Vitamin D in human serum and adipose tissue after supplementation.

BACKGROUND: Serum 25-hydroxyvitamin D [25(OH)D] concentration is an indicator of vitamin D exposure, but it is also influenced by clinical characteristics that affect 25(OH)D production and clearance. Vitamin D is the precursor to 25(OH)D but is analytically challenging to measure in biological specimens. OBJECTIVES: We aimed to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantification of vitamins D3 and D2 in serum and to explore the potential of circulating vitamin D as a biomarker of exposure in supplementation trials. METHODS: The method was validated using guideline C62-A from the Clinical and Laboratory Standards Institute and was applied in 2 pilot clinical trials of oral vitamin D3 supplementation. Pilot study 1 included 22 adults randomly assigned to placebo or 2000 IU/d. Blood was collected at baseline, 1, 3, 6, and 12 mo. Pilot study 2 included 15 adults randomly assigned to 2000 or 4000 IU/d. Blood and subcutaneous (SUBQ) adipose tissue were collected at baseline and 3 mo. RESULTS: In study 1, mean change (baseline to 3 mo) in serum vitamin D3 was -0.1 ng/mL in the placebo group and 6.8 ng/mL in the 2000 IU/d group (absolute difference: 6.9; 95% CI: 4.5, 9.3 ng/mL). In study 2, mean change (baseline to 3 mo) in serum vitamin D3 was 10.4 ng/mL in the 2000 IU/d group and 22.2 ng/mL in the 4000 IU/d group (fold difference: 2.15; 95% CI: 1.40, 3.37). Serum and adipose tissue vitamin D3 concentrations were correlated, and the dose-response of vitamin D3 in adipose mirrored that in serum. CONCLUSIONS: We validated a sensitive, robust, and high-throughput LC-MS/MS method to quantify vitamins D3 and D2 in serum. Serum and SUBQ adipose tissue vitamin D3 concentrations increased proportionally to dose with 3 mo of daily supplementation.These trials were registered at clinicaltrials.gov as NCT00552409 (pilot study 1) and NCT01477034 (pilot study 2).

Postprandial remodeling of high-density lipoprotein following high saturated fat and high carbohydrate meals.

BACKGROUND: Humans spend most of the time in the postprandial state, yet most knowledge about high-density lipoproteins (HDL) derives from the fasted state. HDL protein and lipid cargo mediate HDL's antiatherogenic effects, but whether these HDL constituents change in the postprandial state and are affected by dietary macronutrients remains unknown. OBJECTIVES: This study aimed to assess changes in HDL protein and lipid composition after the consumption of a high-carbohydrate or high saturated fat (HSF) meal. METHODS: We isolated HDL from plasma collected during a randomized, cross-over study of metabolically healthy subjects. Subjects consumed isocaloric meals consisting predominantly of either carbohydrate or fat. At baseline and at 3 and 6 hours postprandial, we quantified HDL protein and lipid composition by liquid chromatography-mass spectrometry. RESULTS: A total of 15 subjects were included (60% female, aged 34 ± 15 years, body mass index: 24.1 ± 2.7 kg/m2). Consumption of the HSF meal led to HDL enrichment in total lipid (P = .006), triglyceride (P = .02), and phospholipid (P = .008) content and a corresponding depletion in protein content. After the HSF meal, 16 of the 25 measured phosphatidylcholine species significantly increased in abundance (P values range from .027 to <.001), along with several sphingolipids including ceramides (P < .004), lactosylceramide (P = .023), and sphingomyelin-14 (P = .013). Enrichment in apolipoprotein A-I (P = .001) was the only significant change in HDL protein composition after the HSF meal. The high-carbohydrate meal conferred only minimal changes in HDL composition. CONCLUSION: Meal macronutrient content acutely affects HDL composition in the postprandial state, with the HSF meal resulting in enrichment of HDL phospholipid content with possible consequences for HDL function.

Consuming glucose-sweetened, not fructose-sweetened, beverages increases fasting insulin in healthy humans.

Fructose-, compared to glucose-, sweetened beverages increase liver triglyceride content in the short-term, prior to weight gain. In secondary analyses of a randomized cross-over design study during which 24 healthy adults consumed 25% of their estimated energy requirement in the form of glucose-, fructose-, and high-fructose corn syrup-sweetened beverages in addition to an identical ad libitum diet for three periods of 8 days each, we investigated the hypothesis that fructose in sweetened beverages also triggers insulin resistance in the short term. Total energy intake, body weight, and fasting glucose did not differ among diet phases. However, there was a significant trend for higher fasting insulin (p = 0.042 for trend) and, among normal-weight participants, homeostasis model assessment index of insulin resistance (p = 0.034 for diet × adiposity interaction) according to the glucose content of the beverages. In conclusion, in contrast to our hypothesis, insulin resistance was increased with higher glucose vs. fructose content of the beverages in this short-term trial.

