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.

Obesity and type-2 diabetes trends continue to worsen in the United States. Dietary anthocyanins (typically provided by berries and other fruits) are reported to have protective effects against both conditions using a variety of experimental research models including animal and human feeding studies. This review highlights studies that explore the biochemical pathways in both tissue and rodent models which could explain clinical improvements noted with anthocyanin consumption. First, the primary mode of intestinal absorption of anthocyanins is through both sGLT1 and GLUT2 glucose transporters. Stronger binding affinities may allow anthocyanins to be more inhibitive to glucose absorption compared to the reverse, where GLUT2 expression may also be affected. Genetic or chemical inhibition of sGLT1 or GLUT2 demonstrate their essential function in anthocyanin absorption across the enterocyte, where the former interacts with a greater variety of anthocyanins but the latter is the major transporter for specific anthocyanin-glycosides. Once absorbed, anthocyanins positively modulate GLUT4 density and function in both skeletal muscle and adipose tissues via the upregulation of AMPK and restoration of insulin sensitivity. Antioxidant properties and phosphodiesterase inhibition by anthocyanins promote both mitochondrial function and density which could be novel targets for dietary management of obesity and its complications.

Phenylketonuria (PKU), caused by phenylalanine (phe) hydroxylase loss of function mutations, requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP), a low-phe whey protein, provides a palatable alternative to AA formula. Skeletal fragility is a poorly understood chronic complication of PKU. We sought to characterize the impact of the PKU genotype and dietary protein source on bone biomechanics. Wild type (WT; Pah^+/+) and PKU (Pah^enu2/enu2) mice on a C57BL/6J background were fed high-phe casein, low-phe AA, and low-phe GMP diets between 3 to 23 weeks of age. Following euthanasia, femur biomechanics were assessed by 3-point bending and femoral diaphyseal structure was determined. Femoral ex vivo bone mineral density (BMD) was assessed by dual-enengy x-ray absorptiometry. Whole bone parameters were used in prinicipal component analysis. Data were analyzed by 3-way ANCOVA with genotype, sex, and diet as the main factors. Regardless of diet and sex, PKU femora were more brittle, as manifested by lower post-yield displacement, weaker, as manifested by lower energy and yield and maximal loads, and showed reduced BMD compared with WT femora. Four principal components accounted for 87% of the variance and all differed significantly by genotype. Regardless of genotype and sex, the AA diet reduced femoral cross-sectional area and consequent maximal load compared with the GMP diet. Skeletal fragility, as reflected in brittle and weak femora, is an inherent feature of PKU. This PKU bone phenotype is attenuated by a GMP diet compared with an AA diet.

Phenylketonuria (PKU) is caused by a mutation in the phenylalanine (phe) hydroxylase gene and requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP) contains minimal phe and provides a palatable alternative to AA formula. Our objective was to compare growth, body composition, and energy balance in Pah^enu2 (PKU) and wild-type mice fed low-phe GMP, low-phe AA, or high-phe casein diets from 3–23 wk of age. The 2 × 2 × 3 design included main effects of genotype, sex, and diet. Fat and lean mass were assessed by dual-energy X-ray absorptiometry, and acute energy balance was assessed by indirect calorimetry. PKU mice showed growth and lean mass similar to wild-type littermates fed the GMP or AA diets; however, they exhibited a 3–15% increase in energy expenditure, as reflected in oxygen consumption, and a 3–30% increase in food intake. The GMP diet significantly reduced energy expenditure, food intake, and plasma phe concentration in PKU mice compared with the casein diet. The high-phe casein diet or the low-phe AA diet induced metabolic stress in PKU mice, as reflected in increased energy expenditure and intake of food and water, increased renal and spleen mass, and elevated plasma cytokine concentrations consistent with systemic inflammation. The low-phe GMP diet significantly attenuated these adverse effects. Moreover, total fat mass, %body fat, and the respiratory exchange ratio (CO₂ produced/O₂ consumed) were significantly lower in PKU mice fed GMP compared with AA diets. In summary, GMP provides a physiological source of low-phe dietary protein that promotes growth and attenuates the metabolic stress induced by a high-phe casein or low-phe AA diet in PKU mice.

Evidence supports the beneficial effects of berries on glucoregulation, possibly related to flavonoid content, fiber content, or both. The purpose of this study was to assess the potential of mixed berries to improve insulin sensitivity and to identify the potential role of flavonoids and fiber. In a randomized cross-over trial with four treatment periods, overweight/obese men and women were fed a controlled 45% fat diet for one week prior to a meal-based glucose tolerance test. The same base diet was provided during each feeding period with the addition of one of four treatments: whole mixed berries, sugar matched mixed berry juice, sugar matched gelatin, and sugar/fiber matched gelatin. Subjects then completed a meal-based oral glucose tolerance test. Serum glucose, insulin and non-esterified fatty acids were not different between individual treatments. However, in a secondary analysis, the combined berry preparations resulted in a lower serum insulin area under the curve (difference of 0.15 ± 0.066 ln pmol min/mL, mean ± SE, p = 0.0228), compared to the combined gelatin treatments, while the difference for serum glucose did not quite meet statistical significance (difference of 0.17 ± 0.093 ln mg·min/dL, mean ± SE, p = 0.0738). These results suggest the potential for mixed berry preparations to improve post-prandial insulin response.

Obesity is a costly and ongoing health complication in the United States and globally. Bioactive-rich foods, especially those providing polyphenols, represent an emerging and attractive strategy to address this issue. Berry-derived anthocyanins and their metabolites are of particular interest for their bioactive effects, including weight maintenance and protection from metabolic aberrations. Earlier findings from small clinical trials suggest modulation of substrate oxidation and glucose tolerance with mediation of prospective benefits attributable to the gut microbiota, but mixed results suggest appropriate anthocyanin dosing poses a challenge. The objective of this randomized, placebo-controlled study was to determine if anthocyanin-dense elderberry juice (EBJ) reproduces glucoregulatory and substrate oxidation effects observed with other berries and if this is mediated by the gut microbiota. Overweight or obese adults (BMI > 25 kg/m²) without chronic illnesses were randomized to a 5-week crossover study protocol with two 1-week periods of twice-daily EBJ or placebo (PL) separated by a washout period. Each treatment period included 4 days of controlled feeding with a 40% fat diet to allow for comparison of measurements in fecal microbiota, meal tolerance testing (MTT), and indirect calorimetry between test beverages. Eighteen study volunteers completed the study. At the phylum level, EBJ significantly increased Firmicutes and Actinobacteria, and decreased Bacteroidetes. At the genus level, EBJ increased Faecalibacterium, Ruminococcaceae, and Bifidobacterium and decreased Bacteroides and lactic acid-producing bacteria, indicating a positive response to EBJ. Supporting the changes to the microbiota, the EBJ treatment significantly reduced blood glucose following the MTT. Fat oxidation also increased significantly both during the MTT and 30 min of moderate physical activity with the EBJ treatment. Our findings confirm the bioactivity of EBJ-sourced anthocyanins on outcomes related to gut health and obesity. Follow-up investigation is needed to confirm our findings and to test for longer durations.