Self-selected meal composition alters the relationship between same-day caloric intake and appetite scores in humans during a long-term ad-libitum feeding study.

PURPOSE: To determine the effect of an off-protocol meal during a long-term ad libitum feeding study on changes in total caloric consumption and ratings of hunger and satiety. METHODS: During the ad libitum portion of a 16 weeks research high-protein feeding study, 19 participants were allowed to eat up to one self-selected meal (SSM) a week instead of an intervention diet meal. The SSM was assessed for total caloric and macronutrient composition and compared to the intervention diet for 3 days before and after the SSM day. Visual analog scores rating daily hunger and fullness were collected and compared as well. RESULTS: On the SSM day, the mean ± SD daily caloric intake increased by 262 ± 332 kcal compared to the previous study days (P < 0.001), with no changes in subjective appetite scores. The following day there was a slight but significant reduction in intake (- 58 ± 85 kcal, P = 0.008) compared to the average pre-SSM day with no change in appetite scores. On the SSM day, percent protein intake was inversely associated mean daily caloric intake (r2 = 0.22, P = 0.03). CONCLUSIONS: During a long-term, ad-libitum high-protein feeding study, one SSM lower in protein increased daily total caloric consumption with no impact on appetite ratings and incomplete caloric consumption during subsequent days. These data suggest that during ad-libitum feeding, a single meal change in protein content impacts the relationships between daily level of hunger, satiety and calorie intake. GOV ID: NCT05002491 (retrospectively registered 07/20/2021).

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.

Diurnal and Long-term Variation in Plasma Concentrations and Renal Clearances of Circulating Markers of Kidney Proximal Tubular Secretion.

BACKGROUND: The renal proximal tubule is essential for removing organic solutes and exogenous medications from the circulation. We evaluated diurnal, prandial, and long-term biological variation of 4 candidate endogenous markers of proximal tubular secretion. METHODS: We used LC-MS to measure plasma and urine concentrations of hippurate (HA), cinnamoylglycine (CMG), indoxyl sulfate (IS), and p-cresol sulfate (PCS) in 25 healthy adults. We measured plasma concentrations of secreted solutes at 13 time points over a 24-h period, and again after 2 weeks and 14 weeks of follow-up. We further measured 24-h renal clearances of secreted solutes at baseline, 2 weeks, and 14 weeks. RESULTS: Plasma concentrations of secreted solutes varied over the 24-h baseline period. Diurnal variation was greatest for HA, followed by CMG, IS, and PCS. Plasma concentrations of HA (P = 0.002) and IS (P = 0.02), but not CMG and PCS, increased significantly following meals. Long-term intraindividual biological variation (CVI) in plasma concentrations of secreted solutes over 14 weeks varied from 21.8% for IS to 67.3% for PCS, and exceeded that for plasma creatinine (CVI, 7.1%). Variation in 24-h renal clearances was similar among the secreted solutes [intraindividual variation (CVA+I), 33.6%-47.3%] and was lower using pooled plasma samples from each study visit. CONCLUSIONS: Plasma concentrations of HA, CMG, IS, and PCS fluctuate within individuals throughout the day and over weeks. Renal clearances of these secreted solutes, which serve as estimates of renal proximal tubule secretion, are also subject to intraindividual biological variation that can be improved by additional plasma measurements.

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.

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.

Adrenal Insufficiency as a Result of Ritonavir and Exogenous Steroid Exposure: Report of 6 Cases and Recommendation for Management.

Numerous cases of Cushing syndrome have been reported as a result of the interaction between ritonavir (RTV) and exogenous steroid medications. Another complication that frequently occurs is secondary adrenal insufficiency, which can be profound and has not been well described. Here, we report 6 cases of adrenal suppression caused by RTV and exogenous steroids, all of which required corticosteroid replacement therapy and 2 of which were severe enough to require hospitalization. These cases add to the body of literature on the dangerous interaction between RTV and corticosteroids and highlight the risk of secondary adrenal suppression. We also review the literature on this complication and make a recommendation for managing and monitoring such cases.

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 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.

