Blackberry Feeding Increases Fat Oxidation and Improves Insulin Sensitivity in Overweight and Obese Males.

Berries and other anthocyanin-rich treatments have prevented weight gain and adiposity in rodent models of diet-induced obesity. Their efficacy may be explained by modulation of energy substrate utilization. However, this effect has never been translated to humans. The objective of this study was to evaluate the effects of berry intake on energy substrate use and glucoregulation in volunteers consuming a high-fat diet. Twenty-seven overweight or obese men were enrolled in a randomized, placebo-controlled crossover study with two treatment periods. Subjects were fed an investigator controlled, high-fat (40% of energy from fat) diet which contained either 600 g/day blackberries (BB, 1500 mg/day flavonoids) or a calorie and carbohydrate matched amount of gelatin (GEL, flavonoid-free control) for seven days prior to a meal-based glucose tolerance test (MTT) in combination with a 24 h stay in a room-sized indirect calorimeter. The washout period that separated the treatment periods was also seven days. The BB treatment resulted in a significant reduction in average 24 h respiratory quotient (RQ) (0.810 vs. 0.817, BB vs. GEL, p = 0.040), indicating increased fat oxidation. RQ during the MTT was significantly lower with the BB treatment (0.84) compared to GEL control (0.85), p = 0.004. A 4 h time isolation during dinner showed similar treatment effects, where RQ was reduced and fat oxidation increased with BB (0.818 vs. 0.836, 28 vs. 25 g, respectively; BB vs. GEL treatments). The glucose AUC was not different between the BB and GEL treatments during the MTT (3488 vs. 4070 mg·min/dL, respectively, p = 0.12). However, the insulin AUC was significantly lower with the BB compared to the GEL control (6485 vs. 8245 µU·min/mL, p = 0.0002), and HOMA-IR improved with BB (p = 0.0318). Blackberry consumption may promote increased fat oxidation and improved insulin sensitivity in overweight or obese males fed a high fat diet.

Effects of sugar solutions on hypothalamic appetite regulation.

Several hypotheses for the causes of the obesity epidemic in the US have been proposed. One such hypothesis is that dietary intake patterns have significantly shifted to include unprecedented amounts of refined sugar. We set out to determine if different sugars might promote changes in the hypothalamic mechanisms controlling food intake by measuring several hypothalamic peptides subsequent to overnight access to dilute glucose, sucrose, high fructose corn syrup, or fructose solutions. Rats were given access to food, water and a sugar solution for 24h, after which blood and tissues were collected. Fructose access (as opposed to other sugars that were tested) resulted in a doubling of circulating triglycerides. Glucose consumption resulted in upregulation of 7 satiety-related hypothalamic peptides whereas changes in gene expression were mixed for remaining sugars. Also, following multiple verification assays, 6 satiety related peptides were verified as being affected by sugar intake. These data provide evidence that not all sugars are equally effective in affecting the control of intake.

High fructose diets increase 11ß-hydroxysteroid dehydrogenase type 1 in liver and visceral adipose in rats within 24-h exposure.

The increased prevalence of overweight and obesity in the United States during the past three decades coincides with a trend of increased sugar intake, especially fructose, leading to speculation that the two trends may be linked. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), that regulates intracellular tissue-specific glucocorticoid levels, is increased in adipose and suppressed in liver of obese humans and animals. Hexose-6-phosphate dehydrogenase (H6PDH) is colocalized with 11ß-HSD1 and generates nicotinamide adenosine dinucleotide phosphate, the required cofactor for 11ß-HSD1 reductase activity that converts inert glucocorticoid metabolite into active hormone. We examined the acute effects of ad lib access to 16% solutions of sucrose, fructose, or glucose and chow and water. Diets high in fructose, but not glucose or sucrose increased 11ß-HSD1 mRNA within 24 h in liver and adipose by greater than two- and threefold, respectively (P ≤ 0.05). After 1 week, hepatic 11ß-HSD1 mRNA and protein were suppressed by >60% in all sugar-fed groups, a phenomenon not previously reported in the absence of obesity. Sucrose- and fructose-fed rats had higher plasma triglycerides than did control or glucose-fed rats at both 24 h and 1 week (P ≤ 0.02), consistent with previously reported effects of fructose on lipid metabolism. We conclude that high-sugar diets initiate glucocorticoid dysregulation associated with obesity prior to the onset of phenotypic changes, and that high fructose diets specifically induce changes in 11ß-HSD1 within 24-h exposure.

Diet and the role of 11beta-hydroxysteroid dehydrogenase-1 on obesity.

11beta-Hydroxysteroid dehydrogenase-1 (11beta-HSD-1) is a key regulatory enzyme in glucocorticoid metabolism, specifically in regulating intracellular concentrations of cortisol, the primary glucocorticoid. While the excessive level of circulating cortisol in Cushing's disease is of adrenal origin, it is the intracellular and not the systemic level of cortisol that is elevated in obesity. This tissue-specific dysregulation of glucocorticoids observed in obesity results from alterations in 11beta-HSD-1 in both liver and mesenteric adipose. While cortisol has been identified as playing a permissive role in obesity, little is known about how diet may regulate message, expression and activity of 11beta-HSD-1. In this review, we have integrated three lines of evidence that, taken together, suggest that dietary composition can play a primary role in promoting increased intracellular cortisol and in that way form the basis of a mechanism that results in excessive adiposity. We review evidence from studies of adrenalectomized rats, as well as studies linking 11beta-HSD-1 to the pentose phosphate pathway and other metabolic pathways via the enzyme hexose-6-phosphate dehydrogenase. Emerging evidence from dietary manipulation experiments suggesting that macronutrient composition may elicit changes in 11beta-HSD-1 and promote obesity is discussed.

