Sleep restriction by sleep timing late night or early wake: The impact on physical activity and dietary intake in adults.

PURPOSE: To date, few studies have assessed whether the timing of sleep restriction impacts physical activity and energy intake patterns. Thus, we aimed to quantify physical activity and energy intake during an early wake (EW) and late sleep (LS) period. METHODS: Fourteen participants who met the inclusion criteria (sleep 7-9 h/night and a BMI of <40 kg/m2) participated in 3 crossover free-living conditions: normal sleep (NS, 7-9 h), EW (2-h early wake-time), and LS (2-h late to sleep) for 4 nights. Sleep duration (via Actiwatch), energy intake (via food diaries), and physical activity (via hip accelerometry) were recorded for 4 days/4 nights throughout each condition. RESULTS: Sleep duration was reduced in both sleep restriction conditions compared to NS (p < 0.001) with no difference between sleep restriction conditions. Daily energy intake tended to increase in the LS condition (p = 0.056) but was unchanged during EW (p = 0.56). Fat (p = 0.031) and sodium (p = 0.039) intake were increased in the LS condition only compared to NS. During the EW condition, fat (p = 0.24) and sodium (p = 0.18) intake were not altered. No changes in carbohydrate or protein intake occurred between conditions. Daily steps tended to increase in the EW condition compared to NS (p = 0.058), while steps during the LS condition were unchanged (p = 0.28), with no differences between sleep restriction conditions. CONCLUSION: The timing of sleep curtailment differentially influences physical activity and EI the following day, such that EW results in increased physical activity, while LS leads to poorer dietary choices.

Modest sleep restriction does not influence steps, physical activity intensity or glucose tolerance in obese adults.

Sleep restriction (SR) (<6 h) and physical activity (PA) are risk factors for obesity, but little work has examined the inter-related influences of both risk factors. In a free-living environment, 13 overweight/obese adults were sleep restricted for five nights to 6 h time-in-bed each night, with and without regular exercise (45 min/65% VO2 max; counterbalanced design). Two days of recovery sleep followed SR. Subjects were measured during a mixed meal tolerance test (MMT), resting metabolic rate, cognitive testing and fat biopsy (n=8). SR increased peak glucose response (+7.3 mg/dl, p = .04), elevated fasting non-esterified fatty acid (NEFA) concentrations (+0.1 mmol/L, p = .001) and enhanced fat oxidation (p < .001) without modifying step counts or PA intensity. Inclusion of daily exercise increased step count (+4,700 steps/day, p < .001) and decreased the insulin response to a meal (p = .01) but did not prevent the increased peak glucose response or elevated NEFA levels. The weekend recovery period improved fasting glucose (p = .02), insulin (p = .02), NEFA concentrations (p = .001) and HOMA-IR (p < .01) despite reduced steps (p < .01) and increased sedentary time (p < .01). Abdominal adipose tissue (AT) samples, obtained after baseline, SR and exercise, did not differ in lipolytic capacity following SR. Fatty acid synthase protein content tended to increase following SR (p = .07), but not following exercise. In a free-living setting, SR adversely affected circulating NEFAs, fuel oxidation and peak glucose response but did not directly affect glucose tolerance or AT lipolysis. SR-associated metabolic impairments were not mitigated by exercise, yet recovery sleep completely rescued its adverse effects on glucose metabolism.

Role of ERß in adipocyte metabolic response to wheel running following ovariectomy.

Estrogen receptor ß (ERb), one of the two major estrogen receptors, acts via genomic and non-genomic signaling pathways to affect many metabolic functions, including mitochondrial biogenesis and respiration. This study assessed the effect of ERb classical genomic activity on adipocyte-specific and -systemic metabolic responses to wheel running exercise in a rodent model of menopause. Female mice lacking the ERb DNA-binding domain (ERbDBDKO, n = 20) and WT (n = 21) littermate controls were fed a high-fat diet (HFD), ovariectomized (OVX), and randomized to control (no running wheel) and exercise (running wheel access) groups and were followed for 8 weeks. Wheel running did not confer protection against metabolic dysfunction associated with HFD+OVX in either ERbDBDKO or WT mice, despite increased energy expenditure. Unexpectedly, in the ERbDBDKO group, wheel running increased fasting insulin and surrogate measures of insulin resistance, and modestly increased adipose tissue inflammatory gene expression (P ≤ 0.05). These changes were not accompanied by significant changes in adipocyte mitochondrial respiration. It was demonstrated for the first time that female WT OVX mice do experience exercise-induced browning of white adipose tissue, indicated by a robust increase in uncoupling protein 1 (UCP1) (P ≤ 0.05). However, KO mice were completely resistant to this effect, indicating that full ERb genomic activity is required for exercise-induced browning. The inability to upregulate UCP1 with exercise following OVX may have resulted in the increased insulin resistance observed in KO mice, a hypothesis requiring further investigation.

