Jürgen Machann

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.

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.

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.

Hepatic lipid accumulation in healthy subjects: A comparative study using spectral fat‐selective MRI and volume‐localized 1H‐MR spectroscopy

Fat‐selective MRI was applied to assess the amount and spatial distribution of hepatic lipids (HL) in healthy subjects. The results were compared with those obtained by localized 1H‐MR spectroscopy (MRS). Ninety subjects (23–63 years old) underwent single‐slice fat‐selective MRI with spatial‐spectral excitation and volume‐localized spectroscopy at 1.5 T. HLs were analyzed in ventral and dorsal regions of interest (ROIs) of the liver in fat‐selective images. Spectra were evaluated using the integral signal of methylene and methyl signals. The fat‐selective images showed smooth and homogeneous distribution of HL over the entire cross section of the liver. There was, however, a marked interindividual variability in the amount of HL. MRS revealed a lipid signal fraction between 0.5% and 39.3%. The fat content in the ROIs in images correlated well with the spectroscopic results (r ≥ 0.95). Both techniques provide sufficient sensitivity for a reliable and quantitative assessment of liver steatosis in subjects without liver disease. 1H‐MRS has a higher sensitivity compared to MRI, especially for small amounts of HL, which may be of interest for metabolic interventions. Fat‐selective images provide more spatial information about fat distribution, which makes this technique suitable for clinical imaging of patients with liver disease. Magn Reson Med, 2006.

Intramyocellular lipids and insulin resistance

Lipids are stored not only in adipocytes but also ‘ectopically’ in tissues such as muscle, liver, beta cells and others. From a metabolic perspective, intramyocellular lipids (IMCLs) have recently become a focus of interest. This review summarizes history, measurement techniques and interpretation of muscle lipid data. Problems in biopsies with the separation of those metabolically active lipid droplets in the cytoplasm of myocytes from further lipids in adipocytes are discussed as well as considerations important for analysis of correlations between IMCL content and insulin sensitivity under various circumstances. The relatively new approach to non‐invasive assessment of the IMCL content by magnetic resonance spectroscopy (MRS) is described in detail and exemplary spectra from different skeletal muscle types in humans are presented. The MRS technique allows human examinations of large cohorts for a detailed assessment of the interactions among metabolic parameters such as age, measures of adiposity, hormonal and ethnic factors and insulin resistance. IMCLs are generally positively correlated with measures of obesity and negatively with insulin sensitivity. Paradoxically, physical fitness (maximal aerobic capacity) increases both IMCL content and insulin sensitivity and therefore has to be taken into account as a confounding factor. Intervention studies with MRS further allowed to elucidate the regulation of IMCL. Molecular mechanisms and potential genetic factors on IMCL regulation are discussed as well as possible mechanisms of current treatment strategies for improving insulin sensitivity.

Individual Stearoyl-CoA Desaturase 1 Expression Modulates Endoplasmic Reticulum Stress and Inflammation in Human Myotubes and Is Associated With Skeletal Muscle Lipid Storage and Insulin Sensitivity In Vivo

OBJECTIVE Increased plasma levels of free fatty acids occur in obesity and type 2 diabetes and contribute to the development of insulin resistance. Saturated fatty acids (SFAs) such as palmitate especially have lipotoxic effects leading to endoplasmatic reticulum (ER) stress, inflammation, and insulin resistance. Stearoyl-CoA desaturase 1 (SCD1) plays a key role in preventing lipotoxic effects, as it converts SFAs to less harmful monounsaturated fatty acids. Here, we tested the hypothesis that individual differences in the regulation of SCD1 expression by palmitate exist and influence insulin sensitivity and the cellular response to palmitate. RESEARCH DESIGN AND METHODS Palmitate-induced gene expression was studied in primary human myotubes of 39 metabolically characterized individuals, as well as in an SCD1-overexpressing cell culture model. RESULTS SCD1 mRNA expression and inducibility by palmitate in cultured myotubes showed a broad interindividual variation, presumably due to inheritable characteristics of the donors. Overexpression of SCD1 prevented the inflammatory and ER stress response to palmitate exposure. In primary human myotubes, high SCD1 inducibility was associated with a low inflammatory (interleukin [IL]-6, IL-8, and chemokine [CXC motif] ligand 3 [CXCL3]) and ER stress (CCAAT/enhancer binding protein [C/EBP] homologous protein, activating transcription factor 3 [ATF3], and X-box binding protein 1 [XBP1]) response to palmitate exposure. Finally, palmitate-stimulated SCD1 mRNA expression, positively correlated with intramyocellular lipid (IMCL) content of the donors, was measured by 1H-magnetic resonance spectroscopy. After adjustment for IMCL, SCD1 expression and inducibility were positively correlated with insulin sensitivity. CONCLUSIONS We hypothesize that myocellular SCD1 inducibility by palmitate is an individual characteristic that modulates lipid storage, palmitate-induced inflammation, ER stress, and insulin resistance. This may describe individuals with increased capability of innoxious free fatty acid handling and benign triglyceride storage.

Exercise-induced normalization of decreased BDNF serum concentration in elderly women with remitted major depression

Major depression (MD) has been associated with decreased brain-derived neurotrophic factor (BDNF) serum levels, while antidepressant drugs were found to increase these decreased BDNF levels. We investigated if this is also caused by a single exercise session in elderly women with remitted MD. In our study 35 elderly women with a (partially) remitted depressive episode of unipolar depression according to DSM-IV criteria within the last year and 20 age-matched healthy female controls were included. Depression severity was assessed by HAMD. Serum levels of BDNF were measured by ELISA. Blood samples were taken during the rest period before beginning the exercise including spiroergometry, at the end of the exercise and after a 30-min recovery period. At baseline MD patients showed significantly decreased BDNF serum levels compared to healthy female controls. After a single 30-min exercise period, we found a significant increase of BDNF serum levels in MD patients towards values comparable with the baseline levels of the healthy controls, followed by a significant decrease after 30 min rest, while the healthy controls showed only a mild but non-significant increase. In conclusion, a single exercise session leads to a significant up-regulation and transient normalization of BDNF serum levels in elderly women with remitted MD. This mechanism may contribute to the beneficial therapeutic and relapse-preventing effects of physical activity on MD.

Fast elevation of the intramyocellular lipid content in the presence of circulating free fatty acids and hyperinsulinemia: a dynamic 1H-MRS study.

The influence of a short‐term elevation of free fatty acids (FFAs) on intramyocellular lipids (IMCL) under hyperinsulinemic conditions was monitored in five healthy male subjects in the course of a 5‐hr hyperinsulinemic glucose clamp. During the glucose clamp a lipid emulsion (Intralipid 20®) and heparin were administered intravenously. IMCL was quantified in the tibialis anterior (TA) and the soleus (SOL) muscle by 1H‐MRS. A rapid elevation of the IMCL pool was found in both muscles (61% in TA and 22% in SOL) in the 5‐hr time period. A control hyperinsulinemic glucose clamp in the same study group, repeated without elevation of circulating FFAs, did not lead to significant changes in IMCL for both muscles. The present study shows for the first time that only the combination of high concentrations of FFAs and insulin lead to marked storage of lipids in skeletal muscle cells in humans. Magn Reson Med 45:179–183, 2001.