Intraindividual Variation in Markers of Intestinal Permeability and Adipose Tissue Inflammation in Healthy Normal-Weight to Obese Adults.

BACKGROUND: Intestinal permeability and adipose tissue inflammation are considered mechanistic links in the relationship between diet, obesity, and chronic disease. However, methods to measure both are not well standardized, and the reliability of commonly used measures is not known. METHODS: We calculated the intraclass correlation coefficient (ICC) for several common measures of intestinal permeability and adipose tissue inflammation from a randomized clinical trial of cross-over design in which normal-weight (n = 12) or overweight/obese (n = 12) individuals each completed three 8-day dietary intervention periods. RESULTS: For biomarkers of intestinal permeability, plasma zonulin, and lipopolysaccharide-binding protein, ICCs were "excellent" (i.e., >0.9). The direct measure of intestinal permeability, the lactulose/mannitol test, exhibited "fair" reliability (ICC = 0.53). A wider range of ICCs (0.6-0.9), suggesting "good" to "excellent" reliability, were obtained for measures of adipose tissue expression of genes encoding major mediators of inflammation. Similarly, individual immune cell populations isolated from adipose tissue, expressed as a percentage of all CD45+ cells, also had "good" to "excellent" ICCs. However, when these populations were expressed as number of cells per gram of tissue, ICC values were "fair," falling below 0.6. CONCLUSIONS: Due to the repeated measures design, our study offered a unique opportunity to assess reliability of commonly used biomarkers of intestinal permeability and adipose tissue inflammation. Our findings suggest that these measures were generally highly reliable in the short-term. IMPACT: Along with other factors, particularly validity, the demonstrated reliabilities can help inform the choice of endpoints in studies of intestinal permeability and adipose tissue inflammation.

Prospective evaluation of insulin and incretin dynamics in obese adults with and without diabetes for 2 years after Roux-en-Y gastric bypass.

AIMS/HYPOTHESIS: In this prospective case-control study we tested the hypothesis that, while long-term improvements in insulin sensitivity (SI) accompanying weight loss after Roux-en-Y gastric bypass (RYGB) would be similar in obese individuals with and without type 2 diabetes mellitus, stimulated-islet-cell insulin responses would differ, increasing (recovering) in those with diabetes but decreasing in those without. We investigated whether these changes would occur in conjunction with favourable alterations in meal-related gut hormone secretion and insulin processing. METHODS: Forty participants with type 2 diabetes and 22 participants without diabetes from the Longitudinal Assessment of Bariatric Surgery (LABS-2) study were enrolled in a separate, longitudinal cohort (LABS-3 Diabetes) to examine the mechanisms of postsurgical diabetes improvement. Study procedures included measures of SI, islet secretory response and gastrointestinal hormone secretion after both intravenous glucose (frequently-sampled IVGTT [FSIVGTT]) and a mixed meal (MM) prior to and up to 24 months after RYGB. RESULTS: Postoperatively, weight loss and SI-FSIVGTT improvement was similar in both groups, whereas the acute insulin response to glucose (AIRglu) decreased in the non-diabetic participants and increased in the participants with type 2 diabetes. The resulting disposition indices (DIFSIVGTT) increased by three- to ninefold in both groups. In contrast, during the MM, total insulin responsiveness did not significantly change in either group despite durable increases of up to eightfold in postprandial glucagon-like peptide 1 levels, and SI-MM and DIMM increased only in the diabetes group. Peak postprandial glucagon levels increased in both groups. CONCLUSIONS/INTERPRETATION: For up to 2 years following RYGB, obese participants without diabetes showed improvements in DI that approach population norms. Those with type 2 diabetes recovered islet-cell insulin secretion response yet continued to manifest abnormal insulin processing, with DI values that remained well below population norms. These data suggest that, rather than waiting for lifestyle or medical failure, RYGB is ideally considered before, or as soon as possible after, onset of type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00433810.

The short-term and long-term effects of bariatric/metabolic surgery on subcutaneous adipose tissue inflammation in humans.

