Fritz Schick

Identification and Characterization of Metabolically Benign Obesity in Humans

BACKGROUND Obesity represents a risk factor for insulin resistance, type 2 diabetes mellitus, and atherosclerosis. In addition, for any given amount of total body fat, an excess of visceral fat or fat accumulation in the liver and skeletal muscle augments the risk. Conversely, even in obesity, a metabolically benign fat distribution phenotype may exist. METHODS In 314 subjects, we measured total body, visceral, and subcutaneous fat with magnetic resonance (MR) tomography and fat in the liver and skeletal muscle with proton MR spectroscopy. Insulin sensitivity was estimated from oral glucose tolerance test results. Subjects were divided into 4 groups: normal weight (body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared], < 25.0), overweight (BMI, 25.0-29.9), obese-insulin sensitive (IS) (BMI, > or = 30.0 and placement in the upper quartile of insulin sensitivity), and obese-insulin resistant (IR) (BMI, > or = 30.0 and placement in the lower 3 quartiles of insulin sensitivity). RESULTS Total body and visceral fat were higher in the overweight and obese groups compared with the normal-weight group (P < .05); however, no differences were observed between the obese groups. In contrast, ectopic fat in skeletal muscle (P < .001) and particularly the liver (4.3% +/- 0.6% vs 9.5% +/- 0.8%) and the intima-media thickness of the common carotid artery (0.54 +/- 0.02 vs 0.59 +/- 0.01 mm) were lower and insulin sensitivity was higher (17.4 +/- 0.9 vs 7.3 +/- 0.3 arbitrary units) in the obese-IS vs the obese-IR group (P < .05). Unexpectedly, the obese-IS group had almost identical insulin sensitivity and the intima-media thickness was not statistically different compared with the normal-weight group (18.2 +/- 0.9 AU and 0.51 +/- 0.02 mm, respectively). CONCLUSIONS A metabolically benign obesity that is not accompanied by insulin resistance and early atherosclerosis exists in humans. Furthermore, ectopic fat in the liver may be more important than visceral fat in the determination of such a beneficial phenotype in obesity.

Measurement of intracellular triglyceride stores by 1H spectroscopy: validation in vivo

We validate the use of 1H magnetic resonance spectroscopy (MRS) to quantitatively differentiate between adipocyte and intracellular triglyceride (TG) stores by monitoring the TG methylene proton signals at 1.6 and 1.4 ppm, respectively. In two animal models of intracellular TG accumulation, intrahepatic and intramyocellular TG accumulation was confirmed histologically. Consistent with the histological changes, the methylene signal intensity at 1.4 ppm increased in both liver and muscle, whereas the signal at 1.6 ppm was unchanged. In response to induced fat accumulation, the TG concentration in liver derived from 1H MRS increased from 0 to 44.9 ± 13.2 μmol/g, and this was matched by increases measured biochemically (2.1 ± 1.1 to 46.1 ± 10.9 μmol/g). Supportive evidence that the methylene signal at 1.6 ppm in muscle is derived from investing interfascial adipose tissue was the finding that, in four subjects with generalized lipodystrophy, a disease characterized by absence of interfacial fat, no signal was detected at 1.6 ppm; however, a strong signal was seen at 1.4 ppm. An identical methylene chemical shift at 1.4 ppm was obtained in human subjects with fatty liver where the fat is located exclusively within hepatocytes. In experimental animals, there was a close correlation between hepatic TG content measured in vivo by 1H MRS and chemically by liver biopsy [ R = 0.934; P < .0001; slope 0.98, confidence interval (CI) 0.70-1.17; y-intercept 0.26, CI -0.28 to 0.70]. When applied to human calf muscle, the coefficient of variation of the technique in measuring intramyocellular TG content was 11.8% in nonobese subjects and 7.9% in obese subjects and of extramyocellular (adipocyte) fat was 22.6 and 52.5%, respectively. This study demonstrates for the first time that noninvasive in vivo 1H MRS measurement of intracellular TG, including that within myocytes, is feasible at 1.5-T field strengths and is comparable in accuracy to biochemical measurement. In addition, in mixed tissue such as muscle, the method is clearly advantageous in differentiating between TG from contaminating adipose tissue compared with intramyocellular lipids.

Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance

Hepatic steatosis is the most prevalent liver disorder in the developed world. It is closely associated with features of metabolic syndrome, especially insulin resistance and obesity. The two most common conditions associated with fatty liver are alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Liver biopsy is considered the gold standard for the assessment of liver fat, but there is a need for less invasive diagnostic techniques. New imaging modalities are emerging, which could provide more detailed information about hepatic tissue or even replace biopsy. In the present review, available imaging modalities (ultrasound, computed tomography, magnetic resonance imaging and proton magnetic resonance spectroscopy) are presented which are employed to detect or even quantify the fat content of the liver. The advantages and disadvantages of the above-mentioned imaging modalities are discussed. Although none of these techniques is able to differentiate between microvesicular and macrovesicular steatosis and to reveal all features visible using histology, the proposed diagnostic modalities offer a wide range of additional information such as anatomical and morphological information non-invasively. In particular, magnetic resonance imaging and proton magnetic resonance spectroscopy are able to quantify the hepatic fat content hence avoiding exposure to radiation. Except for proton magnetic resonance spectroscopy, all modalities offer additional information about regional fat distribution within the liver. MR elastography, which can estimate the amount of fibrosis, also appears promising in the differentiation between simple steatosis and steatohepatitis.