Age, Sex, and Depot-Specific Differences in Adipose-Tissue Estrogen Receptors in Individuals with Obesity.

OBJECTIVE: The aim of this study was to examine the effects of sex and menopausal status on depot-specific estrogen signaling in white adipose tissue (AT) in age-matched men and women with morbid obesity. METHODS: A total of 28 premenopausal women, 16 postmenopausal women, and 27 age-matched men undergoing bariatric surgery were compared for omental (OM) AT (OMAT) and abdominal subcutaneous (SQ) AT (SQAT) genes and proteins. RESULTS: With the exception of fasting nonesterified fatty acids being higher in women (P < 0.01), no differences were found in other indicators of glucose and lipid metabolism. In OMAT, estrogen receptor (ER) beta (ERß) levels were higher in older women than in younger women and older men (sex-age interaction, P < 0.01), and aromatase expression was higher in older men than in older women (P < 0.05). In SQAT, women had lower expression of ERß than men (P < 0.05). Protein content of ER alpha and ERß was highly correlated with the mitochondrial protein uncoupling protein 1 across sexes and ages (P < 0.001). Age increased SQ inflammatory gene expression in both sexes. CONCLUSIONS: In morbid obesity, sex and age affect AT ERs, lipid metabolism, mitochondrial uncoupling protein 1, and inflammatory expression in an AT depot-dependent manner. The SQAT immunometabolic profile is heavily influenced by age and menopause status, more so than OMAT.

Changes in nucleus accumbens gene expression accompany sex-specific suppression of spontaneous physical activity in aromatase knockout mice.

Aromatase catalyzes conversion of testosterone to estradiol and is expressed in a variety of tissues, including the brain. Suppression of aromatase adversely affects metabolism and physical activity behavior, but mechanisms remain uncertain. The hypothesis tested herein was that whole body aromatase deletion would cause gene expression changes in the nucleus accumbens (NAc), a brain regulating motivated behaviors such as physical activity, which is suppressed with loss of estradiol. Metabolic and behavioral assessments were performed in male and female wild-type (WT) and aromatase knockout (ArKO) mice. NAc-specific differentially expressed genes (DEGs) were identified with RNAseq, and associations between the measured phenotypic traits were determined. Female ArKO mice had greater percent body fat, reduced spontaneous physical activity (SPA), consumed less energy, and had lower relative resting energy expenditure (REE) than WT females. Such differences were not observed in ArKO males. However, in both sexes, a top DEG was Pts, a gene encoding an enzyme necessary for catecholamine (e.g., dopamine) biosynthesis. In comparing male and female WT mice, top DEGs were related to sexual development/fertility, immune regulation, obesity, dopamine signaling, and circadian regulation. SPA correlated strongly with Per3, a gene regulating circadian function, thermoregulation, and metabolism (r = -0.64, P = .002), which also correlated with adiposity (r = 0.54, P = .01). In conclusion, aromatase ablation leads to gene expression changes in NAc, which may in turn result in reduced SPA and related metabolic abnormalities. These findings may have significance to post-menopausal women and those treated with an aromatase inhibitor.

Effects of ERß and ERα on OVX-induced changes in adiposity and insulin resistance.

Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERα) or estrogen receptor ß (ERß). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERα-null (αKO), and ERß-null (ßKO) female mice (age ~49 weeks; n = 7-12/group). All mice were fed a phytoestrogen-free diet (<15 mg/kg) and either remained ovary-intact (INT) or were OVX and followed for 12 weeks. Body composition, energy expenditure, glucose tolerance, and adipose tissue gene and protein expression were analyzed. INT αKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and ßKO mice (all P < 0.001). Following OVX, αKO mice did not increase adiposity or experience a further increase in IR, unlike WT and ßKO, suggesting that loss of signaling through ERα mediates OVX-induced metabolic dysfunction. In fact, OVX in αKO mice (i.e., signaling through ERß in the absence of ERα) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). ßKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERα mediates metabolic protection over ERß in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERß may mediate protective metabolic benefits.

Estrogen receptor-α signaling maintains immunometabolic function in males and is obligatory for exercise-induced amelioration of nonalcoholic fatty liver.