CONTEXT: The mechanisms mediating the short- and long-term improvements in glucose homeostasis following bariatric/metabolic surgery remain incompletely understood. OBJECTIVE: To investigate whether a reduction in adipose tissue inflammation plays a role in the metabolic improvements seen after bariatric/metabolic surgery, both in the short-term and longer-term. DESIGN: Fasting blood and subcutaneous abdominal adipose tissue were obtained before (n=14), at one month (n=9), and 6-12months (n=14) after bariatric/metabolic surgery from individuals with obesity who were not on insulin or anti-diabetes medication. Adipose tissue inflammation was assessed by a combination of whole-tissue gene expression and flow cytometry-based quantification of tissue leukocytes. RESULTS: One month after surgery, body weight was reduced by 13.5±4.4kg (p<0.001), with improvements in glucose tolerance reflected by a decrease in area-under-the-curve (AUC) glucose in 3-h oral glucose tolerance tests (-105±98mmol/L * min; p=0.009) and enhanced pancreatic ß-cell function (insulinogenic index: +0.8±0.9pmol/mmol; p=0.032), but no change in estimated insulin sensitivity (Matsuda insulin sensitivity index [ISI]; p=0.720). Furthermore, although biomarkers of systemic inflammation and pro-inflammatory gene expression in adipose tissue remained unchanged, the number of neutrophils increased in adipose tissue 15-20 fold (p<0.001), with less substantial increases in other leukocyte populations. By the 6-12month follow-up visit, body weight was reduced by 34.8±10.8kg (p<0.001) relative to baseline, and glucose tolerance was further improved (AUC glucose -276±229; p<0.001) along with estimated insulin sensitivity (Matsuda ISI: +4.6±3.2; p<0.001). In addition, improvements in systemic inflammation were reflected by reductions in circulating C-reactive protein (CRP; -2.0±5.3mg/dL; p=0.002), and increased serum adiponectin (+1358±1406pg/mL; p=0.003). However, leukocyte infiltration of adipose tissue remained elevated relative to baseline, with pro-inflammatory cytokine mRNA expression unchanged, while adiponectin mRNA expression trended downward (p=0.069). CONCLUSION: Both the short- and longer-term metabolic improvements following bariatric/metabolic surgery occur without significant reductions in measures of adipose tissue inflammation, as assessed by measuring the expression of genes encoding key mediators of inflammation and by flow cytometric immunophenotyping and quantification of adipose tissue leukocytes.

No differential effect of beverages sweetened with fructose, high-fructose corn syrup, or glucose on systemic or adipose tissue inflammation in normal-weight to obese adults: a randomized controlled trial.

BACKGROUND: Sugar-sweetened beverage (SSB) consumption and low-grade chronic inflammation are both independently associated with type 2 diabetes and cardiovascular disease. Fructose, a major component of SSBs, may acutely trigger inflammation, which may be one link between SSB consumption and cardiometabolic disease. OBJECTIVE: We sought to determine whether beverages sweetened with fructose, high-fructose corn syrup (HFCS), and glucose differentially influence systemic inflammation [fasting plasma C-reactive protein and interleukin-6 (IL-6) as primary endpoints] acutely and before major changes in body weight. Secondary endpoints included adipose tissue inflammation, intestinal permeability, and plasma fetuin-A as potential mechanistic links between fructose intake and low-grade inflammation. DESIGN: We conducted a randomized, controlled, double-blind, crossover design dietary intervention (the Diet and Systemic Inflammation Study) in 24 normal-weight to obese adults without fructose malabsorption. Participants drank 4 servings/d of fructose-, glucose-, or HFCS-sweetened beverages accounting for 25% of estimated calorie requirements while consuming a standardized diet ad libitum for three 8-d periods. RESULTS: Subjects consumed 116% of their estimated calorie requirement while drinking the beverages with no difference in total energy intake or body weight between groups as reported previously. Fasting plasma concentrations of C-reactive protein and IL-6 did not differ significantly at the end of the 3 diet periods. We did not detect a consistent differential effect of the diets on measures of adipose tissue inflammation except for adiponectin gene expression in adipose tissue (P = 0.005), which was lowest after the glucose phase. We also did not detect consistent evidence of a differential impact of these sugars on measures of intestinal permeability (lactulose:mannitol test, plasma zonulin, and plasma lipopolysaccharide-binding protein). CONCLUSION: Excessive amounts of fructose, HFCS, and glucose from SSBs consumed over 8 d did not differentially affect low-grade chronic systemic inflammation in normal-weight to obese adults. This trial was registered at clinicaltrials.gov as NCT01424306.

Improvements in glycemic control after gastric bypass occur despite persistent adipose tissue inflammation.

