Verena Haas

Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects

Obesity‐related hepatic steatosis is a major risk factor for metabolic and cardiovascular disease. Fat reduced hypocaloric diets are able to relieve the liver from ectopically stored lipids. We hypothesized that the widely used low carbohydrate hypocaloric diets are similarly effective in this regard. A total of 170 overweight and obese, otherwise healthy subjects were randomized to either reduced carbohydrate (n = 84) or reduced fat (n = 86), total energy restricted diet (−30% of energy intake before diet) for 6 months. Body composition was estimated by bioimpedance analyses and abdominal fat distribution by magnetic resonance tomography. Subjects were also submitted to fat spectroscopy of liver and oral glucose tolerance testing. In all, 102 subjects completed the diet intervention with measurements of intrahepatic lipid content. Both hypocaloric diets decreased body weight, total body fat, visceral fat, and intrahepatic lipid content. Subjects with high baseline intrahepatic lipids (>5.56%) lost ≈7‐fold more intrahepatic lipids compared with those with low baseline values (<5.56%) irrespective of diet composition. In contrast, changes in visceral fat mass and insulin sensitivity were similar between subgroups, with low and high baseline intrahepatic lipids. Conclusion: A prolonged hypocaloric diet low in carbohydrates and high in fat has the same beneficial effects on intrahepatic lipid accumulation as the traditional low‐fat hypocaloric diet. The decrease in intrahepatic lipids appears to be independent of visceral fat loss and is not tightly coupled with changes in whole body insulin sensitivity during 6 months of an energy restricted diet. (HEPATOLOGY 2011)

Cardiorespiratory fitness and insulin sensitivity in overweight or obese subjects may be linked through intrahepatic lipid content

OBJECTIVE Low cardiorespiratory fitness (CRF) predisposes one to cardiovascular disease and type 2 diabetes in part independently of body weight. Given the close relationship between intrahepatic lipid content (IHL) and insulin sensitivity, we hypothesized that the direct relationship between fitness and insulin sensitivity may be explained by IHL. RESEARCH DESIGN AND METHODS We included 138 overweight to obese, otherwise healthy subjects (aged 43.6 ± 8.9 years, BMI 33.8 ± 4 kg/m2). Body composition was estimated by bioimpedance analyses. Abdominal fat distribution, intramyocellular, and IHL were assessed by magnetic resonance spectroscopy and tomography. Incremental exercise testing was performed to estimate an individuals CRF. Insulin sensitivity was determined during an oral glucose tolerance test. RESULTS For all subjects, CRF was related to insulin sensitivity (r = 0.32, P < 0.05), IHL (r = −0.27, P < 0.05), and visceral (r = −0.25, P < 0.05) and total fat mass (r = −0.32, P < 0.05), but not to intramyocellular lipids (r = −0.08, NS). Insulin sensitivity correlated significantly with all fat depots. In multivariate regression analyses, independent predictors of insulin sensitivity were IHL, visceral fat, and fitness (r2 = −0.43, P < 0.01, r2 = −0.34, and r2 = 0.29, P < 0.05, respectively). However, the positive correlation between fitness and insulin sensitivity was abolished after adjustment for IHL (r = 0.16, NS), whereas it remained significant when adjusted for visceral or total body fat. Further, when subjects were grouped into high versus low IHL, insulin sensitivity was higher in those subjects with low IHL, irrespective of fitness levels. CONCLUSIONS Our study suggests that the positive effect of increased CRF on insulin sensitivity in overweight to obese subjects may be mediated indirectly through IHL reduction.