The role of estrogen receptor-α (ERα) signaling in immunometabolic function is established in females. However, its necessity in males, while appreciated, requires further study. Accordingly, we first determined whether lower metabolic function in male mice compared with females is related to reduced ERα expression. ERα protein expression in metabolically active tissues was lower in males than in females, and this lower expression was associated with worse glucose tolerance. Second, we determined whether ERα is required for optimal immunometabolic function in male mice consuming a chow diet. Despite lower expression of ERα in males, its genetic ablation (KO) caused an insulin-resistant phenotype characterized by enhanced adiposity, glucose intolerance, hepatic steatosis, and metaflammation in adipose tissue and liver. Last, we determined whether ERα is essential for exercise-induced metabolic adaptations. Twelve-week-old wild-type (WT) and ERα KO mice either remained sedentary (SED) or were given access to running wheels (WR) for 10 wk while fed an obesogenic diet. Body weight and fat mass were lower in WR mice regardless of genotype. Daily exercise obliterated immune cell infiltration and inflammatory gene transcripts in adipose tissue in both genotypes. In the liver, however, wheel running suppressed hepatic steatosis and inflammatory gene transcripts in WT but not in KO mice. In conclusion, the present findings indicate that ERα is required for optimal immunometabolic function in male mice despite their reduced ERα protein expression in metabolically active tissues. Furthermore, for the first time, we show that ERα signaling appears to be obligatory for exercise-induced prevention of hepatic steatosis.

Voluntary Running Attenuates Metabolic Dysfunction in Ovariectomized Low-Fit Rats.

INTRODUCTION: Ovariectomy and high-fat diet (HFD) worsen obesity and metabolic dysfunction associated with low aerobic fitness. Exercise training mitigates metabolic abnormalities induced by low aerobic fitness, but whether the protective effect is maintained after ovariectomy and HFD is unknown. PURPOSE: This study determined whether, after ovariectomy and HFD, exercise training improves metabolic function in rats bred for low intrinsic aerobic capacity. METHODS: Female rats selectively bred for low (LCR) and high (HCR) intrinsic aerobic capacity (n = 30) were ovariectomized, fed HFD, and randomized to either a sedentary (SED) or voluntary wheel running (EX) group. Resting energy expenditure, glucose tolerance, and spontaneous physical activity were determined midway through the experiment, whereas body weight, wheel running volume, and food intake were assessed throughout the study. Body composition, circulating metabolic markers, and skeletal muscle gene and protein expression were measured at sacrifice. RESULTS: EX reduced body weight and adiposity in LCR rats (-10% and -50%, respectively; P < 0.05) and, unexpectedly, increased these variables in HCR rats (+7% and +37%, respectively; P < 0.05) compared with their respective SED controls, likely because of dietary overcompensation. Wheel running volume was approximately fivefold greater in HCR than LCR rats, yet EX enhanced insulin sensitivity equally in LCR and HCR rats (P < 0.05). This EX-mediated improvement in metabolic function was associated with thee gene upregulation of skeletal muscle interleukin-6 and interleukin-10. EX also increased resting energy expenditure, skeletal muscle mitochondrial content (oxidative phosphorylation complexes and citrate synthase activity), and adenosine monophosphate-activated protein kinase activation similarly in both lines (all P <0.05). CONCLUSION: Despite a fivefold difference in running volume between rat lines, EX similarly improved systemic insulin sensitivity, resting energy expenditure, and skeletal muscle mitochondrial content and adenosine monophosphate-activated protein kinase activation in ovariectomized LCR and HCR rats fed HFD compared with their respective SED controls.

Inverse association between carbohydrate consumption and plasma adropin concentrations in humans.

OBJECTIVE: The role of metabolic condition and diet in regulating circulating levels of adropin, a peptide hormone linked to cardiometabolic control, is not well understood. In this study, weight loss and diet effects on plasma adropin concentrations were examined. METHODS: This report includes data from (1) a weight loss trial, (2) an evaluation of acute exercise effects on mixed-meal (60% kcal from carbohydrates) tolerance test responses, and (3) a meta-analysis to determine normal fasting adropin concentrations. RESULTS: Distribution of plasma adropin concentrations exhibited positive skew and kurtosis. The effect of weight loss on plasma adropin concentrations was dependent on baseline plasma adropin concentrations, with an inverse association between baseline and a decline in concentrations after weight loss (Spearman's ρ = -0.575; P < 0.001). When ranked by baseline plasma adropin concentrations, only values in the upper quartile declined with weight loss. Plasma adropin concentrations under the main area of the bell curve correlated negatively with habitual carbohydrate intake and plasma lipids. There was a negative correlation between baseline values and a transient decline in plasma adropin during the mixed-meal tolerance test. CONCLUSIONS: Plasma adropin concentrations in humans are sensitive to dietary macronutrients, perhaps due to habitual consumption of carbohydrate-rich diets suppressing circulating levels. Very high adropin levels may indicate cardiometabolic conditions sensitive to weight loss.

