Holly S. Callahan

Acyl and Total Ghrelin Are Suppressed Strongly by Ingested Proteins, Weakly by Lipids, and Biphasically by Carbohydrates

CONTEXT Ghrelin is an orexigenic hormone that can increase body weight. Its circulating levels increase before meals and are suppressed after food ingestion. Understanding the effects of specific types of ingested macronutrients on ghrelin regulation could facilitate the design of weight-reducing diets. OBJECTIVE We sought to understand how ingestion of carbohydrates, proteins, or lipids affect acyl (bioactive) and total ghrelin levels among human subjects, hypothesizing that lipids might suppress ghrelin levels less effectively than do either carbohydrates or proteins. DESIGN This was a randomized, within-subjects cross-over 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. MAIN OUTCOME MEASURES The magnitude of postprandial suppression of total and acyl ghrelin levels (measured with a novel acyl-selective, two-site ELISA) was determined. RESULTS All beverages suppressed plasma acyl and total ghrelin levels. A significant effect of macronutrient class on decremental area under the curve for both acyl and total ghrelin was observed; the rank order for magnitude of suppression was protein more than carbohydrate more than lipid. Total ghrelin nadir levels were significantly lower after both carbohydrate and protein, compared with lipid beverages. In the first 3 postprandial hours, the rank order for acyl and total ghrelin suppression was carbohydrate more than protein more than lipid. In the subsequent 3 h, there was a marked rebound above preprandial values of acyl and total ghrelin after carbohydrate ingestion alone. CONCLUSIONS These findings suggest possible mechanisms contributing to the effects of high-protein/low-carbohydrate diets to promote weight loss, and high-fat diets to promote weight gain.

Dairy fat intake is associated with glucose tolerance, hepatic and systemic insulin sensitivity, and liver fat but not β-cell function in humans

BACKGROUND Plasma phospholipid concentrations of trans-palmitoleic acid (trans-16:1n-7), a biomarker of dairy fat intake, are inversely associated with incident type 2 diabetes in 2 US cohorts. OBJECTIVE The objective was to investigate whether the intake of trans-16:1n-7 in particular, or dairy fat in general, is associated with glucose tolerance and key factors determining glucose tolerance. DESIGN A cross-sectional investigation was undertaken in 17 men and women with nonalcoholic fatty liver disease and 15 body mass index (BMI)- and age-matched controls. The concentrations of trans-16:1n-7 and 2 other biomarkers of dairy fat intake, 15:0 and 17:0, were measured in plasma phospholipids and free fatty acids (FFAs). Liver fat was estimated by computed tomography-derived liver-spleen ratio. Intravenous-glucose-tolerance tests and oral-glucose-tolerance test (OGTT) and hyperinsulinemic-euglycemic clamps were performed to assess β-cell function and hepatic and systemic insulin sensitivity. RESULTS In multivariate analyses adjusted for age, sex, and BMI, phospholipid 17:0, phospholipid trans-16:1n-7, FFA 15:0, and FFA 17:0 were inversely associated with fasting plasma glucose, the area under the curve for glucose during an OGTT, and liver fat. Phospholipid trans-16:1n-7 was also positively associated with hepatic and systemic insulin sensitivity. None of the biomarkers were associated with β-cell function. The associations between dairy fat intake and glucose tolerance were attenuated by adjusting for insulin sensitivity or liver fat, but strengthened by adjusting for β-cell function. CONCLUSION Although we cannot rule out reverse causation, these data support the hypothesis that dairy fat improves glucose tolerance, possibly through a mechanism involving improved hepatic and systemic insulin sensitivity and reduced liver fat.

Effect of Aging on the Response of Ghrelin to Acute Weight Loss

OBJECTIVES: To determine whether the failure of the orexigenic hormone ghrelin to increase as it normally does with weight loss contributes to impaired weight recovery in older persons.

Association of cognitive restraint with ghrelin, leptin, and insulin levels in subjects who are not weight-reduced.

Despite widespread efforts at weight loss, the prevalence of obesity continues to rise. Restrained eating is a pattern of attempted weight control characterized by cognitive restriction of food intake that has paradoxically been linked with overeating and/or weight gain. It is not known whether restrained eating is associated with abnormalities in appetite-regulating hormones, independent of its effects on body weight. To address this question, we assessed cognitive restraint using the Three-Factor Eating Questionnaire and obtained fasting measurements of ghrelin, leptin and insulin from 24 healthy, non-obese (body mass index (BMI) 19.7 to 29.6 kg/m(2)) adult subjects who were at a stable, lifetime maximum weight. We chose to study subjects at stable maximum weight to avoid the secondary effects of weight reduction on body-weight regulating hormones. Subjects were classified by cognitive restraint scale score into Low, Indeterminate, and High Restraint groups. Higher ghrelin levels were significantly associated with restraint in an unadjusted model (P=0.004) and after adjustment for BMI (P=0.007). No relationships were found between restraint scores and either leptin (P=0.75) or insulin (P=0.36). These findings show an orexigenic hormonal profile in restrained eaters, independent of changes in body weight.

