Sven Haufe

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)

Influences of normobaric hypoxia training on metabolic risk markers in human subjects.

PURPOSE Endurance exercise and hypoxia regulate pathways that are crucial to glucose and lipid metabolism. We hypothesized that training under hypoxia results in similar or even greater metabolic improvement compared with exercise under normoxia at a lower workload. METHODS We randomly assigned 20 healthy men to single blind training under hypoxia (FiO2 = 15%) or normoxia (FiO2 = 21%). Subjects trained thrice weekly for 60 min over a 4-wk period at a heart rate measured at 3 mmol x L(-1) lactate during pretraining exercise testing. Before and after the training period, we determined body composition, venous blood parameters, oral glucose tolerance, and blood pressure. Furthermore, we assessed oxygen uptake (VO2), lactate, and respiratory quotient, and heart rate (HR) during incremental exercise testing, both in hypoxia and in normoxia. Training workload was 1.39 +/- 0.2 W x kg(-1) in the hypoxia and 1.67 +/- 0.15 W x kg(-1) in the normoxia group (P< 0.001) with an identical training heart rate in both groups. RESULTS Exercise capacity improved similarly with both interventions. With hypoxia training, body fat content, triglycerides, HOMA-Index, fasting insulin (P < 0.05), and area under the curve for insulin (P < 0.01) during the oral glucose tolerance test improved more than with the training in normoxia. We did not observe major changes in adipokine measurements. CONCLUSION Endurance training in hypoxia over a 4-wk period elicits a similar or even better response in terms of cardiovascular and metabolic risk factors than endurance exercise in normoxia. The fact that workload and, therefore, mechanic strain can be reduced in hypoxia could be particularly beneficial in obese patients and in patients with orthopedic conditions.

Myocardial steatosis, cardiac remodelling and fitness in insulin-sensitive and insulin-resistant obese women

Background Obesity predisposes to heart failure and premature cardiovascular death, particularly in sedentary women. In animal models and in men with type 2 diabetes mellitus, impaired cardiac function is associated with myocardial triglyceride (MTG) accumulation. Lipotoxic injury from altered myocardial metabolism may be causative. Whether such association also exists in obese, non-diabetic women is unknown. Objective To explore the relation between MTG content, cardiac remodelling and cardiorespiratory fitness in obese, insulin-sensitive and insulin-resistant non-diabetic women. Design Cross-sectional investigation. Setting Academic clinical research centre. Patients 65 Overweight/obese and sedentary, but otherwise healthy women (body mass index 33±4 kg/m2; age 45±10 years). Interventions None. Main outcome measures Cardiac structure and function measured by cardiovascular magnetic resonance imaging and MTG content of the interventricular septum by 1H MR spectroscopy. Additional outcomes were cardiopulmonary fitness and insulin sensitivity during oral glucose tolerance testing. Results Insulin resistance (composite insulin sensitivity index (C-ISI) <4.6) was present in 29 women. MTG content was higher (0.83±0.30 vs 0.61±0.23, p=0.002) and left ventricular diastolic (p<0.01), but not systolic function was reduced in women with insulin resistance compared with insulin-sensitive women. The remodelling index defined as left ventricular mass divided by end-diastolic volume was increased in women with impaired glucose tolerance (p=0.006). Furthermore, cardiopulmonary fitness was equal in both groups, but was inversely correlated with MTG (r=−0.28, p=0.02). Conclusions In overweight and obese women, insulin resistance is associated with increased MTG content, cardiac remodelling and reduced diastolic function. Clinical Trial Registration ClinicalTrials.gov NCT00956566.

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.

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.

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.

Differential response of the natriuretic peptide system to weight loss and exercise in overweight or obese patients.