Aerobic exercise training in the treatment of non-alcoholic fatty liver disease related fibrosis.

KEY POINTS: Physiologically relevant rodent models of non-alcoholic steatohepatitis (NASH) that resemble the human condition are limited. Exercise training and energy restriction are first-line recommendations for the treatment of NASH. Hyperphagic Otsuka Long-Evans Tokushima fatty rats fed a western diet high in fat, sucrose and cholesterol for 24 weeks developed a severe NASH with fibrosis phenotype. Moderate intensity exercise training and modest energy restriction provided some improvement in the histological features of NASH that coincided with alterations in markers of hepatic stellate cell activation and extracellular matrix remodelling. The present study highlights the importance of lifestyle modification, including exercise training and energy restriction, in the regulation of advanced liver disease. ABSTRACT: The incidence of non-alcoholic steatohepatitis (NASH) is rising but the efficacy of lifestyle modifications to improve NASH-related outcomes remain unclear. We hypothesized that a western diet (WD) would induce NASH in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat and that lifestyle modification would improve this condition. Eight-week-old Long-Evans Tokushima Otsuka (L) and OLETF (O) rats consumed a control diet (10% kcal fat, 3.5% sucrose) or a WD (45% kcal fat, 17% sucrose, 1% cholesterol) for 24 weeks. At 20 weeks of age, additional WD-fed OLETFs were randomized to sedentary (O-SED), food restriction (O-FR; ∼25% kcal reduction vs. O-SED) or exercise training (O-EX; treadmill running 20 m min(-1) with a 15% incline, 60 min day(-1) , 5 days week(-1) ) conditions for 12 weeks. WD induced a NASH phenotype in OLETFs characterized by hepatic fibrosis (collagen 1α1 mRNA and hydroxyproline content), as well as elevated inflammation and non-alcoholic fatty liver disease activity scores, and hepatic stellate cell activation (α-smooth muscle actin) compared to Long-Evans Tokushima Otsuka rats. FR and EX modestly improved NASH-related fibrosis markers (FR: hydroxyproline content, P < 0.01; EX: collagen 1α1 mRNA, P < 0.05; both: fibrosis score, P < 0.01) and inflammation (both: inflammation score; FR: interleukin-1ß and tumor necrosis factor α) vs. O-SED. FR reduced hepatic stellate cell activation markers (transforming growth factor-ß protein and α-smooth muscle actin mRNA), whereas EX increased the hepatic stellate cell senescence marker CCN1 (P < 0.01 vs. O-SED). Additionally, both FR and EX normalized extracellular matrix remodelling markers to levels similar to L-WD (P > 0.05). Although neither EX nor FR led to complete resolution of the WD-induced NASH phenotype, both independently benefitted liver fibrosis via altered hepatic stellate cell activation and extracellular matrix remodelling.

Ovariectomized Highly Fit Rats Are Protected against Diet-Induced Insulin Resistance.

INTRODUCTION: In the absence of exercise training, rats selectively bred for high intrinsic aerobic capacity (high-capacity running (HCR)) are protected against ovariectomy (OVX)-induced insulin resistance (IR) and obesity compared with those bred for low intrinsic aerobic capacity (low-capacity running (LCR)). PURPOSE: This study determined whether OVX HCR rats remain protected with exposure to high-fat diet (HFD) compared with OVX LCR rats. METHODS: Female HCR and LCR rats (n = 36; age, 27-33 wk) underwent OVX and were randomized to a standard chow diet (NC, 5% kcal fat) or HFD (45% kcal fat) ad libitum for 11 wk. Total energy expenditure, resting energy expenditure, spontaneous physical activity (SPA), and glucose tolerance were assessed midway, whereas fasting circulating metabolic markers, body composition, adipose tissue distribution, and skeletal muscle adenosine monophosphate-activated protein kinase (AMPK), and mitochondrial markers were assessed at sacrifice. RESULTS: Both HCR and LCR rats experienced HFD-induced increases in total and visceral adiposity after OVX. Despite similar gains in adiposity, HCR rats were protected from HFD-induced IR and reduced total energy expenditure observed in LCR rats (P < 0.05). This metabolic protection was likely attributed to a compensatory increase in SPA and associated preservation of skeletal muscle AMPK activity in HCR; however, HFD significantly reduced SPA and AMPK activity in LCR (P < 0.05). In both lines, HFD reduced citrate synthase activity, gene expression of markers of mitochondrial biogenesis (tFAM, NRF1, and PGC-1α), and protein levels of mitochondrial oxidative phosphorylation complexes I, II, IV, and V in skeletal muscle (all P < 0.05). CONCLUSION: After OVX, HCR and LCR rats differentially respond to HFD such that HCR increase while LCR decrease SPA. This "physical activity compensation" likely confers protection from HFD-induced IR and reduced energy expenditure in HCR rats.