OBJECTIVE: Type 2 diabetes commonly goes into remission following Roux-en-Y gastric bypass (RYGB). As the mechanisms remain incompletely understood, a reduction in adipose tissue inflammation may contribute to these metabolic improvements. Therefore, whether RYGB reduces adipose tissue inflammation compared with equivalent weight loss from an intensive lifestyle intervention was investigated. METHODS: Sixteen people with obesity and type 2 diabetes were randomized to RYGB or lifestyle intervention. Fasting blood and subcutaneous abdominal adipose tissue were obtained before and after the loss of ∼7% of baseline weight. Adipose tissue inflammation was assessed by whole-tissue gene expression and flow cytometry-based quantification of tissue leukocytes. RESULTS: At 7% weight loss, insulin and metformin use were reduced among the RYGB but not the Lifestyle cohort, while fasting glucose and insulin declined in both. Adipose tissue inflammation increased modestly after RYGB and to a similar extent following nonsurgical weight loss. In both groups, the number of neutrophils increased severalfold (P < 0.001), mRNA levels of the proinflammatory cytokine interleukin-1ß increased (P = 0.037), and mRNA expression of the anti-inflammatory and insulin-sensitizing adipokine adiponectin decreased (P = 0.010). CONCLUSIONS: A reduction in adipose tissue inflammation is not one of the acute weight loss-independent mechanisms through which RYGB exerts its antidiabetes effects.

Gastric bypass surgery vs intensive lifestyle and medical intervention for type 2 diabetes: the CROSSROADS randomised controlled trial.

AIMS/HYPOTHESIS: Mounting evidence indicates that Roux-en-Y gastric bypass (RYGB) ameliorates type 2 diabetes, but randomised trials comparing surgical vs nonsurgical care are needed. With a parallel-group randomised controlled trial (RCT), we compared RYGB vs an intensive lifestyle and medical intervention (ILMI) for type 2 diabetes, including among patients with a BMI <35 kg/m(2). METHODS: By use of a shared decision-making recruitment strategy targeting the entire at-risk population within an integrated community healthcare system, we screened 1,808 adults meeting inclusion criteria (age 25-64, with type 2 diabetes and a BMI 30-45 kg/m(2)). Of these, 43 were allocated via concealed, computer-generated random assignment in a 1:1 ratio to RYGB or ILMI. The latter involved ≥45 min of aerobic exercise 5 days per week, a dietitian-directed weight- and glucose-lowering diet, and optimal diabetes medical treatment for 1 year. Although treatment allocation could not be blinded, outcomes were determined by a blinded adjudicator. The primary outcome was diabetes remission at 1 year (HbA1c <6.0% [<42.1 mmol/mol], off all diabetes medicines). RESULTS: Twenty-three volunteers were assigned to RYGB and 20 to ILMI. Of these, 11 withdrew before receiving any intervention. Hence 15 in the RYGB group and 17 in the IMLI group were analysed throughout 1 year. The groups were equivalent regarding all baseline characteristics, except that the RYGB cohort had a longer diabetes duration (11.4 ± 4.8 vs 6.8 ± 5.2 years, p = 0.009). Weight loss at 1 year was 25.8 ± 14.5% vs 6.4 ± 5.8% after RYGB vs ILMI, respectively (p < 0.001). The ILMI exercise programme yielded a 22 ± 11% increase in [Formula: see text] (p<0.0001), whereas [Formula: see text] after RYGB was unchanged. Diabetes remission at 1 year was 60.0% with RYGB vs 5.9% with ILMI (p = 0.002). The HbA1c decline over 1 year was only modestly more after RYGB than ILMI: from 7.7 ± 1.0% (60.7 mmol/mol) to 6.4 ± 1.6% (46.4 mmol/mol) vs 7.3 ± 0.9% (56.3 mmol/mol) to 6.9 ± 1.3% (51.9 mmol/mol), respectively (p = 0.04); however, this drop occurred with significantly fewer or no diabetes medications after RYGB. No life-threatening complications occurred. CONCLUSIONS/INTERPRETATION: Compared with the most rigorous ILMI yet tested against surgery in a randomised trial, RYGB yielded greater type 2 diabetes remission in mild-to-moderately obese patients recruited from a well-informed, population-based sample. TRIAL REGISTRATION: ClinicalTrials.gov NCT01295229.

No difference in ad libitum energy intake in healthy men and women consuming beverages sweetened with fructose, glucose, or high-fructose corn syrup: a randomized trial.