Is Metabolic Flexibility Altered in Multiple Sclerosis Patients

Objectives Metabolic flexibility is defined as ability to adjust fuel oxidation to fuel availability. Multiple sclerosis (MS) results in reduced muscle strength and exercise intolerance. We tested the hypothesis that altered metabolic flexibility contributes to exercise intolerance in MS patients. Methods We studied 16 patients (all on glatiramer) and 16 matched healthy controls. Energy expenditure (EE), and carbohydrate (COX) and lipid oxidation (LOX) rates were determined by calorimetry, before and after an oral glucose load. We made measurements either at rest (canopy device) or during 40 min low-grade (0.5 W/kg) exercise (metabolic chamber). We also obtained plasma, and adipose tissue and skeletal muscle dialysate samples by microdialysis to study tissue-level metabolism under resting conditions. Results At rest, fasting and postprandial plasma glucose, insulin, and free fatty acid levels did not differ between patients and controls. Fasting and postprandial COX was higher and LOX lower in patients. In adipose, fasting and postprandial dialysate glucose, lactate, and glycerol levels were higher in patients vs. controls. In muscle, fasting and postprandial dialysate metabolite levels did not differ significantly between the groups. During exercise, EE did not differ between the groups. However, COX increased sharply over 20 min in patients, without reaching a steady state, followed by an immediate decrease within the next 20 min and fell even below basal levels after exercise in patients, compared to controls. Conclusions Glucose tolerance is not impaired in MS patients. At rest, there is no indication for metabolic inflexibility or mitochondrial dysfunction in skeletal muscle. The increased adipose tissue lipolytic activity might result from glatiramer treatment. Autonomic dysfunction might cause dysregulation of postprandial thermogenesis at rest and lipid mobilization during exercise.

Left Ventricular Mass and Function With Reduced-Fat or Reduced-Carbohydrate Hypocaloric Diets in Overweight and Obese Subjects

In animals, carbohydrate and fat composition during dietary interventions influenced cardiac metabolism, structure, and function. Because reduced-carbohydrate and reduced-fat hypocaloric diets are commonly used in the treatment of obesity, we investigated whether these interventions differentially affect left ventricular mass, cardiac function, and blood pressure. We randomized 170 overweight and obese subjects (body mass index, 32.9±4.4; range, 26.5–45.4 kg/m2) to 6-month hypocaloric diets with either reduced carbohydrate intake or reduced fat intake. We obtained cardiac MRI and ambulatory blood pressure recordings over 24 hours before and after 6 months. Ninety subjects completing the intervention period had a full cardiac MRI data set. Subjects lost 7.3±4.0 kg (7.9±3.8%) with reduced-carbohydrate diet and 6.2±4.2 kg (6.7±4.4%) with reduced-fat diet (P<0.001 within each group; P=not significant between interventions). Caloric restriction led to similar significant decreases in left ventricular mass with low-carbohydrate diets (5.4±5.4 g) or low-fat diets (5.2±4.8 g; P<0.001 within each group; P=not significant between interventions). Systolic and diastolic left ventricular function did not change with either diet. The 24-hour systolic blood pressure decreased similarly with both interventions. Body weight change (&bgr;=0.33; P=0.02) and percentage of ingested n-3 polyunsaturated fatty acids (&bgr;=−0.27; P=0.03) predicted changes in left ventricular mass. In conclusion, weight loss induced by reduced-fat diets or reduced-carbohydrate diets similarly improved left ventricular mass in overweight and obese subjects over a 6-month period. However, n-3 polyunsaturated fatty acid ingestion may have an independent beneficial effect on left ventricular mass.

The JAK2 variant rs10758669 in Crohn’s disease: altering the intestinal barrier as one mechanism of action

PurposeThe aetiology of intestinal barrier dysfunction in Crohn’s disease (CD) is poorly understood. Associations in relatives of CD families suggest a genetic basis, but the relevant variants are still unknown. We hypothesized that variants in genes occurring in pathways such as autophagy and IL23 signalling might contribute to CD by altering intestinal permeability.MethodsWe analysed five variants (rs10758669 within JAK2, rs744166 within STAT3, rs4958847, rs11747270 and rs13361189 within IRGM) in adult German inflammatory bowel disease patients (CD, n = 464; ulcerative colitis (UC), n = 292) and matched healthy controls (n = 508). These data were correlated with gastrointestinal permeability as assessed by lactulose/mannitol ratio in CD patients (n = 141) in remission.ResultsOur data confirm the association between JAK2 rs10758669 (p = 0.026, OR = 1.25, 95% CI = 1.04–1.50) and STAT3 rs744166 (p = 0.04, OR = 0.83, 95% CI = 0.688–0.998) with CD, but not UC. With respect to all the analysed IRGM variants, no association was found to either CD or UC. Among CD patients, an increased intestinal permeability was detected in 65 out of 141 patients (46.1%). Most importantly, patients carrying the C risk allele within JAK2 rs10758669 displayed an increased permeability more often compared with patients without the C allele (p = 0.004). No association with intestinal permeability was found for STAT3 rs744166 and all IRGM variants.ConclusionsJAK2 rs10758669 and STAT3 rs744166 increase susceptibility for CD. We show that the A>C substitution in rs10758669 of the JAK2 gene is associated with increased intestinal permeability. Altering intestinal barrier function might thus be one mechanism how JAK2 contributes to CD pathogenesis.