Sleep duration and body mass index in twins: a gene-environment interaction.

STUDY OBJECTIVES: To examine whether sleep duration modifies genetic and environmental influences on body mass index (BMI). DESIGN: Genotype-environment interaction twin study. SETTING: University of Washington Twin Registry. PATIENTS OR PARTICIPANTS: A population-based sample of US twins (1,088 pairs, 604 monozygotic, 484 dizygotic; 66% female; mean age = 36.6 yr, standard deviation (SD) = 15.9 yr). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Participants self-reported information on height, weight, and sleep. Mean BMI was calculated as 25.3 kg/m² (SD = 5.4) and mean habitual sleep duration was 7.2 hr/night (SD = 1.2). Data were analyzed using biometric genetic interaction models. Overall the heritability of sleep duration was 34%. Longer sleep duration was associated with decreased BMI (P < 0.05). The heritability of BMI when sleep duration was < 7 hr (h² = 70%) was more than twice as large as the heritability of BMI when sleep duration was ≥ 9 hr (h² = 32%); this interaction was significant (P < 0.05). CONCLUSIONS: Shorter sleep duration is associated with increased BMI and increased genetic influences on BMI, suggesting that shorter sleep duration increases expression of genetic risks for high body weight. At the same time, longer sleep duration may suppress genetic influences on body weight. Future research aiming to identify specific genotypes for BMI may benefit by considering the moderating role of sleep duration.

Frequent intentional weight loss is associated with higher ghrelin and lower glucose and androgen levels in postmenopausal women.

Population-based studies suggest that repetitive cycling of weight loss and regain may be associated with future weight gain. Therefore, to better define the relationship between weight cycling, energy homeostasis, and future weight gain, we examined associations between frequent intentional weight loss and hormonal profiles in postmenopausal women. This cross-sectional study evaluated the relationship between a history of frequent weight loss and biomarkers, including serum glucose, insulin, leptin, and ghrelin, as well as sex steroid hormones. We hypothesized that frequent intentional weight loss would be associated with changes in normal appetite and body weight regulatory hormones, favoring increased appetite and weight gain. One hundred fifty-nine healthy, weight stable, sedentary, overweight, postmenopausal women who had been recruited for an exercise intervention participated in this study. History of intentional weight loss (frequency and magnitude) was assessed by questionnaire. Hormonal assays were performed by radioimmunoassay (insulin, leptin, ghrelin, estrogens, androgens, and dehydroepiandrosterone), chemiluminescence immunoassay (insulin-like growth factor-1), and immunometric assay (sex hormone binding globulin). Analysis of variance and regression analyses were used to investigate the relationship between weight loss history and metabolic hormones. A higher degree of weight cycling, characterized by the frequency of intentionally losing more than 10 lb, was associated with an appetite-stimulating hormonal profile, including higher concentrations of ghrelin (P trend = .04), lower glucose (P trend = .047), and to some extent, lower insulin (P trend = .08). Frequent weight loss was also associated with lower androgen concentrations, including androstenedione (P trend = .02), testosterone (P trend = .04), and free testosterone (P trend = .01). No independent associations between the concentrations of leptin or estrogens and weight cycling were observed. This study suggests that frequent intentional weight loss may affect hormones involved in energy regulation.

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.

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

BACKGROUND: Dietary 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. METHODS: Twenty-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%. RESULTS: Both 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 x 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. CONCLUSION: Our 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.

Hypercaloric diets differing in fat composition have similar effects on serum leptin and weight gain in female subjects with anorexia nervosa.