Impact of Exercise Timing on Appetite Regulation in Individuals with Type 2 Diabetes.

PURPOSE: Exercise improves appetite regulation, but it is not known if premeal or postmeal exercise more effectively improves appetite regulation in individuals with type 2 diabetes. For the first time, this study compared how premeal and postmeal exercise alters appetite regulation in individuals with type 2 diabetes. METHODS: Twelve obese individuals with type 2 diabetes performed 3 different trials, all in a random order, in which they consumed a dinner meal with the following: no resistance exercise (RE), premeal RE, or postmeal RE beginning 45 min after dinner. A visual analog scale was used to assess perceived hunger and fullness, and frequent blood samples were drawn for determination of acylated ghrelin, pancreatic polypeptide (PP), and peptide tyrosine tyrosine (PYY) concentrations. RESULTS: Premeal RE increased premeal perceived fullness, reduced perceived hunger, and reduced acylated ghrelin concentrations compared with the no RE and postmeal RE trial (P < 0.05). In the postprandial period, both premeal and postmeal RE reduced perceived hunger compared with no RE, whereas only postmeal RE reduced postprandial perceived fullness (P < 0.05) compared with no RE. Premeal or postmeal RE did not alter PYY concentrations. In both the premeal and postprandial period, RE reduced PP concentrations compared with no RE (P < 0.05), but upon cessation of RE, PP concentrations rebounded to concentrations that were similar to no RE. CONCLUSIONS: Both premeal and postmeal RE reduced perceived hunger and increased perceived fullness, effects that may help control food intake and aid in weight management efforts in individuals with type 2 diabetes.

Prior exercise does not alter the incretin response to a subsequent meal in obese women.

Prior research has shown an increase in GLP-1 concentrations during exercise but this exercise bout was conducted postprandially. The purpose of this study was to examine the incretin response to a meal following an exercise bout of different intensities in obese subjects. Eleven women (BMI>37.3±7.0kg/m(2); Age 24.3±4.6year) participated in 3 counter- balanced study days, where a standardized meal was preceded by: (1) No exercise (NoEx), (2) ModEx (55% VO2max), and (3) IntEx (4min (80% VO2max)/3min (50% VO2max). Frequent blood samples were analyzed for glucose, lactate, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and C-peptide concentrations throughout 280min of testing. Glucose concentrations were not different between conditions during exercise or meals. There were no differences between conditions in insulin levels during exercise and recovery, but postprandial insulin incremental area under the curve was lower in ModEx vs. NoEx (p<0.01). GIP and GLP-1 levels were not different between conditions during exercise, but during exercise recovery, GLP-1 concentrations were higher in ModEx vs. NoEx (p=0.03). The meal increased the incretin responses (p<0.01) but this response was not affected by prior exercise. Glucagon concentrations increased with exercise (p<0.05) and continued to be elevated during recovery, with the greatest increase with IntEx compared with NoEx (p<0.05). No differences between conditions were detected for hepatic insulin extraction, insulin secretion, or insulin sensitivity. Exercise prior to an evening meal has no impact on the incretin response to the subsequent meal, yet insulin concentrations were lower during the meals that followed exercise. Exercise intensity had no impact on this response.

A high-protein breakfast induces greater insulin and glucose-dependent insulinotropic peptide responses to a subsequent lunch meal in individuals with type 2 diabetes.