Influence of dietary fat intake on the endocannabinoid system in lean and obese subjects

Endocannabinoid system (ECS) activation promotes obesity‐associated metabolic disease. Increased dietary fat intake increases blood endocannabinoids and alters adipose and skeletal muscle ECS gene expression in human.

Body composition changes in female adolescents with anorexia nervosa

BACKGROUND Body weight provides limited information about nutritional status of patients with anorexia nervosa (AN). OBJECTIVES Our objectives were to determine body composition (BC) changes, to find clinical predictors and endocrine correlates of total body protein (TBPr) depletion, and to compare results on fat mass (FM) obtained with anthropometry (skinfold measurements) and dual-energy X-ray absorptiometry (DXA) in patients with AN. DESIGN Body weight, body mass index (BMI; in kg/m(2)), BC (with DXA and skinfold measurements), and TBPr [with in vivo neutron activation analysis (IVNAA)] was assessed in 50 AN patients (15.2 y) and 40 healthy sex- and age-matched controls. In 47 AN patients and 22 controls, hormone concentrations were measured. RESULTS In AN patients, body weight (44.4 +/- 5.5 kg), BMI (16.7 +/- 1.6), and FM(DXA) (7.0 +/- 3.4 kg) were lower than in controls. Lean tissue mass by DXA (LTM(DXA)) was similar in AN patients and controls (35.7 +/- 4.3 compared with 35.8 +/- 4.5 kg), but TBPr was 87% of that of controls (8.1 +/- 1.0 compared with 9.2 +/- 1.2 kg; P < 0.001). Cortisol was high, testosterone was unchanged, and estradiol and insulin-like growth factor I were low. Severe protein depletion measured by IVNAA seen in 17 AN patients could not be identified with simpler methods. All except 1 of 26 AN patients with a BMI > 16.5 had normal TBPr. The difference in individual percentage of body fat measured with DXA and skinfold measurements came up to 9%. CONCLUSION The severe protein depletion in 34% of AN patients was not accurately identified by LTM(DXA) or simpler methods, but a BMI > 16.5 indicated normal TBPr. Future studies need to compare DXA and skinfold measurements with a reference technique to assess FM in AN patients.

Increased small intestinal permeability in ulcerative colitis: Rather genetic than environmental and a risk factor for extensive disease?

Background: A disturbed epithelial barrier could play a pivotal role in ulcerative colitis (UC). We performed a family‐based study analyzing in vivo gastrointestinal permeability in patients with UC, their healthy relatives, spouses, and controls. Methods: In total, 89 patients with UC in remission, 35 first‐degree relatives (UC‐R), 24 nonrelated spouses (UC‐NR), and 99 healthy controls (HC) were studied. Permeability was assessed by a sugar‐drink test using sucrose (gastroduodenal permeability), lactulose/mannitol (intestinal permeability), and sucralose (colonic permeability). Data were correlated with clinical characteristics including medical treatment. Results: Increased intestinal permeability was detected significantly more often in UC patients in remission (25/89, 28.1%) compared with HC (6/99, 6.1%; P < 0.001). Similar results were obtained in UC‐R (7/35, 20.0%; P = 0.01 compared with HC) regardless of sharing the same household with the patients or not. No difference was found between UC‐NR (3/24, 12.5%) and HC. Notably, in UC patients increased intestinal permeability was found in 12/28 patients (42.9%) with pancolitis, 7/30 (23.3%) patients with left‐sided colitis, and in 2/19 (10.5%) patients with proctitis (P = 0.04). Gastroduodenal and colonic permeability were similar in all groups. Among patients on azathioprine, increased intestinal permeability was only seen in 1/18 (5.6%) patients. In contrast, in 24/70 (34.3%) patients without azathioprine, an increased intestinal permeability was found (P = 0.005). Conclusions: An increased intestinal but not colonic permeability was found in UC patients in clinical remission that could mark a new risk factor for extensive disease location. Similar findings in healthy relatives but not spouses suggest that this barrier defect is genetically determined. (Inflamm Bowel Dis 2012)