BACKGROUND: Increased energy intake is consistently observed in individuals consuming sugar-sweetened beverages (SSBs), likely mainly because of an inadequate satiety response to liquid calories. However, SSBs have a high content of fructose, the consumption of which acutely fails to trigger responses in key signals involved in energy homeostasis. It is unclear whether the fructose content of SSBs contributes to the increased energy intake in individuals drinking SSBs. OBJECTIVE: We investigated whether the relative amounts of fructose and glucose in SSBs modifies ad libitum energy intake over 8 d in healthy adults without fructose malabsorption. DESIGN: We conducted 2 randomized, controlled, double-blind crossover studies to compare the effects of consuming 4 servings/d of a fructose-, glucose-, or aspartame-sweetened beverage (study A; n = 9) or a fructose-, glucose-, or high-fructose corn syrup (HFCS)-sweetened beverage (study B; n = 24) for 8 d on overall energy intake. SSBs were provided at 25% of estimated energy requirement, or an equivalent volume of the aspartame-sweetened beverage, and consumption was mandatory. All solid foods were provided at 125% of estimated energy requirements and were consumed ad libitum. RESULTS: In study A, ad libitum energy intake was 120% ± 10%, 117% ± 12%, and 102% ± 15% of estimated energy requirements when subjects consumed the fructose-, glucose-, and aspartame-sweetened beverages. Energy intake was significantly higher in the fructose and glucose phases than in the aspartame phase (P < 0.003 for each), with no difference between the fructose and glucose phases (P = 0.462). In study B, total energy intake during the fructose, HFCS, and glucose phases was 116% ± 14%, 116% ± 16%, and 116% ± 16% of the subject's estimated total energy requirements (P = 0.880). CONCLUSIONS: In healthy adults, total 8-d ad libitum energy intake was increased in individuals consuming SSBs compared with aspartame-sweetened beverages. The energy overconsumption observed in individuals consuming SSBs occurred independently of the relative amounts of fructose and glucose in the beverages. These trials were registered at clinicaltrials.gov as NCT00475475 and NCT01424306.

No effect of caloric restriction or exercise on radiation repair capacity.

INTRODUCTION: Maintenance of normal weight and higher levels of physical activity are associated with a reduced risk of several types of cancer. Because genomic instability is regarded as a hallmark of cancer development, one proposed mechanism is improvement of DNA repair function. We investigated links between dietary weight loss, exercise, and strand break rejoining in an ancillary study to a randomized-controlled trial. METHODS: Overweight/obese postmenopausal women (n = 439) were randomized to the following: a) reduced calorie weight loss diet ("diet," n = 118), b) moderate- to vigorous-intensity aerobic exercise ("exercise," n = 117), c) a combination ("diet + exercise," n = 117), or d) control (n = 87). The reduced calorie diet had a 10% weight loss goal. The exercise intervention consisted of 45 min of moderate to vigorous aerobic activity 5 d·wk for 12 months. DNA repair capacity was measured in a subset of 226 women at baseline and 12 months from cryopreserved peripheral mononuclear cells using the comet assay. Anthropometric and body composition measures were performed at baseline and 12 months. RESULTS: DNA repair capacity did not change significantly with any of the 12-month interventions compared with control; there were also no significant changes when stratified by changes in body composition or aerobic fitness (V˙O2max). At baseline, DNA repair capacity was positively associated with weight, body mass index, and fat mass (r = 0.20, P = 0.003; r = 0.19, P = 0.004; r = 0.13, P = 0.04, respectively) and inversely with lean body mass (r = -0.14, P = 0.04). CONCLUSION: In conclusion, DNA repair capacity in cryopreserved PBMCs (Comet Assay) did not change with dietary weight loss or exercise interventions in postmenopausal women within a period of 12 months. Other assays that capture different facets of DNA repair function may be needed.

The effects of separate and combined dietary weight loss and exercise on fasting ghrelin concentrations in overweight and obese women: a randomized controlled trial.

OBJECTIVE: Compensatory metabolic changes that accompany weight loss, for example, increased ghrelin, contribute to weight regain and difficulty in long-term weight loss maintenance; however, the separate effects of long-term caloric restriction and exercise on total circulating ghrelin in humans are unknown. DESIGN: A 12-month randomized controlled trial comparing: i) dietary weight loss with a 10% weight loss goal ('diet'; n = 118); ii) moderate-to-vigorous intensity aerobic exercise for 45 min/day, 5 days/week ('exercise'; n = 117); iii) dietary weight loss and exercise ('diet + exercise'; n = 117); or iv) no-lifestyle-change control (n = 87). PARTICIPANTS: 439 overweight or obese postmenopausal women (50-75 y). MEASUREMENTS: Fasting total serum ghrelin was measured by radioimmunoassay at baseline and 12 months. Fasting serum leptin, adiponectin and insulin were also measured. RESULTS: Fasting total ghrelin significantly increased in the diet + exercise arm (+7·4%, P = 0·008) but not in either the diet (+6·5%, P = 0·07) or exercise (+1·0%, P = 0·53) arms compared with control. Greater weight loss was associated with increased ghrelin concentrations, regardless of intervention. Neither baseline ghrelin nor body composition modified the intervention effects on changes in total ghrelin. The 12-month change in total ghrelin was inversely associated with changes in leptin, insulin and insulin resistance, and positively associated with change in adiponectin. CONCLUSIONS: Greater weight loss, achieved through a reduced calorie diet or exercise, is associated with increased total ghrelin concentrations in overweight or obese postmenopausal women.

