition lipids toward anabolic pathways. The unraveling of the details of these cellular events has proceeded rapidly, but their physiologic relevance to lifestyle modification has been largely ignored. Here we highlight the role of dietary input, specifically carbohydrate intake, in the mechanism of metabolic regulation germane to metabolic syndrome. The key principle is that carbohydrate, directly or indirectly through the effect of insulin, controls the disposition of excess dietary nutrients. Dietary carbohydrate modulates lipolysis, lipoprotein assembly and processing and affects the relation between dietary intake of saturated fat intake and circulating levels. Several of these processes are the subject of intense investigation at the cellular level. We see the need to integrate these cellular mechanisms with results from low-carbohydrate diet trials that have shown reduced cardiovascular risk through improvement in hepatic, intravascular, and peripheral processing of lipoproteins, alterations in fatty acid composition, and reductions in other cardiovascular risk factors, notably inflammation. From the current state of the literature, however, low-carbohydrate diets are grounded in basic metabolic principles and the data suggest that some form of carbohydrate restriction is a candidate to be the preferred dietary strategy for cardiovascular health beyond weight regulation.

The effect of dietary arachidonic acid on plasma lipoprotein distributions, apoproteins, blood lipid levels, and tissue fatty acid composition in humans.

Normal healthy male volunteers (n=10) were fed diets (high-AA) containing 1.7 g/d of arachidonic acid (AA) for 50 d. The control (low-AA) diet contained 210 mg/d of AA. Dietary AA had no statistically significant effect on the blood cholesterol levels, lipoprotein distribution, or apoprotein levels. Adipose tissue fatty acid composition was not influenced by AA feeding. The plasma total fatty acid composition was markedly enriched in AA after 50 d (P<0.005). The fatty acid composition of plasma lipid fractions, cholesterol esters, triglycerides, free fatty acids, and phospholipid (PL) showed marked differences in the degree of enrichment in AA. The PL plasma fraction from the subjects consuming the low-AA diet contained 10.3% AA while the subjects who consumed the high-AA diet had plasma PL fractions containing 19.0% AA. The level of 22:4n-6 also was different (0.67 to 1.06%) in the plasma PL fraction after 50 d of AA feeding. After consuming the high-AA diet, the total red blood cell fatty acid composition was significantly enriched in AA which mainly replaced linoleic acid. These results indicate that dietary AA is incorporated into tissue lipids, but selectively into different tissues and lipid classes. Perhaps more importantly, the results demonstrate that dietary AA does not alter blood lipids or lipoprotein levels or have obvious adverse health effects at this level and duration of feeding.

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.

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.

It is time to bust the myth of physical inactivity and obesity: you cannot outrun a bad diet

A recent report from the UKs Academy of Medical Royal Colleges described ‘the miracle cure’ of performing 30 min of moderate exercise, five times a week, as more powerful than many drugs administered for chronic disease prevention and management.1 Regular physical activity reduces the risk of developing cardiovascular disease, type 2 diabetes, dementia and some cancers by at least 30%. However, physical activity does not promote weight loss. In the past 30 years, as obesity has rocketed, there has been little change in physical activity levels in the Western population.2 This places the blame for our expanding waist lines directly on the type and amount of calories consumed. However, the obesity epidemic represents only the tip of a much larger iceberg of the adverse health consequences of poor diet. According to The Lancet global burden of disease reports, poor diet now generates more disease than physical inactivity, alcohol and smoking combined. Up to 40% of those with a normal body mass index will harbour metabolic abnormalities typically associated with obesity, which include hypertension, dyslipidaemia, non-alcoholic fatty liver disease and cardiovascular disease.3 However, this is little appreciated by scientists, doctors, media writers and policymakers, despite the extensive scientific literature on the vulnerability of all ages and all …