Dietary n-3-polyunsaturated fatty acids and energy balance in overweight or moderately obese men and women: a randomized controlled trial

BackgroundDietary n-3-polyunsaturated fatty acids (n-3-PUFA) have been shown to reduce body weight and fat mass in rodents as well as in humans in one small short-term study. We conducted this controlled randomized dietary trial to test the hypothesis that n-3-PUFA lower body weight and fat mass by reducing appetite and ad libitum food intake and/or by increasing energy expenditure.MethodsTwenty-six overweight or moderately obese (body mass index 28–33 kg/m2) men and women were included, and received either a diet rich in n-3-PUFA from both plant and marine sources or a control diet. Diets were administered in an isocaloric fashion for 2 weeks followed by 12 weeks of ad libitum intake. The n-3-PUFA and control diets were identical in all regards except for the fatty acid composition. All foods were provided to subjects, and leftovers were weighed back to assess actual food intake accurately for each day of the study. This design gave us 80% power to detect a difference in weight change between the n-3-PUFA and control diet groups of 2.25 kg at an α-error level of 5%.ResultsBoth groups lost similar amounts of weight when these diets were consumed ad libitum for 12 weeks [mean (SD): -3.5 (3.7) kg in the control group vs. -2.8 (3.7) kg in the n-3-PUFA group, F(1,24) = 13.425, p = 0.001 for time effect; F(1,24) = 0.385, p = 0.541 for time × group interaction]. Consistent with this finding, we also found no differences between the n-3-PUFA and control groups with regard to appetite as measured by visual analogue scale, ad libitum food intake, resting energy expenditure as measured by indirect calorimetry, diurnal plasma leptin concentrations, or fasting ghrelin concentrations.ConclusionOur results suggest that dietary n-3-PUFA do not play an important role in the regulation of food intake, energy expenditure, or body weight in humans.

n3 PUFAs Do Not Affect Adipose Tissue Inflammation in Overweight to Moderately Obese Men and Women

Recent studies have indicated that omega-3 (n3) polyunsaturated fatty acids (PUFAs) decrease adipose tissue inflammation in rodents and in morbidly obese humans. We investigated whether a diet rich in n3 PUFAs from both marine and plant sources reduces adipose tissue and systemic inflammation in overweight to moderately obese adults. We conducted a randomized, single-blind, parallel-design, placebo-controlled feeding trial. Healthy men and women with a body mass index between 28 and 33 kg/m(2) consumed a diet rich in n3 PUFAs (3.5% of energy intake; n = 11) from plant and marine sources or a control diet (0.5% of energy intake from n3 PUFAs; n = 13). These diets were consumed for 14 wk (ad libitum for 12 wk). All foods were provided for the entire study period. Subcutaneous abdominal adipose tissue and fasting plasma were collected after the first 2 wk with the control diet and again at the end of the 14-wk dietary period. The primary outcome of this ex post analysis was the adipose tissue gene expression of 13 key mediators of inflammation. Adipose tissue gene expression of inflammatory mediators did not differ between the 2 groups, after adjustment for weight change. Furthermore, none of the 5 plasma markers of systemic inflammation differed significantly as an effect of diet treatment. We conclude that a relatively high dose of n3 PUFAs from plant and marine sources did not significantly lower adipose tissue or systemic inflammation in overweight to moderately obese healthy men and women over 14 wk.

Effects of Dietary Fat and Saturated Fat Content on Liver Fat and Markers of Oxidative Stress in Overweight/Obese Men and Women under Weight-Stable Conditions

