[Show abstract][Hide abstract] ABSTRACT: The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represents an adaptive response that preserves WAT lipid homeostasis in obese and insulin resistant states.In our experiments we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance, from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 down-regulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation, facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.
[Show abstract][Hide abstract] ABSTRACT: Context:Brown adipose tissue (BAT) is a metabolically highly active organ with increased thermogenic activity in rodents exposed to cold temperature. Recently its presence in the cervical adipose tissue of human adults and its association with a favorable metabolic phenotype has been reported.Objective:The objective of the study was to determine the prevalence of retroperitoneal BAT in human adults.Design:This was an observational cohort study.Setting:The study was conducted at a tertiary referral hospital.Patients:57 patients who underwent surgery for benign adrenal tumors were included in this study.Main outcome measures:Prevalence of retroperitoneal BAT adjacent to the removed adrenal tumor as determined by UCP1 protein and mRNA expression.Results:Using protein and mRNA expression analysis, we detected UCP1 protein in 26 out of 57 patients (45.6%) as well as high mRNA expression of genes characteristic for brown adipocytes, independent of the adrenal tumor type. The presence of brown adipocytes within the retroperitoneal fat was associated with a significantly lower outdoor temperature during the month prior to surgery. Importantly, UCP1 expression both on mRNA and on protein level was inversely correlated to outdoor temperature, while BMI, sex, age, and diabetes status were not.Conclusions:These findings suggest that human retroperitoneal adipose tissue can acquire a BAT phenotype, thereby adapting to environmental challenges. These adaptive processes might provide a valuable therapeutic target in the treatment of obesity and insulin resistance.
The Journal of Clinical Endocrinology and Metabolism 06/2013; · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The previously observed supraclavicular depot of brown adipose tissue (BAT) in adult humans was commonly believed to be the equivalent of the interscapular thermogenic organ of small mammals. This view was recently disputed on the basis of the demonstration that this depot consists of beige (also called brite) brown adipocytes, a newly identified type of brown adipocyte that is distinct from the classical brown adipocytes that make up the interscapular thermogenic organs of other mammals. A combination of high-resolution imaging techniques and histological and biochemical analyses showed evidence for an anatomically distinguishable interscapular BAT (iBAT) depot in human infants that consists of classical brown adipocytes, a cell type that has so far not been shown to exist in humans. On the basis of these findings, we conclude that infants, similarly to rodents, have the bona fide iBAT thermogenic organ consisting of classical brown adipocytes that is essential for the survival of small mammals in a cold environment.
[Show abstract][Hide abstract] ABSTRACT: Mice lacking Peroxisome Proliferator-Activated Receptor γ2 (PPARγ2) have unexpectedly normal glucose tolerance and mild insulin resistance. Mice lacking PPARγ2 were found to have elevated levels of Lipocalin prostaglandin D synthase (L-PGDS) expression in BAT and subcutaneous white adipose tissue (WAT). To determine if induction of L-PGDS was compensating for a lack of PPARγ2, we crossed L-PGDS KO mice to PPARγ2 KO mice to generate Double Knock Out mice (DKO). Using DKO mice we demonstrated a requirement of L-PGDS for maintenance of subcutaneous WAT (scWAT) function. In scWAT, DKO mice had reduced expression of thermogenic genes, the de novo lipogenic program and the lipases ATGL and HSL. Despite the reduction in markers of lipolysis in scWAT, DKO mice had a normal metabolic rate and elevated serum FFA levels compared to L-PGDS KO alone. Analysis of intra-abdominal white adipose tissue (epididymal WAT) showed elevated expression of mRNA and protein markers of lipolysis in DKO mice, suggesting that DKO mice may become more reliant on intra-abdominal WAT to supply lipid for oxidation. This switch in depot utilisation from subcutaneous to epididymal white adipose tissue was associated with a worsening of whole organism metabolic function, with DKO mice being glucose intolerant, and having elevated serum triglyceride levels compared to any other genotype. Overall, L-PGDS and PPARγ2 coordinate to regulate carbohydrate and lipid metabolism.
