S Hornemann

Effects of supplemented isoenergetic diets differing in cereal fiber and protein content on insulin sensitivity in overweight humans

BACKGROUND Despite their beneficial effects on weight loss and blood lipids, high-protein (HP) diets have been shown to increase insulin resistance and diabetes risk, whereas high-cereal-fiber (HCF) diets have shown the opposite effects on these outcomes. OBJECTIVE We compared the effects of isoenergetic HP and HCF diets and a diet with moderate increases in both cereal fibers and dietary protein (Mix diet) on insulin sensitivity, as measured by using euglycemic-hyperinsulinemic clamps with infusion of [6,6-(2)H(2)]glucose. DESIGN We randomly assigned 111 overweight adults with features of the metabolic syndrome to 1 of 4 two-phased, 18-wk isoenergetic diets by group-matching. Per 3-d food protocols, the percentages of energy derived from protein and carbohydrates and the intake of cereal fiber per day, respectively, were as follows-after 6 wk: 17%, 52%, and 14 g (control); 17%, 52%, and 43 g (HCF); 28%, 43%, and 13 g (HP); 23%, 44%, and 26 g (Mix); after 18 wk: 17%, 51%, and 15 g (control); 17%, 51%, and 41 g (HCF); 26%, 45%, and 14 g (HP); and 22%, 46%, and 26 g (Mix). Eighty-four participants completed the study successfully and were included in the final analyses. Adherence was supported by the provision of tailored dietary supplements twice daily in all groups. RESULTS Insulin sensitivity expressed as an M value was 25% higher after 6 wk of the HCF diet than after 6 wk of the HP diet (subgroup analysis: 4.61 ± 0.38 compared with 3.71 ± 0.36 mg · kg(-1) · min(-1), P = 0.008; treatment × time interaction: P = 0.005). Effects were attenuated after 18 wk (treatment × time interaction: P = 0.054), which was likely explained by lower adherence to the HP diet. HP intake was associated with a tendency to increased protein expression in adipose tissue of the translation initiation factor serine-kinase-6-1, which is known to mediate amino acid-induced insulin resistance. Biomarkers of protein intake indicated interference of cereal fibers with dietary protein absorption. CONCLUSION Greater changes in insulin sensitivity after intake of an isoenergetic HCF than after intake of an HP diet might help to explain the diverse effects of these diets on diabetes risk. This trial is registered at clinicaltrials.gov as NCT00579657.

Inhibition of 11β-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND The prevalence of non-alcoholic fatty liver disease is increasing worldwide and an effective and safe pharmacological treatment is needed. We investigated whether inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, also known as HSD11B1) by RO5093151 could safely and effectively decrease liver-fat content in patients with this disorder. METHODS We did this phase 1b trial at four centres in Germany and Austria. Participants with non-alcoholic fatty liver disease (defined as (1)H magnetic resonance spectroscopy liver-fat content >5·56%), insulin resistance (homoeostatic model assessment of insulin resistance [HOMA-IR] of at least 2·0 mmol/L·mU/L), BMI greater than 27 kg/m(2), and aged 35-65 years were randomly assigned by interactive voice response system in a 1:1 ratio, stratified for triglyceride concentration (<1·7 mmol/L or ≥1·7 mmol/L), to oral RO5093151 (200 mg twice daily) or matching placebo for 12 weeks. The main exclusion criteria were other liver diseases, aspartate aminotransferase or alanine aminotransferase concentrations of more than two and a half times the upper limit of normal, history of diabetes or bariatric surgery, and use of weight lowering drugs. Participants and investigators were masked to assignment throughout the study. The primary endpoint was change in liver-fat content from baseline to week 12. Efficacy analysis was by modified intention to treat, including all patients who received at least one dose of study drug and had a baseline and follow-up measurement of liver-fat content. Safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01277094. FINDINGS We did this trial between Jan 13, 2011, and March 28, 2012. 41 patients were randomly assigned to RO5093151 and 41 to placebo. 35 patients in the RO5093151 group and 39 in the placebo group were included in the efficacy analysis. Mean liver-fat content decreased in the RO5093151 group (from 16·75% [SD 8·67] to 14·28% [8·89]), but not in the placebo group (from 18·53% [10·00] to 18·46% [10·78], p=0·02 for between group difference). 26 participants (65%) in the RO5093151 group had adverse events, compared with 21 (53%) in the placebo group. The most common adverse events were gastrointestinal disorders (12 patients [30%] in the RO5093151 group vs seven [18%] in the placebo group), and infections and infestations (eight [20%] vs nine [23%]). Nervous system disorders occurred in significantly more patients in the RO5093151 group than in the placebo group (nine [23%] vs two [5%]; p=0·02); all other differences in adverse events were non-significant. One participant (3%) in the placebo group and three participants (8%) in the RO5093151 group had serious adverse events. All serious adverse events were deemed unrelated to study treatment. INTERPRETATION Inhibition of 11β-HSD1 by RO5093151 was effective and safe in reducing liver-fat content, suggesting that targeting of 11β-HSD1 might be a promising approach for the treatment of non-alcoholic fatty liver disease. FUNDING F Hoffmann-La Roche.

