Exchanging carbohydrate or protein for fat improves lipid-related cardiovascular risk profile in overweight men and women when consumed ad libitum.

BACKGROUND: The impact of low-fat diets on the plasma lipoprotein profile is incompletely understood. METHODS: We conducted two 16-week dietary studies to compare the effects of a moderate-fat (mod-FAT) baseline diet with isocaloric and ad libitum low-fat diets rich in either carbohydrates (high-CHO, n = 16) or protein (high-PRO, n = 19) on plasma lipids, post-heparin lipase activities, cholesteryl ester transfer protein, and phospholipid transfer protein. RESULTS: Switching from the mod-FAT to the isocaloric high-CHO diet lowered plasma high-density lipoprotein cholesterol concentrations (P < 0.001) and tended to increase triglyceride levels (P = 0.087). Cholesterol content in the larger, buoyant low-density lipoprotein (LDL) fractions decreased, whereas those of the very-low-density lipoprotein, intermediate-density lipoprotein, and smaller, denser LDL fractions tended to increase. These changes were largely reversed when subjects lost weight by consuming this high-CHO diet ad libitum. Switching from the mod-FAT diet to the isocaloric high-PRO diet did not increase cholesterol content in the small-dense LDL fraction and led to decreases in both LDL and high-density lipoprotein cholesterol in plasma (P < 0.001 for both).Consumption of the high-protein ad libitum diet accompanied by weight loss did not change plasma lipids further, except for a shift of cholesterol from dense low-density lipoprotein fractions to more buoyant low-density lipoprotein fractions. Cholesteryl ester transfer protein concentrations decreased with high-cholesterol feeding, whereas cholesteryl ester transfer protein concentrations and hepatic lipase and phospholipid transfer protein activities all decreased during high-protein feeding. CONCLUSIONS: Both high-CHO and high-PRO diets improve plasma lipid-related risk of cardiovascular disease when consumed ad libitum.

Reduced adipogenic gene expression in thigh adipose tissue precedes human immunodeficiency virus-associated lipoatrophy.

CONTEXT: The expression of adipogenic genes in sc adipose tissue has been reported to be lower among patients with HIV-associated lipoatrophy than HIV-uninfected controls. It is unclear whether this is a result or cause of lipoatrophy. OBJECTIVE: The objective of the study was to investigate the temporal relationships among changes in adipogenic gene expression in sc adipose tissue and changes in body fat distribution and metabolic complications in HIV-infected subjects on antiretroviral therapy. DESIGN: This was a prospective longitudinal study. SETTING: The study was conducted at HIV clinics in Seattle, Washington. PARTICIPANTS: The study population included 31 HIV-infected and 12 control subjects. INTERVENTIONS: Subjects were followed up for 12 months after they initiated or modified their existing antiretroviral regimen. MAIN OUTCOME MEASURES: Changes in body composition, plasma lipids, insulin sensitivity, and gene expression in sc abdominal and thigh adipose tissue. RESULTS: Subjects who developed lipoatrophy (n=10) had elevated fasting triglycerides [3.16 (sd 2.79) mmol/liter] and reduced insulin sensitivity as measured by frequently sampled iv glucose tolerance test [1.89 (sd 1.27)x10(-4) min(-1)/microU.ml] after 12 months, whereas those without lipoatrophy (n=21) did not show any metabolic complications [triglycerides 1.32 (sd 0.58) mmol/liter, P=0.01 vs. lipoatrophy; insulin sensitivity 3.52 (sd 1.91)x10(-4) min(-1)/microU.ml, P=0.01 vs. lipoatrophy]. In subjects developing lipoatrophy, the expression of genes involved in adipocyte differentiation, lipid uptake, and local cortisol production in thigh adipose tissue was significantly reduced already at the 2-month visit, several months before any loss of extremity fat mass was evident. CONCLUSIONS: In HIV-infected subjects, lipoatrophy is associated with elevated fasting triglycerides and insulin resistance and might be caused by a direct or indirect effect of antiretroviral drugs on sc adipocyte differentiation.

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.

Plasma C-reactive protein concentration is not affected by isocaloric dietary fat reduction.