BACKGROUND: The previous meal modulates the postprandial glycemic responses to a subsequent meal; this is termed the second-meal phenomenon. OBJECTIVE: This study examined the effects of high-protein vs. high-carbohydrate breakfast meals on the metabolic and incretin responses after the breakfast and lunch meals. METHODS: Twelve type 2 diabetic men and women [age: 21-55 y; body mass index (BMI): 30-40 kg/m(2)] completed two 7-d breakfast conditions consisting of 500-kcal breakfast meals as protein (35% protein/45% carbohydrate) or carbohydrate (15% protein/65% carbohydrate). On day 7, subjects completed an 8-h testing day. After an overnight fast, the subjects consumed their respective breakfast followed by a standard 500-kcal high-carbohydrate lunch meal 4 h later. Blood samples were taken throughout the day for assessment of 4-h postbreakfast and 4-h postlunch total area under the curve (AUC) for glucose, insulin, C-peptide, glucagon, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide 1 (GLP-1). RESULTS: Postbreakfast glucose and GIP AUCs were lower after the protein (17%) vs. after the carbohydrate (23%) condition (P < 0.05), whereas postbreakfast insulin, C-peptide, glucagon, and GLP-1 AUCs were not different between conditions. A protein-rich breakfast may reduce the consequences of hyperglycemia in this population. Postlunch insulin, C-peptide, and GIP AUCs were greater after the protein condition vs. after the carbohydrate condition (second-meal phenomenon; all, P < 0.05), but postlunch AUCs were not different between conditions. The overall glucose, glucagon, and GLP-1 responses (e.g., 8 h) were greater after the protein condition vs. after the carbohydrate condition (all, P < 0.05). CONCLUSIONS: In type 2 diabetic individuals, compared with a high-carbohydrate breakfast, the consumption of a high-protein breakfast meal attenuates the postprandial glucose response and does not magnify the response to the second meal. Insulin, C-peptide, and GIP concentrations demonstrate the second-meal phenomenon and most likely aid in keeping the glucose concentrations controlled in response to the subsequent meal. The trial was registered at www.clinicaltrials.gov/ct2/show/NCT02180646 as NCT02180646.

Alteration of postprandial glucose and insulin concentrations with meal frequency and composition.

A frequent eating pattern may alter glycaemic control and augment postprandial insulin concentrations in some individuals due to the truncation of the previous postprandial period by a subsequent meal. The present study examined glucose, insulin, C-peptide and glucose-dependent insulinotropic peptide (GIP) responses in obese individuals when meals were ingested in a high-frequency pattern (every 2 h, 6M) or in a low-frequency pattern (every 4 h, 3M) over 12 h. It also examined these postprandial responses to high-frequency, high-protein meals (6MHP). In total, thirteen obese subjects completed three 12 h study days during which they consumed 6276 kJ (1500 kcal): (1) 3M - 15 % protein and 65 % carbohydrate; (2) 6M - 15 % protein and 65 % carbohydrate; (3) 6MHP - 45 % protein and 35 % carbohydrate. Blood samples were collected every 10 min and analysed for glucose, insulin, C-peptide and GIP. Insulin total AUC (tAUC) and peak insulin concentrations (P< 0·05) were higher in the 3M condition than in the 6M condition, but there were no differences in glucose tAUC between the conditions. The 6MHP regimen (glucose: 3569 (se 83) mmol/l × min (64·3 (se 1·5) g/dl × min), insulin: 1·577 (se 0·146) pmol/l (22·7 (se 2·1) µIU/dl) for 12 h) lowered glucose and insulin excursions more so over 12 h than either the 3M regimen (glucose: 3913 (se 78) mmol/l × min (70·5 (se 1·4) g/dl × min), insulin: 2·195 (se 0·146) pmol/l × min (31·6 (se 2·1) µIU/dl × min) for 12 h) or the 6M regimen (glucose: 3902 (se 83) mmol/l × min (70·3 (se 1·5) g/dl × min), insulin: 1·861 (se 0·174) pmol/l × min (26·8 (se 2·5) µIU/dl × min) for 12 h; P< 0·01). Insulin secretion, GIP concentrations and the glucose:insulin ratio were not altered by meal frequency or composition. In obese subjects, ingestion of meals in a low-frequency pattern does not alter glucose tAUC, but increases postprandial insulin responses. The substitution of carbohydrates with protein in a frequent meal pattern results in tighter glycaemic control and reduced postprandial insulin responses.

Physical activity offsets the negative effects of a high-fructose diet.