Dietary fat and oxidative stress are hypothesized to contribute to non-alcoholic fatty liver disease and progression to steatohepatitis. To determine the effects of dietary fat content on hepatic triglyceride, body fat distribution and markers of inflammation and oxidative stress, overweight/obese subjects with normal glucose tolerance consumed a control diet (CONT: 35% fat/12% saturated fat/47% carbohydrate) for ten days, followed by four weeks on a low fat (LFD (n = 10): 20% fat/8% saturated fat/62% carbohydrate) or high fat diet (HFD (n = 10): 55% fat/25% saturated fat/27% carbohydrate). Hepatic triglyceride content was quantified by MRS and abdominal fat distribution by MRI. Fasting biomarkers of inflammation (plasma hsCRP, IL-6, IL-12, TNFα, IFN-γ) and oxidative stress (urinary F2-α isoprostanes) were measured. Body weight remained stable. Compared to the CONT, hepatic triglyceride decreased on the LFD (mean (95% CI): change −2.13% (−3.74%, −0.52%)), but did not change on the HFD and there was no significant difference between the LFD and HFD. Intra-abdominal fat did not change significantly on either diet, but subcutaneous abdominal fat increased on the HFD. There were no significant changes in fasting metabolic markers, inflammatory markers and urinary F2-α isoprostanes. We conclude that in otherwise healthy overweight/obese adults under weight-neutral conditions, a diet low in fat and saturated fat has modest effects to decrease liver fat and may be beneficial. On the other hand, a diet very high in fat and saturated fat had no effect on hepatic triglyceride or markers of metabolism, inflammation and oxidative stress.

Effects of a High-Protein Diet on Regulation of Phosphorus Homeostasis

CONTEXT High-protein diets, which are popular for weight loss, contain large quantities of phosphorus. Phosphorus excess and consequent changes in phosphorus regulatory hormones are implicated in vascular calcification and cardiovascular disease. OBJECTIVE We tested the hypothesis that a moderate increase in dietary phosphorus during a high-protein diet leads to changes in phosphorus-responsive hormones. DESIGN, PARTICIPANTS, AND SETTING We conducted a post hoc analysis of a sequential dietary modification trial in 19 healthy volunteers in the general community. INTERVENTION Participants received 2 weeks of a weight-maintaining, low-protein (15%) diet, followed by 2 weeks of an isocaloric, high-protein (30%) diet, followed by 12 weeks of an ad libitum high-protein (30%) diet. MAIN OUTCOME MEASURES Using previously collected samples, plasma concentrations of fibroblast growth factor-23 (FGF-23), PTH, 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D were measured at 8 time points to assess 24-hour variability and in 24-hour pooled samples to delineate changes at the end of each diet period. RESULTS Mean dietary phosphorus intake during each study period was 1556, 2071, and 1622 mg/d, respectively. Plasma concentrations of FGF-23 and vitamin D metabolites varied in a diurnal pattern; plasma PTH concentrations varied in a bimodal pattern. After changing from a low- to high-protein isocaloric diet, plasma FGF-23 concentrations decreased slightly (mean -4.48 pg/mL, 95% confidence interval 1.88-7.07). There were no other statistically significant changes in phosphorus regulatory hormones in response to diet modifications. CONCLUSIONS Among healthy people, an approximate 33% increase in dietary phosphorus after institution of a high-protein diet does not cause large changes in measured concentrations of phosphorus regulatory hormones.

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 subjects 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.

Changes in Plasma Amino Acid Levels Do Not Predict Satiety and Weight Loss on Diets with Modified Macronutrient Composition

Objective: Serotonin mediates satiety in the central nervous system. Brain serotonin content depends on the plasma ratio of tryptophan (Trp) to large neutral amino acids (LNAA) and may be affected by diet composition. We examined whether high-carbohydrate or high-protein diets induce satiety and weight loss by altering plasma concentrations of these amino acids. Methods: In study 1 (n = 16, BMI = 27.0 ± 2.3), we compared plasma Trp and LNAA concentrations averaged over 24 h after 2 weeks of consuming isocaloric diets containing either 45 or 65% of total energy as carbohydrate. In study 2 (n = 19, BMI = 26.2 ± 2.1), we made the same measurements following diets containing either 15 or 30% of total energy as protein. To assess satiety in both studies, we recorded caloric intake and weight changes during a subsequent 12-week period of ad libitum consumption of the experimental diets. Results: Ad libitum caloric intake fell by 222 ± 81 kcal/day with a 3.7 ± 0.6 kg weight loss at 12 weeks in study 1. Ad libitum caloric intake fell by 441 ± 63 kcal/ day with a 4.9 ± 0.5 kg weight loss at 12 weeks in study 2. The 24-hour averaged plasma concentration of Trp and the Trp:LNAA ratio were unaffected by the isocaloric increase in carbohydrate or protein consumption that preceded the ad libitum administration of the 2 diets. Conclusion: An increase in either carbohydrate or protein intake increases satiety and leads to significant weight loss, however, these effects are not mediated by an increase in plasma concentration of Trp or the Trp:LNAA ratio.