Rethinking fat as a fuel for endurance exercise

Abstract A key element contributing to deteriorating exercise capacity during physically demanding sport appears to be reduced carbohydrate availability coupled with an inability to effectively utilize alternative lipid fuel sources. Paradoxically, cognitive and physical decline associated with glycogen depletion occurs in the presence of an over-abundance of fuel stored as body fat that the athlete is apparently unable to access effectively. Current fuelling tactics that emphasize high-carbohydrate intakes before and during exercise inhibit fat utilization. The most efficient approach to accelerate the body’s ability to oxidize fat is to lower dietary carbohydrate intake to a level that results in nutritional ketosis (i.e., circulating ketone levels >0.5 mmol/L) while increasing fat intake for a period of several weeks. The coordinated set of metabolic adaptations that ensures proper interorgan fuel supply in the face of low-carbohydrate availability is referred to as keto-adaptation. Beyond simply providing a stable source of fuel for the brain, the major circulating ketone body, beta-hydroxybutyrate, has recently been shown to act as a signalling molecule capable of altering gene expression, eliciting complementary effects of keto-adaptation that could extend human physical and mental performance beyond current expectation. In this paper, we review these new findings and propose that the shift to fatty acids and ketones as primary fuels when dietary carbohydrate is restricted could be of benefit for some athletes.

Metabolic characteristics of keto-adapted ultra-endurance runners.

BACKGROUND Many successful ultra-endurance athletes have switched from a high-carbohydrate to a low-carbohydrate diet, but they have not previously been studied to determine the extent of metabolic adaptations. METHODS Twenty elite ultra-marathoners and ironman distance triathletes performed a maximal graded exercise test and a 180 min submaximal run at 64% VO2max on a treadmill to determine metabolic responses. One group habitually consumed a traditional high-carbohydrate (HC: n=10, %carbohydrate:protein:fat=59:14:25) diet, and the other a low-carbohydrate (LC; n=10, 10:19:70) diet for an average of 20 months (range 9 to 36 months). RESULTS Peak fat oxidation was 2.3-fold higher in the LC group (1.54±0.18 vs 0.67±0.14 g/min; P=0.000) and it occurred at a higher percentage of VO2max (70.3±6.3 vs 54.9±7.8%; P=0.000). Mean fat oxidation during submaximal exercise was 59% higher in the LC group (1.21±0.02 vs 0.76±0.11 g/min; P=0.000) corresponding to a greater relative contribution of fat (88±2 vs 56±8%; P=0.000). Despite these marked differences in fuel use between LC and HC athletes, there were no significant differences in resting muscle glycogen and the level of depletion after 180 min of running (-64% from pre-exercise) and 120 min of recovery (-36% from pre-exercise). CONCLUSION Compared to highly trained ultra-endurance athletes consuming an HC diet, long-term keto-adaptation results in extraordinarily high rates of fat oxidation, whereas muscle glycogen utilization and repletion patterns during and after a 3 hour run are similar.

Assessment of dietary and genetic factors influencing serum and adipose fatty acid composition in obese female identical twins

Fourteen pairs of obese female monozygotic twins were recruited for a study of genetic influences on serum and adipose fatty acid (FA) composition. Following 1 wk of inpatient stabilization, fasting serum and adipose tissue obtained by surgical excision were analyzed by thin-layer and gas chromatography. Intrapair resemblances (IPR) for individual FA were assessed by Spearman rank correlation and by analysis of variance and were found in serum cholesteryl esters (CE), triglycerides (TG), and adipose TG. With two exceptions (CE linoleate and adipose eicosapentaenoate), these IPR were limited to the nonessential FA. Palmitate had significant IPR in four lipid fractions; in serum CE and adipose TG palmitate was strongly correlated with multiple measures of adiposity. In contrast to other lipid fractions, serum phosphatidylcholine (PC) FA had 12 IPR, of which 6 were essential FA including arachidonate (r=0.76, P<0.0005), eicosapentaenoate (r=0.78, P<0.0005), and docosahexaenoate (r=0.86, P<0.0001). The PC IPR could not be explained by analysis of preadmission 7-d food records. After dividing the pairs into two groups differing and nondiffering according to fat intake of individuals in the pair, there was no evidence of a gene-environment interaction between fat intake and FA composition. The IPR for nonessential FA indicate that there is active genetic control of either food choices or postabsorptive metabolic processing. The high level of IPR in the PC fraction in contrast to the other lipid fractions suggests strong genetic influence over selection of specific FA for this membrane fraction independent of diet.

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.