Weight regain in subjects with anorexia nervosa is associated with an increase in serum leptin concentrations that is hypothesized to impair full weight restoration. As diets rich in n-3 polyunsaturated fatty acids (PUFA) have been described to lower serum leptin concentrations, we tested the hypothesis that consumption of a hypercaloric diet rich in n-3 PUFA is associated with an attenuated increase in serum leptin and a higher efficiency of body weight gain in subjects with anorexia nervosa. Twenty-five female subjects with anorexia nervosa were enrolled into this controlled dietary intervention study. Four subjects discontinued therapy or participation in the study prematurely, and six were excluded. 15 subjects completed the study. Subjects consumed hypercaloric diets rich in either saturated fatty acids (SFA, n = 8) or n-3 PUFA (n = 7) for 5 weeks. Primary endpoints were the change in serum leptin concentrations and body weight gain relative to energy consumed. Serum leptin concentrations increased distinctly throughout the study (P < .001), and to a similar extend in both groups [+2.9 (SD 2.4) vs. +2.8 (SD 3.4) ng/mL in the SFA- and n-3 PUFA group, respectively; P = .487]. The efficiency of body weight gain also did not differ significantly between groups, with a body weight gain of 63.1 (SD 12.4) vs. 79.2 (SD 26.0) g per 4.2 MJ (1000 kcal) consumed in the SFA- and n-3 PUFA group, respectively (P = .132). Hypercaloric diets rich in either SFA or n-3 PUFA do not differ in their effects on serum leptin concentrations and the efficiency of body weight gain in female subjects with anorexia nervosa.

Serum leptin concentrations and markers of immune function in overweight or obese postmenopausal women.

Experimental studies and case reports suggest a multifunctional role of leptin in immune function. However, clinical studies of leptin in healthy individuals with a comprehensive assessment of immunity are lacking. This study investigated associations between serum leptin concentrations and multiple biomarkers of cellular immunity and inflammation among 114 healthy postmenopausal, overweight, or obese women. Leptin was measured by RIA. C-reactive protein (CRP) and serum amyloid A (SAA) were measured by nephelometry. Flow cytometry was used to measure natural killer (NK) cell cytotoxicity and to enumerate and phenotype lymphocyte subsets. T-lymphocyte proliferation was assessed in response to phytohemagluttinin, as well as to anti-CD3 antibodies by the flow cytometric cell division tracking method. Multiple linear regression analysis with adjustment for confounding factors and log transformation, where appropriate, was used. Serum leptin concentrations were positively associated with serum CRP, SAA, and interleukin 6 (IL6) (P<0.0001, P=0.01, and P=0.04 respectively), more strongly among women with a body mass index (BMI) <30 kg/m(2). The associations were attenuated after adjustment for measured body composition, yet remained significant for CRP and SAA. No statistically significant associations were observed between leptin and NK cytotoxicity, lymphocyte subpopulations, or T-lymphocyte proliferation. This study fills an important gap in knowledge about the relationship between leptin concentrations and immune function in healthy individuals. Findings support an association between serum leptin and the inflammatory proteins CRP and SAA, which appears to be mediated only partly by adipose tissue. Our study does not support a link between leptin and other immune parameters among overweight or obese, but otherwise healthy postmenopausal women, perhaps because such effects are only present at low or deficient leptin concentrations.

Energy balance in congenital generalized lipodystrophy type I.

Congenital generalized lipodystrophy type 1 (CGL-1) is characterized by an absence of adipose tissue and decreased serum leptin levels. Low leptin levels in CGL-1 support the claim that subjects are hypermetabolic and hyperphagic. The present study examines this claim. We determined 24-hour energy expenditure (24-h EE) (kilocalories) (n = 2) and resting metabolic rate (RMR) per kilogram of lean body mass (LBM) (n = 3) in CGL-1 and in 18 healthy control subjects. The 24-h EEs of control and subjects with CGL were compared with respect to kilocalories required per day relative to kilograms of LBM and with respect to RMR relative to kilograms of LBM. Fasting leptin, adiponectin, and 24-hour ghrelin levels were also measured in subjects with CGL-1. The 24-h EE per kilogram of LBM for the subjects with CGL-1 falls on the same regression line observed for this relationship in the controls. The RMR per kilogram of LBM in subjects with CGL-1 also was similar to that in controls. Both 24-h EE and RMR were quite increased when reported per kilogram of total body weight. Subjects with CGL-1 also have decreased fasting leptin and adiponectin hormone levels and no premeal ghrelin rise. People with CGL-1 have similar RMR and daily caloric requirements as healthy controls when these parameters are expressed as a function of LBM. Appetite-regulating hormone levels in CGL-1 suggest that multiple factors act to control appetite in these individuals.