Relaxivity of Gadopentetate Dimeglumine (Magnevist), Gadobutrol (Gadovist), and Gadobenate Dimeglumine (MultiHance) in human blood plasma at 0.2, 1.5, and 3 Tesla.

Objectives:We sought to determine the relaxivity and accurate relaxation rates of Gd-DTPA, Gd-BT-DO3A, and Gd-BOPTA at 0.2, 1.5, and 3 T in human blood plasma. Materials and Methods:Contrast media concentrations between 0.01 and 16 mM in human plasma were used for relaxation measurements. The R1 and R2 relaxation rates and r1 and r2 relaxivities were determined. Results:Gd-BOPTA produced the highest relaxation rates and relaxivities at all field strengths. The r1 and r2 values for Gd-BOPTA were 107–131% and 91–244% higher than for Gd-DTPA, respectively, and 72–98% and 82–166% higher than for Gd-BT-DO3A. Higher field strengths resulted in lower values of R1, R2, and r1 for all contrast agents tested and of r2 for Gd-DTPA and Gd-BT-DO3A. A linear dependence of R1 and R2 on concentration was found for Gd-DTPA and Gd-BT-DO3A and a nonlinear dependence for Gd-BOPTA for concentrations larger than 1 mM. The r1 and r2 relaxivity of Gd-BOPTA increased with decreasing concentration. Conclusions:Gd-BOPTA demonstrates the highest longitudinal r1 at all field strengths, which is ascribable to weak protein interaction. The R2/R1 ratio increases at higher field strength only for Gd-BOPTA, hence very short echo times are required for Gd-BOPTA to benefit from the higher longitudinal relaxivity.

Dissociation Between Fatty Liver and Insulin Resistance in Humans Carrying a Variant of the Patatin-Like Phospholipase 3 Gene

OBJECTIVE In a genome-wide association scan, the rs738409 C>G single nucleotide polymorphism (SNP) in the patatin-like phospholipase 3 gene (PNPLA3) was strongly associated with increased liver fat but not with insulin resistance estimated from fasting values. We investigated whether the SNP determines liver fat independently of visceral adiposity and whether it may even play a role in protecting from insulin resistance. RESEARCH DESIGN AND METHODS Liver fat was measured by 1H magnetic resonance spectroscopy and total and visceral fat by magnetic resonance tomography in 330 subjects. Insulin sensitivity was estimated during an oral glucose tolerance test and the euglycemic-hyperinsulinemic clamp (n = 222). PNPLA3 and tumor necrosis factor-α mRNA and triglyceride content were measured in liver biopsies from 16 subjects. RESULTS Liver fat correlated strongly with insulin sensitivity (P < 0.0001) independently of age, sex, total fat, and visceral fat. G allele carriers of the SNP rs738409 had higher liver fat (P < 0.0001) and an odds ratio of 2.38 (95% CI 1.37–4.20) for having fatty liver compared to C allele homozygotes. Interestingly, insulin sensitivity (oral glucose tolerance test: P = 0.99; clamp: P = 0.32), serum C-reactive protein levels, lipids, or liver enzymes (all P > 0.14) were not different among the genotypes. Additional adjustment for liver fat actually revealed increased insulin sensitivity in more obese carriers of the G allele (P = 0.01). In liver biopsies triglyceride content correlated positively with expression of the proinflammatory gene tumor necrosis factor-α in C allele homozygotes (n = 6, P = 0.027) but not in G allele carriers (n = 10, P = 0.149). CONCLUSIONS PNPLA3 may be an important key to understand the mechanisms discriminating fatty liver with and without metabolic consequences.

Standardized assessment of whole body adipose tissue topography by MRI

To assess standardized whole body adipose tissue topography in a cohort of subjects at an increased risk for type 2 diabetes and to compare fat distribution in subgroups regarding anthropometric (age, body mass index [BMI]) and metabolic parameters (insulin sensitivity).

High Cardiorespiratory Fitness is an independent Predictor of the Reduction in Liver Fat during a Lifestyle Intervention in Non-Alcoholic Fatty Liver Disease