Macrophage metalloelastase (MMP12) regulates adipose tissue expansion, insulin sensitivity, and expression of inducible nitric oxide synthase.

Macrophage metalloelastase, a matrix metallopeptidase (MMP12) predominantly expressed by mature tissue macrophages, is implicated in pathological processes. However, physiological functions for MMP12 have not been described. Because mRNA levels for the enzyme increase markedly in adipose tissue of obese mice, we investigated the role of MMP12 in adipose tissue expansion and insulin resistance. In humans, MMP12 expression correlated positively and significantly with insulin resistance, TNF-α expression, and the number of CD14(+)CD206(+) macrophages in adipose tissue. MMP12 was the most abundant matrix metallopeptidase detected by proteomic analysis of conditioned medium of M2 macrophages and dendritic cells. In contrast, it was detected only at low levels in bone marrow derived macrophages and M1 macrophages. When mice received a high-fat diet, adipose tissue mass increased and CD11b(+)F4/80(+)CD11c(-) macrophages accumulated to a greater extent in MMP12-deficient (Mmp12(-/-)) mice than in wild-type mice (Mmp12(+/+)). Despite being markedly more obese, fat-fed Mmp12(-/-) mice were more insulin sensitive than fat-fed Mmp12(+/+) mice. Expression of inducible nitric oxide synthase (Nos2) by Mmp12(-/-) macrophages was significantly impaired both in vivo and in vitro, suggesting that MMP12 might mediate nitric oxide production during inflammation. We propose that MMP12 acts as a double-edged sword by promoting insulin resistance while combatting adipose tissue expansion.

Carbohydrate feeding dissociates the postprandial FGF19 response from circulating bile acid levels in humans.

CONTEXT: Fibroblast growth factor 19 (FGF19) improves glycemic control in diabetic animals and is secreted from the gastrointestinal tract after meals in response to bile acid stimulation. OBJECTIVE: We sought to understand how ingestion of carbohydrates, protein or lipids affect both FGF19 and bile acid concentrations in human plasma, with the hypothesis that variation in the bile acid response to different macronutrients would predict differences in plasma FGF19 levels. DESIGN: This was a randomized, within-subjects crossover study. SETTING: The study was conducted at a university clinical research center. PARTICIPANTS: There were 16 healthy human subjects included in the study. INTERVENTIONS: Isocaloric, isovolemic beverages composed primarily of carbohydrates, proteins, or lipids were provided to each participant on 3 separate occasions. MAIN OUTCOME MEASURES: The magnitudes of postprandial rises of plasma FGF19 and total bile acid levels were determined. RESULTS: All beverages induced an initial transient decline of plasma FGF19 levels during the first 60 minutes after consumption. For FGF19, the ingestion of carbohydrate was associated with the fastest and highest increase of plasma levels, returning to baseline at 5 hours. By comparison, the protein beverage induced a modest but significant elevation of FGF19 levels that peaked at the end of the 6-hour sampling interval, whereas a lipid beverage was without effect. In contrast, total bile acid levels increased in plasma only in response to a high-lipid beverage, demonstrating a marked divergence between the FGF19 and bile acid response to lipid vs carbohydrate. CONCLUSIONS: A bile acid-independent mechanism is implicated in the effect of meals to raise plasma FGF19 concentrations.

Weight and metabolic effects of dietary weight loss and exercise interventions in postmenopausal antidepressant medication users and non-users: a randomized controlled trial.