The obesity epidemic: pharmacological challenges.

Obesity, defined by a body mass index greater than 30kg/m(2), claims an increasing number of lives every year, underscoring a dire need for effective therapeutic interventions. The origins of the obesity epidemic are complex, but commonly cited factors include the large quantities of calorie-rich food that are readily accessible in modern society; eating habits adapted to fast-paced lifestyles; low levels of physical activity; and genetic programs that have evolved, especially in populations prone to famine, to favor the storage of excess calories (i.e., the thrifty-gene theory). It is estimated that more than thirty percent of adults, and about fifteen percent of juveniles, are obese. These high rates have led to dramatic increases in diseases such as type 2 diabetes, cardiovascular and respiratory diseases, depression, and some forms of cancer.

Peripheral ghrelin treatment stabilizes body weights of senescent male Brown Norway rats at baseline and after surgery.

Unintentional weight loss may occur spontaneously in older humans and animals. Further weight losses after surgery or illness in the older patients result in increased morbidity, mortality, and hospital readmission rate. A growing body of work has shown increased appetite and weight gain in response to administration of ghrelin, the "hunger hormone." We conducted two studies in senescent male Brown Norway rats to assess the ability of peripheral administration of ghrelin to increase body weight and food intake. One study assessed the effect of 2 wk of daily subcutaneous ghrelin administration (1 mg.kg(-1).day(-1)) to senescent rats in a baseline condition; a second study used the same administration protocol in an interventional experiment with aged rats subjected to a surgery with 10-15% blood loss as a model of elective surgery. In both studies, animals receiving ghrelin maintained their body weights, whereas control animals lost weight. Body weight stability was achieved in ghrelin-treated animals despite a lack of increase in daily or cumulative food intake in both experiments. Hormone and proinflammatory cytokine levels were measured before surgery and after 14 days of treatment. Ghrelin treatment appeared to blunt declining ghrelin levels and also to blunt cytokine increases seen in the surgical control group. The ability of peripheral ghrelin treatment to maintain body weights of senescent rats without concomitant increases in food intake may be due to its known ability to decrease sympathetic activity and metabolic rate, perhaps by limiting cytokine-driven inflammation.

Effect of dietary n-3 polyunsaturated fatty acids on plasma total and high-molecular-weight adiponectin concentrations in overweight to moderately obese men and women.

BACKGROUND: Recent studies indicated that dietary n-3 polyunsaturated fatty acids (PUFAs) increase circulating adiponectin concentrations in rodents. OBJECTIVE: We aimed to investigate whether a diet rich in n-3 PUFAs increased plasma concentrations of total or high-molecular-weight (HMW) adiponectin in healthy overweight-to-moderately obese men and women. DESIGN: Sixteen women and 10 men with a body mass index (in kg/m(2)) between 28 and 33 were randomly assigned to consume a diet rich in n-3 PUFAs (3.5% of energy intake) from both plant and marine sources or a control diet (0.5% of energy intake from n-3 PUFAs). For the first 2 wk, these diets were consumed under isocaloric conditions; then followed a 12-wk period of ad libitum consumption that was associated with a moderate loss of approximately 3.5% of body weight in both groups. Total and HMW adiponectin plasma concentrations were measured before and after each diet phase. RESULTS: Plasma fasting adiponectin concentrations did not change during the isocaloric period, but they increased modestly ( approximately 10%) during the ad libitum period when subjects lost weight [P = 0.009 for time in repeated-measures analysis of variance] and to a similar extent in subjects consuming the control (x +/- SD: 0.42 +/- 0.69 microg/mL) and n-3 PUFA (0.45 +/- 0.85 microg/mL) diets (P = 0.920 for time x treatment interaction). Plasma concentrations of HMW adiponectin did not change significantly during the study. CONCLUSION: Dietary n-3 PUFAs consumed at levels of 3.5% of energy intake do not significantly increase plasma or HMW adiponectin concentrations in overweight-to-moderately obese healthy men and women over the course of 14 wk.

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.