Objective: Relative atrial natriuretic peptide (ANP) deficiency has been implicated in the pathogenesis of obesity-associated cardiovascular and metabolic disease. We tested the hypothesis that more than 5% body weight reduction through 6 months hypocaloric dieting alters ANP release at rest and more so during exercise in overweight or obese patients. Methods: Venous mid-regional pro-ANP concentration was assessed at rest and after incremental exhaustive exercise testing before and after weight reduction. We also measured natriuretic peptide receptor A and C mRNA expression in subcutaneous adipose tissue to gauge both ANP responsiveness and clearance mechanisms. Results: The average weight reduction of 9.1 ± 3.8 kg was associated with reductions in visceral and subcutaneous abdominal fat mass, liver fat content, insulin resistance, and ambulatory blood pressure. However, mid-regional pro-ANP plasma concentrations were unchanged with weight loss (51 ± 24 vs. 53 ± 24 pmol/l). Exercise elicited similar acute mid-regional pro-ANP increases before and after weight loss. Adipose tissue natriuretic peptide receptor type A mRNA expression remained unchanged, whereas natriuretic peptide receptor type C mRNA decreased with weight loss. Conclusions: We conclude that physical exercise acutely increases ANP release in obese patients, whereas modest diet-induced weight loss primarily affects ANP clearance mechanisms. Interventions combining weight loss and regular physical exercise may be particularly efficacious in reversing obesity-associated relative natriuretic peptide deficiency.

Fatty acid binding protein 4 predicts left ventricular mass and longitudinal function in overweight and obese women

Objective To explore whether increased adipocyte-derived serum fatty acid binding protein 4 (FABP4) predisposes to cardiac remodelling and left ventricular dysfunction in human obesity. Design Cross-sectional investigation. Setting Academic clinical research centre. Patients 108 overweight and obese non-diabetic women (body-mass index 33±5 kg/m²). Interventions None. Main outcome measures Relationship between serum FABP4 and abdominal adipose tissue quantified by MRI. Relationship between serum FABP4 and left ventricular morphology and function assessed by cardiac MRI. Results FABP4 was independently associated with visceral abdominal adipose tissue (β=0.34, p<0.01) and subcutaneous abdominal adipose tissue (β=0.22, p<0.05). After stratification into serum FABP4 tertiles, left ventricular masses were 92±16 g, 86±13 g and 81±12 g in women with high, intermediate and low FABP4 concentrations (p<0.01), respectively. Longitudinal systolic function was reduced by 8% in women with intermediate and high versus low FABP4 concentrations (p<0.01), whereas ejection fraction did not differ among tertiles (p=0.5). In multivariate linear analysis FABP4 remained an independent predictor of left ventricular mass (β=0.17, p<0.05) and reduced longitudinal fractional shortening (β=0.21, p<0.05). Conclusions In overweight and obese women, FABP4 showed an independent association with parameters of left ventricular remodelling.

Patients With Continuous-Flow Left Ventricular Assist Devices Provide Insight in Human Baroreflex Physiology

The superior clinical outcome of new continuous-flow left ventricular assist devices (LVADs) challenges the physiological dogma that cardiovascular autonomic homeostasis requires pulsatile blood flow and pressure. We tested the hypothesis that continuous-flow LVADs impair baroreflex control of sympathetic nerve traffic, thus further exacerbating sympathetic excitation. We included 9 male heart failure patients (26–61 years; 18.9–28.3 kg/m2) implanted with a continuous-flow LVAD. We recorded ECG, respiration, finger blood pressure, brachial blood pressure, and muscle sympathetic nerve activity. After baseline measurements had been taken, patients underwent autonomic function testing including deep breathing, a Valsalva maneuver, and 15° head-up tilt. Finally, we increased the LVAD speed in 7 patients. Spontaneous sympathetic baroreflex sensitivity was analyzed. Brachial blood pressure was 99±4 mm Hg with 14±2 mm Hg finger pulse pressure. Muscle sympathetic nerve activity bursts showed a normal morphology, were linked to the cardiac cycle, and were suppressed during blood pressure increases. Mean burst frequency was lower compared with age- and body mass index–matched controls in 2 patients, slightly increased in 4 patients, and increased in 2 patients (P=0.11). Muscle sympathetic nerve activity burst latency and the median values of the burst amplitude distribution were similar between groups. Muscle sympathetic nerve activity increased 4±1 bursts per minute with head-up tilt (P<0.0003) and decreased 3±4 bursts per minute (P<0.031) when LVAD speed was raised. The mean sympathetic baroreflex slope was −3.75±0.79%/mm Hg in patients and −3.80±0.55%/mm Hg in controls. We conclude that low pulse pressure levels are sufficient to restrain sympathetic nervous system activity through baroreflex mechanisms.