PLoS ONE 07/2012; 7(7):e39512. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The melanocortin system is involved in central and peripheral regulation of energy homeostasis. In adipocytes, the melanocortin 2 receptor (MC2R) transmits ACTH-dependent signaling and its expression rises substantially during adipocyte differentiation. An in vitro system of retrovirally expressed shRNA directed against Mc2r mRNA in 3T3-L1 cells was established and effects of Mc2r knockdown (kd) in comparison to cells expressing non-targeting shRNA (control) were explored in differentiated adipocytes. Morphology, gene expression, lipolysis and fatty acid composition were analyzed. While gross morphology was unchanged extractable amount of lipids was reduced to 70-80% in kd cell lines (p<0.01). Moreover, expression changes of Pparγ2, aP2, and Pref1 indicated reduced differentiation in Mc2r kd cells. Intriguingly, not only ACTH, but also norepinephrine stimulated lipolysis were substantially reduced demonstrating functional significance of MC2R for general lipolysis pathway. Analysis of fatty acid composition in triglyceride and phospholipid fractions showed a lowered ratio of C16:1/C16:0 and C18:1/C18:0, but increased concentrations of arachidonic acid upon Mc2r knockdown. Reduction of mono-unsaturated fatty acids (MUFAs) was associated with lower expression of stearoyl-Coenzyme A desaturase 1 and 2 in kd cells (21 ± 8% vs. 100 ± 13%, p=0.01 and 32 ± 3% vs. 100 ± 15%, p=0.046). Conversely, high doses of ACTH resulted in gene expression changes, mirroring Mc2r knockdown (higher Pparγ2, Scd1, Hsl expression). MC2R plays an important role for regular lipolytic function and lipid composition in 3T3-L1 adipocytes. Of interest, desaturase expression was reduced and MUFA content accordingly altered in kd cells.
Hormone and Metabolic Research 06/2012; 44(9):670-5. · 2.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Low-carbohydrate, high-fat (LC-HF) diets are popular for inducing weight loss in overweighed adults. Adaptive thermogenesis increased by specific effects of macronutrients on energy expenditure has been postulated to induce this weight loss. We studied brown adipose tissue (BAT) morphology and function following exposure to different LC-HF diets.
Male Wistar rats were fed a standard control diet ad libitum or pair-fed isoenergetic amounts of three experimental diets for 4 weeks. The diets had the following macronutrient composition (% metabolizable energy: carbohydrates, fat, protein): control (64.3/16.7/19), LC-HF-low protein (LC-HF-LP, 1.7/92.8/5.5), LC-HF-normal-protein (LC-HF-NP, 2.2/78.7/19.1), and a high fat diet with carbohydrates ("high fat", 19.4/61.9/18.7).
Body weight gain was reduced in all pair-fed experimental groups as compared to rats fed the control diet, with more pronounced effect in rats on LC-HF diets than on the high fat diet with carbohydrates. High fat diets increased expression of PGC1α and ADRB3 in BAT indicating higher SNS outflow. However, UCP1 mRNA expression and expression of UCP1 assessed by immunohistochemistry was not different between diet groups. In accordance, analysis of mitochondrial function in-vitro by extracellular flux analyser (Seahorse Bioscience) and measurement of inducible thermogenesis in vivo (primary endpoint), explored by indirect calorimetry following norepinephrine injection, did not show significant differences between groups. Histology of BAT revealed increased lipid droplet size in rats fed the high-fat diet and both LC-HF diets.
All experimental diets upregulated expression of genes which are indicative for increased BAT activity. However, the functional measurements in vivo revealed no increase of inducible BAT thermogenesis. This indicates that lower body weight gain with LC-HF diets and a high fat diet in a pair-feeding setting is not caused by increased adaptive thermogenesis in BAT.
PLoS ONE 06/2012; 7(6):e38997. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT.
[Show abstract][Hide abstract] ABSTRACT: In den westlichen Industrienationen hat die Prävalenz von Übergewicht und Adipositas seit Beginn der 1980er Jahre deutlich
zugenommen und lässt in Deutschland nach jüngeren Untersuchungen eine Einordnung von 15% aller Erwachsenen als adipös zu.