OBJECTIVE: Antidepressants may attenuate the effects of diet and exercise programs. We compared adherence and changes in body measures and biomarkers of glucose metabolism and inflammation between antidepressant users and non-users in a 12-month randomized controlled trial. METHODS: Overweight or obese, postmenopausal women were assigned to: diet (10% weight loss goal, N=118); moderate-to-vigorous aerobic exercise (225 min/week, N=117); diet+exercise (N=117); and control (N=87) in Seattle, WA 2005-2009. Women using antidepressants at baseline were classified as users (N=109). ANCOVA and generalized estimating equation approaches, respectively, were used to compare adherence (exercise amount, diet session attendance, and changes in percent calorie intake from fat, cardiopulmonary fitness, and pedometer steps) and changes in body measures (weight, waist and percent body fat) and serum biomarkers (glucose, insulin, homeostasis assessment-insulin resistance, and high-sensitivity C-reactive protein) between users and non-users. An interaction term (intervention×antidepressant use) tested effect modification. RESULTS: There were no differences in adherence except that diet session attendance was lower among users in the diet+exercise group (P<0.05 vs. non-users). Changes in body measures and serum biomarkers did not differ by antidepressant use (Pinteraction>0.05). CONCLUSION: Dietary weight loss and exercise improved body measures and biomarkers of glucose metabolism and inflammation independent of antidepressant use.

Effects of dietary weight loss and exercise on insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in postmenopausal women: a randomized controlled trial.

High levels of insulin-like growth factor (IGF)-I may increase the risk of common cancers in humans. We hypothesized that weight loss induced by diet and/or exercise would reduce IGF-I in postmenopausal women. Four hundred and thirty nine overweight or obese [body mass index (BMI) ≥ 25 kg/m(2)] women (50-75 years) were randomly assigned to: (i) exercise (N = 117), (ii) dietary weight loss (N = 118), (iii) diet + exercise (N = 117), or (iv) control (N = 87). The diet intervention was a group-based program with a 10% weight loss goal. The exercise intervention was 45 minutes/day, 5 days/week of moderate-to-vigorous intensity activity. Fasting serum IGF-I and IGF-binding protein (IGFBP)-3 were measured at baseline and 12 months by radioimmunoassay. Higher baseline BMI was associated with lower IGF-I and IGF-I/IGFBP-3 molar ratio. Although no significant changes in either IGF-I or IGFBP-3 were detected in any intervention arm compared with control, the IGF-I/IGFBP-3 ratio increased significantly in the diet (+5.0%, P < 0.01) and diet + exercise (+5.4%, P < 0.01) groups compared with control. Greater weight loss was positively associated with change in both IGF-I (P(trend) = 0.017) and IGF-I/IGFBP-3 ratio (P(trend) < 0.001) in the diet group, but inversely with change in IGFBP-3 in the diet + exercise group (P(trend) = 0.01). No consistent interaction effects with baseline BMI were detected. Modified IGF-I bioavailability is unlikely to be a mechanism through which caloric restriction reduces cancer risk in postmenopausal women.

Independent and combined effects of dietary weight loss and exercise on leukocyte telomere length in postmenopausal women.

OBJECTIVE: Investigate the effects of 12 months of dietary weight loss and/or aerobic exercise on leukocyte telomere length in postmenopausal women. DESIGN AND METHODS: Four hundred and thirty nine overweight or obese women (50-75 years) were randomized to: (i) dietary weight loss (N = 118); (ii) aerobic exercise (N = 117), (iii) diet + exercise (N = 117), or (iv) control (N = 87). The diet intervention was a group-based program with a 10% weight loss goal. The exercise intervention was 45 min day(-1) , 5 days week(-1) of moderate-to-vigorous aerobic activity. Fasting blood samples were taken at baseline and 12 months. DNA was extracted from isolated leukocytes and telomere length was measured by quantitative-polymerase chain reaction (qPCR). Mean changes were compared between groups (intent-to-treat) using generalized estimating equations. RESULTS: Baseline telomere length was inversely associated with age (r = -0.12 P < 0.01) and positively associated with maximal oxygen uptake (r = 0.11, P = 0.03), but not with BMI or %body fat. Change in telomere length was inversely correlated with baseline telomere length (r = -0.47, P < 0.0001). No significant difference in leukocyte telomere length was detected in any intervention group compared to controls, nor was the magnitude of weight loss associated with telomere length at 12 months. CONCLUSIONS: Twelve months of dietary weight loss and exercise did not change telomere length in postmenopausal women.

Gene expression changes in adipose tissue with diet- and/or exercise-induced weight loss.