Objective: Lifestyle intervention with diet modification and increase in physical activity is effective for reducing hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD). However, for a similar weight loss, there is a large variability in the change in liver fat. We hypothesised that cardiorespiratory fitness may predict the response to the intervention. Design: Longitudinal study with increase in physical activity and diet modification. Setting: University teaching hospital. Patients: 50 adults with NAFLD and 120 controls at risk for metabolic diseases. Main outcome measures: Total-, subcutaneous abdominal- and visceral adipose tissue by magnetic resonance tomography, liver fat by 1HMR spectroscopy and cardiorespiratory fitness (VO2,max) by a maximal cycle exercise test at baseline and after 9 months of follow-up. Results: In all subjects total-, subcutaneous abdominal- and visceral adipose tissue decreased and fitness increased (all p<0.0001) during the intervention. The most pronounced changes were found for liver fat (−31%, p<0.0001). Among the parameters predicting the change in liver fat, fitness at baseline emerged as the strongest factor, independently of total- and visceral adipose tissue as well as exercise intensity (p = 0.005). In the group of subjects with NAFLD at baseline, a resolution of NAFLD was found in 20 individuals. For 1 standard deviation increase in VO2,max at baseline the odds ratio for resolution of NAFLD was 2.79 (95% confidence interval, 1.43–6.33). Conclusions: Cardiorespiratory fitness, independently of total adiposity, body fat distribution and exercise intensity, determines liver fat content in humans, suggesting that fitness and liver fat are causally related to each other. Moreover, measurement of fitness at baseline predicts the effectiveness of a lifestyle intervention in reducing hepatic steatosis in patients with NAFLD.

FAIR True-FISP perfusion imaging of the kidneys

Most arterial spin labeling (ASL) techniques apply echoplanar imaging (EPI) because this strategy provides relatively high SNR in short measuring times. Unfortunately, those techniques are very susceptible to static magnetic field inhomogeneities and perfusion signals from organs with fast transverse relaxation might decrease due to the exchange of water molecules in capillaries and organ tissue combined with relatively long echo times of EPI sequences. To overcome these problems a novel imaging technique, FAIR True‐FISP, was developed. It combines a FAIR (flow‐sensitive alternating inversion recovery) perfusion preparation and a true fast imaging with steady precession (True‐FISP) data acquisition strategy. True‐FISP was chosen since this sequence type does not show the mentioned disadvantages of EPI, but provides a similar SNR per measuring time. An important problem of this approach is that True‐FISP sequences usually work in a steady state which is independent of a previous preparation of magnetization. For this reason a sequence structure had to be developed which keeps the advantages of True‐FISP and makes the signal intensity sensitive to the FAIR preparation. Breathhold and nonbreathhold examinations of kidneys are presented and possible strategies to quantitative flow measurements are reported. It is shown that correction of spatially inhomogeneous receiver coil characteristics is easily feasible and leads to clinically valuable perfusion examinations of kidneys without application of potentially nephrotoxic contrast media. Magn Reson Med 51:353–361, 2004.

The obese brain: Association of body mass index and insulin sensitivity with resting state network functional connectivity

Obesity is a key risk factor for the development of insulin resistance, Type 2 diabetes and associated diseases; thus, it has become a major public health concern. In this context, a detailed understanding of brain networks regulating food intake, including hormonal modulation, is crucial. At present, little is known about potential alterations of cerebral networks regulating ingestive behavior. We used “resting state” functional magnetic resonance imaging to investigate the functional connectivity integrity of resting state networks (RSNs) related to food intake in lean and obese subjects using independent component analysis. Our results showed altered functional connectivity strength in obese compared to lean subjects in the default mode network (DMN) and temporal lobe network. In the DMN, obese subjects showed in the precuneus bilaterally increased and in the right anterior cingulate decreased functional connectivity strength. Furthermore, in the temporal lobe network, obese subjects showed decreased functional connectivity strength in the left insular cortex. The functional connectivity magnitude significantly correlated with body mass index (BMI). Two further RSNs, including brain regions associated with food and reward processing, did not show BMI, but insulin associated functional connectivity strength. Here, the left orbitofrontal cortex and right putamen functional connectivity strength was positively correlated with fasting insulin levels and negatively correlated with insulin sensitivity index. Taken together, these results complement and expand previous functional neuroimaging findings by demonstrating that obesity and insulin levels influence brain function during rest in networks supporting reward and food regulation. Hum Brain Mapp, 2011.

Magnetic resonance imaging of the body trunk using a single-slab, 3-dimensional, T2-weighted turbo-spin-echo sequence with high sampling efficiency (SPACE) for high spatial resolution imaging: Initial clinical experiences

Purpose:The authors conducted a clinical evaluation of single-slab, 3-dimensional, T2-weighted turbo-spin-echo (TSE) with high sampling efficiency (SPACE) for high isotropic body imaging with large field-of-view (FoV). Materials and Methods:Fifty patients were examined in clinical routine with SPACE (regions of interest: pelvis n = 30, lower spine n = 12, upper spine n = 6, extremities n = 4) at 1.5 T. For achieving a high sampling efficiency, parallel imaging, high turbofactor, and magnetization restore pulses were used. In contrast to a conventional TSE imaging technique with constant flip angle refocusing, the refocusing pulse train of the SPACE sequence consists of variable flip angle radiofrequency pulses along the echo train. Results:Signal-to-noise ratio and contrast-to-noise ratio of SPACE images were of sufficient diagnostic value. The possibility of image reconstruction in multiple planes was of clinical relevance in all cases and simplified data analysis. Conclusion:The achievement of 3-dimensional, T2-weighted TSE magnetic resonance imaging with isotropic and high spatial resolution and interactive 3-dimensional visualization essentially improve the diagnostic potential of magnetic resonance imaging.