Sucrose access differentially modifies 11beta-hydroxysteroid dehydrogenase-1 and hexose-6-phosphate dehydrogenase message in liver and adipose tissue in rats.

11Beta-hydroxysteroid dehydrogenase-1 (11beta-HSD-1) plays a key role in the regulation of intracellular glucocorticoid concentrations. Increased message and/or activity of adipose 11beta-HSD-1 are characteristics of human and animal models of obesity. Hexose-6-phosphate dehydrogenase (H6PDH) is colocalized with 11beta-HSD-1 and may be a critical factor in determining the oxo-reductase activity of 11beta-HSD-1. This study examined the effects of sucrose solution access on body weight, body composition, and message of 11beta-HSD-1 and H6PDH in mesenteric adipose and liver. Rats were assigned to 3 groups: 1) control (ad libitum intake of nonpurified diet and water only); 2) ad libitum intake of 16% sucrose solution (S16); or 3) ad libitum intake of 32% sucrose solution (S32) in addition to ad libitum intake of diet and water. The S32 group consumed more energy daily than the S16 and control groups, yet body weight did not differ among groups. Percentages of body fat did not differ between the S16 and S32 groups but were higher than in controls. Hepatic 11beta-HSD-1 message was suppressed by 46% in the S16 group and by 47% in the S32 group, whereas the H6PDH message nearly doubled in the S16 group compared to the control group. In mesenteric fat, 11beta-HSD-1 message increased 23-fold in the S16 group and 32-fold in the S32 group and the H6PDH message increased 3.5-fold in the S16 group compared to the control group. These data demonstrate that sucrose can promote increased 11beta-HSD-1 and H6PDH message in mesenteric fat while concomitantly decreasing 11beta-HSD-1 message and increasing H6PDH message in liver. These observations support the hypothesis that sucrose access causes obesity via its ability to increase adipose 11beta-HSD-1.

Relationship between serum leptin levels and alcohol consumption in a controlled feeding and alcohol ingestion study.

We examined serum leptin levels in a controlled feeding and alcohol ingestion study to elucidate potential mechanisms by which alcohol may affect cancer and immunologically related health risks. A total of 53 healthy, nonsmoking postmenopausal women completed a random-order, three-period crossover design study in which each woman received zero (0 g of alcohol), one (15 g of alcohol), or two (30 g alcohol) drinks per day. After accounting for differences in body mass index, women who consumed 15 or 30 g of alcohol per day had 7.3% (95% confidence interval [CI] = 3.0% to 15.1%) and 8.9% (95% CI = 1.6% to 16.7%) higher serum leptin levels, respectively (P(trend) =.018), than women who consumed 0 g of alcohol per day. Younger women (i.e., 49-54 years) demonstrated a statistically significantly larger association of alcohol consumption level with the increase in serum leptin levels than older women (i.e., 55-79 years) (24.4%, 95% CI = 9.3% to 42.0% versus 3.7%, 95% CI = -4.1% to 12.1% increase in serum leptin levels for 30 g of alcohol per day relative to 0 g of alcohol per day for the lowest age quartile compared with the three highest age quartiles combined; P =.022). These results indicate that moderate alcohol consumption (15-30 g of alcohol per day) increases serum leptin levels in postmenopausal women and may predispose moderate drinkers to the morbidities associated with chronic elevations of this hormone including cancer.

Ingestional responses to metabolic challenges in rats selectively bred for high and low saccharin intake.

Rats selectively bred on the basis of saccharin intake also differ on some measures of emotional reactivity. The present studies were designed to contribute to our understanding of this association. Rats selectively bred for relatively high (HiS) versus low (LoS) saccharin intake were tested in two paradigms useful in assessing the ability to respond adaptively to internal perturbations of metabolic regulation or to external events that may produce metabolic challenges. The first study concerned slow-onset (regular insulin) and rapid-onset (2-deoxy-D-glucose [2-DG], fast-acting insulin) glucoprivation and resultant feeding behavior. LoS and HiS lines did not differ in response to saline or slow-onset challenges, but LoS rats ate less in the first half hour after rapid-onset challenges; the line differences were eliminated by pretreatment with caffeine. The second study revealed significantly higher plasma corticosterone (CORT) among LoS rats relative to HiS rats, both in the light and in the dark. Preliminary assessments after a single stressor and a single dose of dexamethasone showed, respectively, CORT elevation and suppression that was comparable in the two lines. These results add further support to the ideas that voluntary consumption of saccharin is related to the expression of classically defined emotional behaviors, and that responsiveness to diverse metabolic challenges may share a common basis, such as genetic pleiotropism.