OBJECTIVE: There is a strong correlation between plasma C-reactive protein (CRP) concentration and risk of cardiovascular death. Low-fat diets have been recommended for maintenance of cardiovascular health, and it is known that a low-fat diet associated with weight loss lowers CRP concentration. However, it remains unclear whether dietary fat has an effect independent from weight change on markers of inflammation. METHODS: Sixteen overweight subjects who were 46 +/- 14 y old were placed on a weight-maintaining baseline diet consisting of 35% fat, 45% carbohydrate, and 20% energy as protein. After 2 wk, subjects were switched to an isocaloric low-fat diet consisting of 15% fat, 65% carbohydrate, and 20% protein for another 2 wk. For the final 12 wk of the study, subjects consumed the same 15% fat diet ad libitum. At the end of each diet phase, CRP was measured by a high-sensitivity CRP assay. RESULTS: The weight of subjects remained stable during the first 4 wk of isocaloric diets. Plasma CRP concentrations after 2 wk on the weight-maintaining 35% fat diet and 2 wk on the isocaloric 15% fat diet were not significantly different (median +/- interquartile range 1.42 +/- 3.30 and 1.59 +/- 3.29 mg/L, respectively). Three months of ad libitum low-fat diet consumption resulted in a 4.1 +/- 0.7 kg weight loss associated with a decrease in CRP concentration to 1.17 +/- 2.03 mg/L (P = 0.03). CONCLUSION: Loss of body weight decreases CRP concentration, but a decrease in dietary fat without a concurrent change in body weight does not affect CRP concentration in overweight healthy subjects.

A high-protein diet induces sustained reductions in appetite, ad libitum caloric intake, and body weight despite compensatory changes in diurnal plasma leptin and ghrelin concentrations.

BACKGROUND: Ad libitum, low-carbohydrate diets decrease caloric intake and cause weight loss. It is unclear whether these effects are due to the reduced carbohydrate content of such diets or to their associated increase in protein intake. OBJECTIVE: We tested the hypothesis that increasing the protein content while maintaining the carbohydrate content of the diet lowers body weight by decreasing appetite and spontaneous caloric intake. DESIGN: Appetite, caloric intake, body weight, and fat mass were measured in 19 subjects placed sequentially on the following diets: a weight-maintaining diet (15% protein, 35% fat, and 50% carbohydrate) for 2 wk, an isocaloric diet (30% protein, 20% fat, and 50% carbohydrate) for 2 wk, and an ad libitum diet (30% protein, 20% fat, and 50% carbohydrate) for 12 wk. Blood was sampled frequently at the end of each diet phase to measure the area under the plasma concentration versus time curve (AUC) for insulin, leptin, and ghrelin. RESULTS: Satiety was markedly increased with the isocaloric high-protein diet despite an unchanged leptin AUC. Mean (+/-SE) spontaneous energy intake decreased by 441 +/- 63 kcal/d, body weight decreased by 4.9 +/- 0.5 kg, and fat mass decreased by 3.7 +/- 0.4 kg with the ad libitum, high-protein diet, despite a significantly decreased leptin AUC and increased ghrelin AUC. CONCLUSIONS: An increase in dietary protein from 15% to 30% of energy at a constant carbohydrate intake produces a sustained decrease in ad libitum caloric intake that may be mediated by increased central nervous system leptin sensitivity and results in significant weight loss. This anorexic effect of protein may contribute to the weight loss produced by low-carbohydrate diets.

Postprandial suppression of plasma ghrelin level is proportional to ingested caloric load but does not predict intermeal interval in humans.

Plasma ghrelin levels rise before meals and fall rapidly afterward. If ghrelin is a physiological meal-initiation signal, then a large oral caloric load should suppress ghrelin levels more than a small caloric load, and the request for a subsequent meal should be predicted by recovery of the plasma ghrelin level. To test this hypothesis, 10 volunteers were given, at three separate sessions, liquid meals (preloads) with widely varied caloric content (7.5%, 16%, or 33% of total daily energy expenditure) but equivalent volume. Preloads were consumed at 0900 h, and blood was sampled every 20 min from 0800 h until 80 min after subjects spontaneously requested a meal. The mean (+/- SE) intervals between ingestion of the 7.5%, 16%, and 33% preloads and the subsequent voluntary meal requests were 247 +/- 24, 286 +/- 20, and 321 +/- 27 min, respectively (P = 0.015), and the nadir plasma ghrelin levels were 80.2 +/- 2.8%, 72.7 +/- 2.7%, and 60.8 +/- 2.7% of baseline (the 0900 h value), respectively (P < 0.001). A Cox regression analysis failed to show a relationship between ghrelin profile and the spontaneous meal request. We conclude that the depth of postprandial ghrelin suppression is proportional to ingested caloric load but that recovery of plasma ghrelin is not a critical determinant of intermeal interval.

Roles of leptin and ghrelin in the loss of body weight caused by a low fat, high carbohydrate diet.