Der Zusammenhang zwischen Übergewicht und erhöhter Morbidität und Mortalität ist gut belegt, wobei v.a. die Fettverteilung
das individuelle metabolische Risiko bestimmt. Auch wenn die letzten 2 Dekaden wesentliche Erkenntnisse zum Verständnis der
Adipositas erbracht haben, zeigen die meist unbefriedigenden Erfolge der Lebensstiländerung und die derzeit nur begrenzten
medikamentösen Optionen, welch weiten Weg die Adipositasforschung und -behandlung noch zu gehen hat. Vor diesem Hintergrund
können für Personen mit einer morbiden Adipositas chirurgische Therapien (bariatrische Chirurgie) erwogen werden. Lediglich
für operative Interventionen konnte eine langfristig wirksame Senkung des Körpergewichts, der Folgeerkrankungen und Mortalität
gezeigt werden, wobei auch diese invasiven Therapieansätze langfristige Verlaufsuntersuchungen erforderlich machen.
Over the last 30years the prevalence of overweight and obesity has sharply increased in western industrialized countries.
Accordingly, in Germany 15% of the adult population can be regarded as obese. The association between adiposity and increased
morbidity and mortality has been well established but the individual metabolic risk is mainly dependent on the distribution
of adipose depots. During the last two decades knowledge of the pathophysiology of obesity has increased substantially. However,
current therapeutic options including life-style modifications and a few anti-obesity drugs show overall disappointing results
in long-term body weight control indicating the need for therapeutic improvements. For patients with morbid obesity surgical
therapies (bariatric surgery) can be considered. While long-lasting weight control and decrease of adiposity-related morbidity
and mortality has been demonstrated only for these procedures, after bariatric surgery patients also require long-term follow
up and treatment.
Der Radiologe 05/2011; 51(5):346-351. · 0.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Over the last 30 years the prevalence of overweight and obesity has sharply increased in western industrialized countries. Accordingly, in Germany 15% of the adult population can be regarded as obese. The association between adiposity and increased morbidity and mortality has been well established but the individual metabolic risk is mainly dependent on the distribution of adipose depots. During the last two decades knowledge of the pathophysiology of obesity has increased substantially. However, current therapeutic options including life-style modifications and a few anti-obesity drugs show overall disappointing results in long-term body weight control indicating the need for therapeutic improvements. For patients with morbid obesity surgical therapies (bariatric surgery) can be considered. While long-lasting weight control and decrease of adiposity-related morbidity and mortality has been demonstrated only for these procedures, after bariatric surgery patients also require long-term follow up and treatment.
Der Radiologe 05/2011; 51(5):346, 348-51. · 0.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Low-carbohydrate, high-fat (LC-HF) diets are popular for inducing weight loss in adults and are also used as part of a treatment for children with epilepsy. However, potential risks and side effects remain controversial. We investigated effects of LC-HF diets on growth, bone mineral density (BMD), and turnover in growing rats fed for 4 weeks either normal chow (CH, 9% fat, 33% protein, and 58% carbohydrates), LC-HF-1 (66% fat, 33% protein, and 1% carbohydrates), or LC-HF-2 (94.5% fat, 4.2% protein, and 1.3% carbohydrates). Rats fed LC-HF diets accumulated significantly more visceral and bone marrow fat and showed increased leptin but decreased insulin-like growth-factor 1 (IGF-1). Both LC-HF diets significantly decreased body length (nose to rump), but lengths of humerus, tibia, and femur were significantly reduced with LC-HF-2 only. Peripheral quantitative computed tomography (pQCT) and micro-CT (microCT) independently revealed significant reductions in BMD of tibiae in both LC-HF groups, and tibial maximum load was impaired. Bone-formation marker N-terminal propeptide of type I procollagen was reduced in sera of LC-HF groups, whereas bone resorption marker CrossLaps remained unchanged. Real-time PCR analysis revealed significant reductions by 70% to 80% of transcription factors influencing osteoblastogenesis (Runx2, osterix, and C/EBPbeta) in bone marrow of rats fed LC-HF diets. In conclusion, both LC-HF diets impaired longitudinal growth, BMD, and mechanical properties, possibly mediated by reductions in circulating IGF-1. Serum bone-formation markers as well as expression of transcription factors influencing osteoblastogenesis were reduced. This might indicate a lower rate of mesenchymal stem cells differentiating into osteoblasts, thus explaining reduced bone formation with LC-HF diets.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 09/2009; 25(2):275-84. · 6.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dosage of T(4) in central hypothyroidism is primarily guided by the free serum T(4) level (fT4). However, the optimum fT4 range is ill defined, and subtle hypothyroidism might be missed using this approach.
Our aim was to investigate the effects of a body weight (bw)-adapted T(4) treatment, alone or in combination with T(3), on metabolism, well-being, and cognitive function in comparison to a regimen leading to normal fT4.