WISP1 Is a Novel Adipokine Linked to Inflammation in Obesity

WISP1 (Wnt1-inducible signaling pathway protein-1, also known as CCN4) is a member of the secreted extracellular matrix–associated proteins of the CCN family and a target gene of the Wingless-type (WNT) signaling pathway. Growing evidence links the WNT signaling pathway to the regulation of adipogenesis and low-grade inflammation in obesity. We aimed to validate WISP1 as a novel adipokine. Human adipocyte differentiation was associated with increased WISP1 expression and secretion. Stimulation of human macrophages with WISP1 led to a proinflammatory response. Circulating WISP1 and WISP1 subcutaneous adipose tissue expression were regulated by weight changes in humans and mice. WISP1 expression in visceral and subcutaneous fat tissue was associated with markers of insulin resistance and inflammation in glucose-tolerant subjects. In patients with nonalcoholic fatty liver disease, we found no correlation among disease activity score, liver fat content, and WISP1 expression. Insulin regulated WISP1 expression in adipocytes in vitro but had no acute effect on WISP1 gene expression in subcutaneous fat tissue in overweight subjects who had undergone hyperinsulinemic clamp experiments. The data suggest that WISP1 may play a role in linking obesity to inflammation and insulin resistance and could be a novel therapeutic target for obesity.

Dietary rapeseed/canola-oil supplementation reduces serum lipids and liver enzymes and alters postprandial inflammatory responses in adipose tissue compared to olive-oil supplementation in obese men

SCOPE Obesity is associated with hyperlipidemia, hepatic steatosis, and low-grade inflammation. Studies have shown that MUFA as well as PUFA have beneficial effects on blood lipids and the inflammatory state. METHODS AND RESULTS This study investigates the effects of a daily supplementation of either 50 g of rapeseed/canola (RA) or olive (OL) oil over 4 wk on serum lipids, serum liver enzymes, and inflammatory gene expression in subcutaneous (s. c.) adipose tissue in obese men. Consuming RA resulted in increased serum n-3 fatty acids and a reduction in total cholesterol, LDL cholesterol, and serum aspartate aminotransferase compared to OL. In s. c. adipose tissue, gene expression of the pro-inflammatory cytokine IL6 was reduced in RA compared to OL. However, after 4 h after a test meal, containing the appropriate oil, white bread, and 400 mL of liquid diet drink (835 kcal in total), gene expression of IL6, IL1B, and EMR1 (egf-like module containing Mucin-like hormone receptor-like 1) was increased in RA and of monocyte chemoattractant protein-1 (CCL2) in both RA and OL. CONCLUSION This demonstrates that consuming RA for 4 wk improves serum lipids, liver enzymes, and basal inflammation in s. c. adipose tissue, but it mediates an acute pro-inflammatory response in adipose tissue upon consuming a meal.