Loss of body fat by caloric restriction is accompanied by decreased circulating leptin levels, increased ghrelin levels, and increased appetite. In contrast, dietary fat restriction often decreases adiposity without increasing appetite. Substitution of dietary carbohydrate for fat has been shown to increase the area under the plasma leptin vs. time curve (AUC) over the course of 24 h. This effect, if sustained, could explain the absence of a compensatory increase in appetite on a low fat diet. To clarify the effect of dietary fat restriction on leptin and ghrelin, we measured AUC for these hormones in human subjects after each of the following sequential diets: 2 wk on a weight-maintaining 35% fat (F), 45% carbohydrate (C), 20% protein (P) diet (n = 18); 2 wk on an isocaloric 15% F, 65% C, 20% P diet (n = 18); and 12 wk on an ad libitum 15% F, 65% C, 20% P diet (n = 16). AUC for leptin was similar on the isocaloric 15% F and 35% F diets (555 +/- 57 vs. 580 +/- 56 ng/ml.24 h; P = NS). Body weight decreased from 74.6 +/- 2.4 to 70.8 +/- 2.7 kg on the ad libitum 15% F diet (P < 0.001) without compensatory increases in food consumption or AUC for ghrelin. Proportional amplitude of the 24-h leptin profile was increased after 12 wk on the 15% fat diet. We conclude that weight loss early in the course of dietary fat restriction occurs independently of increased plasma leptin levels, but that a later increase in amplitude of the 24-h leptin signal may contribute to ongoing weight loss. Fat restriction avoids the increase in ghrelin levels caused by dietary energy restriction.

Absence of hypersensitivity to glucocorticoids in antiretroviral-associated lipodystrophy.

OBJECTIVE: The lipodystrophy syndrome, which is associated with the use of antiretroviral drugs in some human immunodeficiency virus (HIV)-infected individuals, bears a striking similarity to the fat redistribution observed in Cushing's disease. Although urinary free cortisol excretion and glucocorticoid receptor binding affinity are not elevated in subjects with lipodystrophy, glucocorticoid action at the cellular level has not been examined in affected individuals. The objective of this study was to determine whether tissue sensitivity to glucocorticoids is increased in subjects with lipodystrophy taking protease inhibitors. RESEARCH METHODS AND PROCEDURES: Subjects included 11 HIV-infected men on protease inhibitor therapy with lipodystrophy and 10 control HIV-infected men not on protease inhibitor therapy and without lipodystrophy. Trunk to extremity fat ratio was measured by DXA. Dexamethasone suppression of peripheral blood mononuclear cell proliferation was measured as an index of tissue sensitivity to glucocorticoid action. RESULTS: Compared with the control group, subjects with lipodystrophy had a significant elevation of the trunk to extremity fat ratio [median (interquartile range): 2.9 (1.3) vs. 1.6 (1.2); p < 0.05]. The concentration of dexamethasone resulting in 50% maximal suppression of proliferation was 11.7 nM (9.3 nM) in subjects with lipodystrophy and 19.6 nM (9.7 nM) in control subjects (p = not significant), and the percentage minimal proliferation was 4% (12%) and 17% (18%) in the two groups, respectively (p = not significant). DISCUSSION: Despite the Cushingoid appearance of affected individuals, these data suggest that body fat redistribution in antiretroviral-associated lipodystrophy does not arise through an increase in postreceptor glucocorticoid signaling.

Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery.

BACKGROUND: Weight loss causes changes in appetite and energy expenditure that promote weight regain. Ghrelin is a hormone that increases food intake in rodents and humans. If circulating ghrelin participates in the adaptive response to weight loss, its levels should rise with dieting. Because ghrelin is produced primarily by the stomach, weight loss after gastric bypass surgery may be accompanied by impaired ghrelin secretion. METHODS: We determined the 24-hour plasma ghrelin profiles, body composition, insulin levels, leptin levels, and insulin sensitivity in 13 obese subjects before and after a six-month dietary program for weight loss. The 24-hour ghrelin profiles were also determined in 5 subjects who had lost weight after gastric bypass and 10 normal-weight controls; 5 of the 13 obese subjects who participated in the dietary program were matched to the subjects in the gastric-bypass group and served as obese controls. RESULTS: Plasma ghrelin levels rose sharply shortly before and fell shortly after every meal. A diet-induced weight loss of 17 percent of initial body weight was associated with a 24 percent increase in the area under the curve for the 24-hour ghrelin profile (P=0.006). In contrast, despite a 36 percent weight loss after gastric bypass, the area under the curve for the ghrelin profile in the gastric-bypass group was 77 percent lower than in normal-weight controls (P<0.001) and 72 percent lower than in matched obese controls (P=0.01). The normal, meal-related fluctuations and diurnal rhythm of the ghrelin level were absent after gastric bypass. CONCLUSIONS: The increase in the plasma ghrelin level with diet-induced weight loss is consistent with the hypothesis that ghrelin has a role in the long-term regulation of body weight. Gastric bypass is associated with markedly suppressed ghrelin levels, possibly contributing to the weight-reducing effect of the procedure.