Long-Lasting Improvements in Liver Fat and Metabolism Despite Body Weight Regain After Dietary Weight Loss

OBJECTIVE Weight loss reduces abdominal and intrahepatic fat, thereby improving metabolic and cardiovascular risk. Yet, many patients regain weight after successful diet-induced weight loss. Long-term changes in abdominal and liver fat, along with liver test results and insulin resistance, are not known. RESEARCH DESIGN AND METHODS We analyzed 50 overweight to obese subjects (46 ± 9 years of age; BMI, 32.5 ± 3.3 kg/m2; women, 77%) who had participated in a 6-month hypocaloric diet and were randomized to either reduced carbohydrates or reduced fat content. Before, directly after diet, and at an average of 24 (range, 17–36) months follow-up, we assessed body fat distribution by magnetic resonance imaging and markers of liver function and insulin resistance. RESULTS Body weight decreased with diet but had increased again at follow-up. Subjects also partially regained abdominal subcutaneous and visceral adipose tissue. In contrast, intrahepatic fat decreased with diet and remained reduced at follow-up (7.8 ± 9.8% [baseline], 4.5 ± 5.9% [6 months], and 4.7 ± 5.9% [follow-up]). Similar patterns were observed for markers of liver function, whole-body insulin sensitivity, and hepatic insulin resistance. Changes in intrahepatic fat und intrahepatic function were independent of macronutrient composition during intervention and were most effective in subjects with nonalcoholic fatty liver disease at baseline. CONCLUSIONS A 6-month hypocaloric diet induced improvements in hepatic fat, liver test results, and insulin resistance despite regaining of weight up to 2 years after the active intervention. Body weight and adiposity measurements may underestimate beneficial long-term effects of dietary interventions.

Moderate dietary weight loss reduces myocardial steatosis in obese and overweight women

BACKGROUND Excessive myocardial triglyceride (MTG) content in obesity and type 2 diabetes is associated with impaired cardiac function. Previous studies suggest that MTG could be mobilized through lifestyle interventions. We assessed influences of moderate dietary weight loss in non diabetic obese and overweight women on MTG content and cardiac function. METHODS We selected a subgroup of 38 women from the B-SMART study population. The B-SMART study compared weight loss and associated metabolic and cardiovascular markers with reduced-carbohydrate and reduced-fat hypocaloric diets. Selected subjects had completed a cardiac magnetic resonance (MR) scan including imaging and proton spectroscopy to assess cardiac structure and function as well as MTG content. RESULTS An average weight reduction of 5.4 ± 4.3 kg at six months was associated with a relative decrease of MTG of 25% (from 0.72 ± 0.29% at baseline to 0.54 ± 0.23% at follow-up, p<0.001). The response was similar with carbohydrate and fat restriction. Diastolic function expressed as ratio of peak filling rate in E- and A-Phase (PFRE/PFRA) was unchanged. Reductions of left atrial size (from 21.9 ± 4.0 cm(2) to 20.0 ± 3.7 cm(2), p=0.002), the normalized ratio of PFRE and early diastolic lengthening velocity PLV (from 8.2 ± 2.6 to 7.5 ± 2.5, p<0.001) and fat free mass (from 55.1 ± 6.9 kg to 52.7 ± 6.5 kg, p=0.007) reflected altered cardiac volume loading after diet, but did not correlate to MTG content. CONCLUSIONS Moderate dietary weight loss significantly reduced MTG content in women with uncomplicated overweight or obesity. Macronutrient composition of the diet did not significantly affect the extent of MTG reduction.