Changes of Dietary Fat and Carbohydrate Content Alter Central and Peripheral Clock in Humans

CONTEXT The circadian clock coordinates numerous metabolic processes with light-dark and feeding regimens. However, in humans it is unknown whether dietary patterns influence circadian rhythms. OBJECTIVE We examined the effects of switching from a high-carbohydrate, low-fat diet to a low-carbohydrate, high fat (LC/HFD) isocaloric diet on the central and peripheral circadian clocks in humans. DESIGN Diurnal patterns of salivary cortisol and gene expression were analyzed in blood monocytes of 29 nonobese healthy subjects before and 1 and 6 weeks after the dietary switch. For this, we established a method of rhythm prediction by 3-time point data. RESULTS The centrally driven cortisol rhythm showed a phase delay 1 and 6 weeks after the dietary switch to a LC/HFD as well as an amplitude increase. The dietary switch altered diurnal oscillations of core clock genes (PER1, PER2, PER3, and TEF) and inflammatory genes (CD14, CD180, NFKBIA, and IL1B). The LC/HFD also affected the expression of nonoscillating genes contributing to energy metabolism (SIRT1) and fat metabolism (ACOX3 and IDH3A). Expression of clock genes but not of salivary cortisol in monocytes tightly correlated with levels of blood lipids and with expression of metabolic and inflammatory genes. CONCLUSIONS Our results suggest that the modulation of the dietary fat and carbohydrate content alters the function of the central and peripheral circadian clocks in humans.

Odd-chain fatty acids as a biomarker for dietary fiber intake: a novel pathway for endogenous production from propionate

Background: The risk of type 2 diabetes is inversely correlated with plasma concentrations of odd-chain fatty acids [OCFAs; pentadecanoic acid (15:0) and heptadecanoic acid (17:0)], which are considered as biomarkers for dairy fat intake in humans. However, rodent studies suggest that OCFAs are synthesized endogenously from gut-derived propionate. Propionate increases with dietary fiber consumption and has been shown to improve insulin sensitivity.Objective: We hypothesized that OCFAs are produced in humans from dietary fibers by a novel endogenous pathway.Design: In a randomized, double-blind crossover study, 16 healthy individuals were supplemented with cellulose (30 g/d), inulin (30 g/d), or propionate (6 g/d) for 7 d. In addition, human hepatoma cells were incubated with different propionate concentrations. OCFAs were determined in plasma phospholipids and hepatoma cells by gas chromatography.Results: Cellulose did not affect plasma OCFA levels, whereas inulin and propionate increased pentadecanoic acid by ∼17% (P < 0.05) and 13% (P = 0.05), respectively. The effect on heptadecanoic acid was even more pronounced, because it was elevated in almost all participants by inulin (11%; P < 0.01) and propionate (13%; P < 0.001). Furthermore, cell culture experiments showed a positive association between propionate and OCFA levels (R2 = 0.99, P < 0.0001), whereas palmitate (16:0) was negatively correlated (R2 = 0.83, P = 0.004).Conclusions: Our data show that gut-derived propionate is used for the hepatic synthesis of OCFAs in humans. The association of OCFAs with a decreased risk of type 2 diabetes may therefore also relate to dietary fiber intake and not only dairy fat. This trial was registered at www.germanctr.de as DRKS00010121.

Modulation of Amino Acid Metabolic Signatures by Supplemented Isoenergetic Diets Differing in Protein and Cereal Fiber Content

CONTEXT Amino-acid (AA) metabolic signatures differ in insulin-resistant (IR) obese vs normal-weight subjects, improve after weight loss, and seem to predict the risk of type 2 diabetes. It is unknown whether weight-maintaining dietary measures aimed at influencing IR alter AA signatures of high-risk subjects. SETTING AND DESIGN In the randomized controlled Protein, Fiber and Metabolic Syndrome (ProFiMet) trial we investigated effects of four isoenergetic, moderately fat-reduced diets varying in protein and cereal-fiber contents on complete AA metabolic signatures in 76 group-matched overweight or obese high-risk subjects. We analyzed the relation of whole-body and hepatic IR with AA signatures, body fat composition and liver fat, after 0, 6, and 18 weeks of dietary intervention. Discrimination between diets was further enhanced by providing tailored dietary supplements for twice-daily consumption over 18 weeks in all groups. RESULTS Baseline AA, including branched-chain signatures significantly related to IR, liver fat, and visceral fat mass. Isoenergetic variation of protein and cereal-fiber dietary contents, but not fat restriction, significantly influenced IR, whereas the relation of AA with IR changed with all diets. The tryptophan ratio was significantly suppressed in obese vs overweight participants, but increased after 6 weeks of high cereal-fiber intake to a nonobese phenotype. Modeling analyses revealed diet-induced alterations of complex AA profiles to relate to 70% and 62% of changes in whole-body and hepatic IR. CONCLUSIONS We demonstrate that relatively short-term isoenergetic changes in the diet significantly alter the relation of AA signatures with IR, with possible implications on the determination and treatment of diabetes risk.