Adipose tissue plays a role in obesity-related cancers via increased production of inflammatory factors, steroid hormones, and altered adipokines. The impact of weight loss on adipose tissue gene expression may provide insights into pathways linking obesity with cancer risk. We conducted an ancillary study within a randomized trial of diet, exercise, or combined diet + exercise versus control among overweight/obese postmenopausal women. In 45 women, subcutaneous adipose tissue biopsies were conducted at baseline and after 6 months, and changes in adipose tissue gene expression were determined by microarray with an emphasis on prespecified candidate pathways as well as by unsupervised clustering of more than 37,000 transcripts (Illumina). Analyses were conducted first by randomization group and then by degree of weight change at 6-months in all women combined. At 6 months, diet, exercise, and diet + exercise participants lost a mean of 8.8, 2.5, and 7.9 kg (all P < 0.05 vs. no change in controls). There was no significant change in candidate gene expression by intervention group. In analysis by weight change category, greater weight loss was associated a decrease in 17ß-hydroxysteroid dehydrogenase-1 (HSD17B1, Ptrend < 0.01) and leptin (LEP, Ptrend < 0.01) expression, and marginally significant increased expression of estrogen receptor-1 (ESR1, Ptrend = 0.08) and insulin-like growth factor-binding protein-3 (IGFBP3, Ptrend = 0.08). Unsupervised clustering revealed 83 transcripts with statistically significant changes. Multiple gene expression changes correlated with changes in associated serum biomarkers. Weight loss was associated with changes in adipose tissue gene expression after 6 months, particularly in two pathways postulated to link obesity and cancer, that is, steroid hormone metabolism and IGF signaling. Cancer Prev Res; 6(3); 217-31. ©2013 AACR.

Exercise adherence, cardiopulmonary fitness and anthropometric changes improve exercise self-efficacy and health-related quality of life.

BACKGROUND: Regular exercise increases exercise self-efficacy and health-related quality of life (HRQOL); however, the mechanisms are unknown. We examined the associations of exercise adherence and physiological improvements with changes in exercise self-efficacy and HRQOL. METHODS: Middle-aged adults (N = 202) were randomized to 12 months aerobic exercise (360 minutes/week) or control. Weight, waist circumference, percent body fat, cardiopulmonary fitness, HRQOL (SF-36), and exercise self-efficacy were assessed at baseline and 12 months. Adherence was measured in minutes/day from activity logs. RESULTS: Exercise adherence was associated with reduced bodily pain, improved general health and vitality, and reduced role-emotional scores (P(trend) ≤ 0.05). Increased fitness was associated with improved physical functioning, bodily pain and general health scores (P(trend) ≤ 0.04). Reduced weight and percent body fat were associated with improved physical functioning, general health, and bodily pain scores (P(trend) < 0.05). Decreased waist circumference was associated with improved bodily pain and general health but with reduced role-emotional scores (P(trend) ≤ 0.05). High exercise adherence, increased cardiopulmonary fitness and reduced weight, waist circumference and percent body fat were associated with increased exercise self-efficacy (P(trend) < 0.02). CONCLUSIONS: Monitoring adherence and tailoring exercise programs to induce changes in cardiopulmonary fitness and body composition may lead to greater improvements in HRQOL and self-efficacy that could promote exercise maintenance.

History of weight cycling does not impede future weight loss or metabolic improvements in postmenopausal women.

OBJECTIVE: Given that the repetitive loss and regain of body weight, termed weight cycling, is a prevalent phenomenon that has been associated with negative physiological and psychological outcomes, the purpose of this study was to investigate weight change and physiological outcomes in women with a lifetime history of weight cycling enrolled in a 12-month diet and/or exercise intervention. METHODS: 439 overweight, inactive, postmenopausal women were randomized to: i) dietary weight loss with a 10% weight loss goal (N=118); ii) moderate-to-vigorous intensity aerobic exercise for 45 min/day, 5 days/week (n=117); ii) both dietary weight loss and exercise (n=117); or iv) control (n=87). Women were categorized as non-, moderate- (≥3 losses of ≥4.5 kg), or severe-cyclers (≥3 losses of ≥9.1 kg). Trend tests and linear regression were used to compare adherence and changes in weight, body composition, blood pressure, insulin, C-peptide, glucose, insulin resistance (HOMA-IR), C-reactive protein, leptin, adiponectin, and interleukin-6 between cyclers and non-cyclers. RESULTS: Moderate (n=103) and severe (n=77) cyclers were heavier and had less favorable metabolic profiles than non-cyclers at baseline. There were, however, no significant differences in adherence to the lifestyle interventions. Weight-cyclers (combined) had a greater improvement in HOMA-IR compared to non-cyclers participating in the exercise only intervention (P=.03), but no differences were apparent in the other groups. CONCLUSION: A history of weight cycling does not impede successful participation in lifestyle interventions or alter the benefits of diet and/or exercise on body composition and metabolic outcomes.