OBJECTIVE: This study aimed to determine the interaction between a high-fructose diet and PA levels on postprandial lipidemia and inflammation in normal-weight, recreationally active individuals. METHODS: Twenty-two men and women (age, 21.2 ± 0.6 yr; body mass index, 22.5 ± 0.6 kg · m(-2)) consumed an additional 75 g of fructose for 14 d on two separate occasions: high physical activity (PA) (approximately 12,500 steps per day) (FR+active) and low PA (approximately 4500 steps per day) (FR+inactive). A fructose-rich test meal was given before and at the end of each intervention. Blood was sampled at baseline and for 6 h after the meal for triglycerides (TG), VLDL, total cholesterol, glucose, insulin, tumor necrosis factor-α, interleukin 6, and C-reactive protein. RESULTS: Log-transformed TG area under the curve (AUC) significantly increased from before (10.1 ± 0.1 mg · dL(-1) × min for 6 h) to after (10.3 ± 0.08 mg · dL(-1) × min for 6 h, P = 0.04) the FR+inactive intervention, with an 88% increase in Δ peak TG (P = 0.009) and an 84% increase in Δ peak VLDL (P = 0.002). Δ Peak interleukin 6 also increased by 116% after the FR+inactive intervention (P = 0.009). Insulin total AUC significantly decreased after FR+active intervention (P = 0.04), with no change in AUC after the FR+inactive intervention. No changes were observed in glucose, tumor necrosis factor-α, and C-reactive protein concentrations (P > 0.05). CONCLUSIONS: Low PA during a period of high fructose intake augments fructose-induced postprandial lipidemia and inflammation, whereas high PA minimizes these fructose-induced metabolic disturbances. Even within a young healthy population, maintenance of high PA (>12,500 steps per day) decreases susceptibility to cardiovascular risk factors associated with elevated fructose consumption.

Hyperinsulinemia and skeletal muscle fatty acid trafficking.

We hypothesized that insulin alters plasma free fatty acid (FFA) trafficking into intramyocellular (im) long-chain acylcarnitines (imLCAC) and triglycerides (imTG). Overnight-fasted adults (n = 41) received intravenous infusions of [U-¹³C]palmitate (0400-0900 h) and [U-¹³C]oleate (0800-1400 h) to label imTG and imLCAC. A euglycemic-hyperinsulinemic (1.0 mU·kg fat-free mass⁻¹·min⁻¹) clamp (0800-1400 h) and two muscle biopsies (0900 h, 1400 h) were performed. The patterns of [U-¹³C]palmitate incorporation into imTG-palmitate and palmitoylcarnitine were similar to those we reported in overnight postabsorptive adults (saline control); the intramyocellular palmitoylcarnitine enrichment was not different from and correlated with imTG-palmitate enrichment for both the morning (r = 0.38, P = 0.02) and afternoon (r = 0.44, P = 0.006) biopsy samples. Plasma FFA concentrations, flux, and the incorporation of plasma oleate into imTG-oleate during hyperinsulinemia were ~1/10th of that observed in the previous saline control studies (P < 0.001). At the time of the second biopsy, the enrichment in oleoylcarnitine was <25% of that in imTG-oleate and was not correlated with imTG-oleate enrichment. The intramyocellular nonesterified fatty acid-palmitate-to-imTG-palmitate enrichment ratio was greater (P < 0.05) in women than men, suggesting that sex differences in intramyocellular palmitate trafficking may occur under hyperinsulinemic conditions. We conclude that plasma FFA trafficking into imTG during hyperinsulinemia is markedly suppressed, and these newly incorporated FFA fatty acids do not readily enter the LCAC preoxidative pools. Hyperinsulinemia does not seem to inhibit the entry of fatty acids from imTG pools that were labeled under fasting conditions, possibly reflecting the presence of two distinct imTG pools that are differentially regulated by insulin.

Prior exercise and postprandial incretin responses in lean and obese individuals.

PURPOSE: The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) help regulate postprandial triacylglycerol (TAG) and insulin concentrations, but the effects of acute aerobic exercise on GLP-1 or GIP responses are unclear. The purpose of this study was to determine whether reductions in postprandial TAG and insulin with exercise are associated with GLP-1 and GIP responses. METHODS: Thirteen normal-weight (NW) and 13 obese (Ob) individuals participated in two, 4-d trials in random order including an exercise (EX) and a no exercise (NoEX) trial. Diet was controlled during both trials. The EX trial consisted of 1 h of treadmill walking (55%-60% of V˙O2peak) during the evening of day 3 of the trial, 12 h before a 4-h mixed meal test on day 4, during which frequent blood samples were collected to assess postprandial lipemia, glycemia, insulin, C-peptide, GIP, and GLP-1 responses. Insulin secretion was estimated using the insulinogenic index, and insulin clearance was estimated using the ratio of insulin to C-peptide. RESULTS: Postprandial TAG were 29% lower after EX in Ob individuals (P < 0.05) but were not significantly altered in NW individuals (P > 0.05). The drop in postprandial HDL cholesterol was attenuated with EX in Ob individuals (P < 0.05). Insulin responses were 14% lower after EX in Ob individuals (P < 0.05), and this was associated with reduced insulin secretion (P < 0.05), with no change in insulin clearance (P > 0.05). Glucose, C-peptide, GIP, and GLP-1 were not different between trials. CONCLUSION: A 1-h bout of moderate-intensity aerobic exercise the night before a mixed meal attenuates TAG and insulin responses in Ob but not NW individuals, an effect not associated with altered GLP-1 or GIP responses.