Regulation of nutrition-associated receptors in blood monocytes of normal weight and obese humans.

Obesity, type 2 diabetes and associated metabolic diseases are characterized by low-grade systemic inflammation which involves interplay of nutrition and monocyte/macrophage functions. We suggested that some factors such as nutrient components, neuropeptides involved in the control of gastrointestinal functions, and gastrointestinal hormones might influence immune cell functions and in this way contribute to the disease pathogenesis. The aim of this study was to investigate the mRNA expression of twelve nutrition-associated receptors in peripheral blood mononuclear cells (PBMC), isolated monocytes and monocyte-derived macrophages and their regulation under the switching from the high-carbohydrate low-fat diet to the low-carbohydrate high-fat (LC/HFD) isocaloric diet in healthy humans. The mRNA expression of receptors for short chain fatty acids (GPR41, GPR43), bile acids (TGR5), incretins (GIPR, GLP1R), cholecystokinin (CCKAR), neuropeptides VIP and PACAP (VIPR1, VIPR2), and neurotensin (NTSR1) was detected in PBMC and monocytes, while GPR41, GPR43, GIPR, TGR5, and VIPR1 were found in macrophages. Correlations of the receptor expression in monocytes with a range of metabolic and inflammatory markers were found. In non-obese subjects, the dietary switch to LC/HFD induced the increase of GPR43 and VIPR1 expression in monocytes. No significant differences of receptor expression between normal weight and moderately obese subjects were found. Our study characterized for the first time the expression pattern of nutrition-associated receptors in human blood monocytes and its dietary-induced changes linking metabolic responses to nutrition with immune functions in health and metabolic diseases.

Comparison of the effects of diets high in animal or plant protein on metabolic and cardiovascular markers in type 2 diabetes: A randomized clinical trial

To compare high animal protein (AP) with high plant protein (PP) diets, differing in amino acid composition, in people with type 2 diabetes (T2DM).

High‐Saturated‐Fat Diet Increases Circulating Angiotensin‐Converting Enzyme, Which Is Enhanced by the rs4343 Polymorphism Defining Persons at Risk of Nutrient‐Dependent Increases of Blood Pressure

Background Angiotensin‐converting enzyme (ACE) plays a major role in blood pressure regulation and cardiovascular homeostasis. Contrary to the assumption that ACE levels are stable, circulating ACE has been shown to be altered in obesity and weight loss. We sought to examine effects of a high‐saturated‐fat (HF) diet on ACE within the NUtriGenomic Analysis in Twins (NUGAT) study. Methods and Results Forty‐six healthy and nonobese twin pairs initially consumed a carbohydrate‐rich, low‐fat diet over a period of 6 weeks to standardize for nutritional behavior prior to the study, followed by 6 weeks of HF diet under isocaloric conditions. After 6 weeks of HF diet, circulating ACE concentrations increased by 15% (P=1.6×10−30), accompanied by an increased ACE gene expression in adipose tissue (P=3.8×10−6). Stratification by ACE rs4343, a proxy for the ACE insertion/deletion polymorphism (I/D), revealed that homozygous carriers (GG) of the variant had higher baseline ACE concentrations (P=7.5×10−8) and additionally showed a 2‐fold increase in ACE concentrations in response to the HF diet as compared to non‐ or heterozygous carriers (AA/AG, P=2×10−6). GG carriers also responded with higher systolic blood pressure as compared to AA/AG carriers (P=0.008). The strong gene‐diet interaction was confirmed in a second independent, cross‐sectional cohort, the Metabolic Syndrome Berlin Potsdam (MeSyBePo) study. Conclusions The HF‐diet‐induced increase of ACE serum concentrations reveals ACE to be a potential molecular link between dietary fat intake and hypertension and cardiovascular disease (CVD). The GG genotype of the ACE rs4343 polymorphism represents a robust nutrigenetic marker for an unfavorable response to high‐saturated‐fat diets. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01631123.