Liquid meal composition, postprandial satiety hormones, and perceived appetite and satiety in obese women during acute caloric restriction.

OBJECTIVE: The purpose of this study was to compare postprandial satiety regulating hormone responses (pancreatic polypeptide (PP) and peptide tyrosine tyrosine (PYY)) and visual analog scale- (VAS) assessed perceived appetite and satiety between liquid high-protein (HP) and high-carbohydrate (HC) meals in obese women during acute (24-h) caloric restriction. DESIGN: Eleven obese premenopausal women completed two conditions in random order in which they consumed 1500 calories as six 250-calorie HP meals or six 250-calorie HC meals over a 12-h period. Blood samples were taken at baseline and every 20 min thereafter and analyzed for PP and PYY concentrations. At these same points, perceived hunger and fullness were assessed with a VAS. The incremental area under the curve (iAUC) was used to compare postprandial responses. RESULTS: The 12-h PP and PYY iAUC were greater (P≤0.05) during the HP condition (PP: 4727±1306 pg/ml×12 h, PYY: 1373±357 pg/ml×12 h) compared with the HC condition (PP: 2300±528 pg/ml×12 h, PYY: 754±246 pg/ml×12 h). Perceived hunger and fullness were not different between conditions (P>0.05). The greatest changes in PYY and perceived fullness occurred after the morning meals during both conditions. CONCLUSIONS: These data suggest that in obese women during acute caloric restriction before weight loss, i) liquid HP meals, compared with HC meals, result in greater postprandial PP and PYY concentrations, an effect not associated with differential appetite or satiety responses, and ii) meal-induced changes in PYY and satiety are greatest during the morning period, regardless of dietary macronutrient composition.

Long-term aerobic exercise and omega-3 supplementation modulate osteoporosis through inflammatory mechanisms in post-menopausal women: a randomized, repeated measures study.

BACKGROUND: Evidence indicates that dietary fats and physical activity influence bone health. The purpose of this study was to examine the effects of long-term aerobic exercise and omega-3 (N-3) supplementation on serum inflammatory markers, bone mineral density (BMD), and bone biomarkers in post-menopausal women. METHODS: Seventy-nine healthy sedentary post-menopausal women aged 58-78 years participated in this study. Subjects were randomized to one of 4 groups: exercise + supplement (E+S, n = 21), exercise (E, n = 20), supplement (S, n = 20), and control (Con, n = 18) groups. The subjects in the E+S and E groups performed aerobic exercise training (walking and jogging) up to 65% of HRmax, three times a week for 24 weeks. Subjects in the E+S and S groups consumed 1000 mg/d N-3 for 24 weeks. The lumbar spine (L2-L4) and femoral neck BMD, serum tumor necrosis factor (TNF) α, interleukin (IL) 6, prostaglandin (PG) E2, estrogen, osteocalcin, 1, 25-dihydroxyvitamin D3 (1, 25 Vit D), C-telopeptide (CTX), parathyroid hormone (PTH) and calcitonin (CT) were measured at baseline, the end of week 12 and 24. RESULTS: Serum estrogen, osteocalcin, 1, 25 Vit D, CT, L2-L4 and femoral neck BMD measures increased (P < 0.05) and the serum CTX, PTH, TNF-α, IL-6, and PGE2 decreased (P < 0.05) in E + S group after the 24 wk intervention but not in the E or S intervention groups. L2-L4 and femoral neck BMD, estrogen, osteocalcin, and CT were negatively (P < 0.05) correlated with TNF-α and PGE2. PTH and CT were correlated positively and negatively with IL-6, respectively (P < 0.05). CONCLUSIONS: The present study demonstrates that long-term aerobic exercise training plus N-3 supplementation have a synergistic effect in attenuating inflammation and augmenting BMD in post-menopausal osteoporosis.