This was a placebo-controlled trial (double-blind, crossover).
A total of 29 patients (age 52 +/- 2 yr; females/males, 8/21) with hypopituitarism, including TSH deficiency, participated in the study.
Three regimens were compared (5 wk each): "EMPIRICAL-T4," empirical T(4) dosage (1 +/- 0.05 microg/kg bw) leading to normal fT4; BW-ADAPTED-T4 (1.6 microg/kg bw T(4)); and "BW-ADAPTED-T3T4," bw-adapted combination of T(3) and T(4) (ratio of 1:10).
BW-ADAPTED-T4 administration increased mean fT4 concentrations to the upper limit of the normal range (peak levels). Compared with EMPIRICAL-T4, BW-ADAPTED-T4 treatment resulted in a lower body mass index (BMI) (29.0 +/- 0.7 vs. 29.5 +/- 0.7 kg/m(2); P < 0.03), lower total cholesterol (198 +/- 9 vs. 226 +/- 7 mg/dl; P < 0.01), and lower low-density lipoprotein (LDL) cholesterol (116 +/- 5 vs. 135 +/- 7 mg/dl; P < 0.01). BW-ADAPTED-T3T4 treatment was associated with additional beneficial effects on ankle reflex time and working memory but resulted in supraphysiological free serum T(3) (fT(3)) levels.
Long-term side effects may have been missed.
Using a dose of 1.6 microg/kg bw improved markers commonly associated with central hypothyroidism. This suggests that T(4) dosage based on bw and aiming at fT4 in the upper reference range is superior to titration of T(4) aiming at middle normal fT4 concentrations in those patients.
[Show abstract][Hide abstract] ABSTRACT: Despite the fact that the last decade has seen major advances in our knowledge of obesity, the average unsatisfactory successes of lifestyle changes and pharmacological treatment strategies clearly show how very far obesity research and treatment still has to go. What is most regrettable, however, is the fact that, in contrast to the WHO, the German Social Security Code V does not recognize obesity as a disease. This means ignoring the approaching flood of costs associated with obesity, which will put a great strain our health system.
MMW Fortschritte der Medizin 09/2006; 148(33-34):20-4.
[Show abstract][Hide abstract] ABSTRACT: Mouse models of adrenal tumorigenesis have the potential to give insights in the dysregulation of adrenal growth and differentiation. The inbred mouse strain CE/J has been reported to develop adrenal tumors upon gonadectomy (GDX) similar to mice with targeted deletions of the inhibin alpha subunit (Inh-/-). We performed a detailed morphological and molecular characterization of adrenal glands from CE/J mice 8-50 weeks of age to define the cellular origin of these tumors as well as the spatial and temporal expression of marker genes associated with tumor growth. In contrast to the induction of x-zone growth upon GDX in Inh-/- mice, GDX in CE/J mice induced the appearance of sub-capsular nests of densely packed cells that progress into adrenal tumors. Staining for proliferative cell nuclear antigen confirms a substantial increased in cellular proliferation within this sub-capsular compartment and lack of apoptosis upon GDX. Induction of adrenal tumor growth was accompanied by transcriptional changes that otherwise define gonadal endocrine cells. These regulated genes included transcription factors such as GATA-4, WT-1, FOG-1, and steroidogenic factor-1 (SF-1), peptide hormones such as Mullerian-inhibiting substance (MIS), hormone receptors including luteinizing hormone and MIS receptor, and steroidogenic enzymes such as P450c17 and P450 aromatase. The functional significance of steroid enzyme expression was demonstrated by a gradual increase of adrenal androgens after GDX. Taken together these data suggest that adrenal tumors in gonad-ectomized CE/J mice are direct derivatives from cells of the proposed sub-capsular stem cell zone. The distinct expression pattern of this cell population is consistent with a defect in the differentiation of these cells into a cell population with functional properties that otherwise define a gonadal endocrine phenotype.
Journal of Endocrinology 08/2006; 190(1):47-57. · 3.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 6-8-fold higher insulin-like growth factor 1 (IGF-1) receptor binding affinity in vitro is reported for the insulin analogue glargine compared with human insulin. This study evaluates the in vivo significance by exploring the growth hormone (GH)-IGF-1 axis. Assuming a higher binding affinity of insulin glargine to pituitary IGF-1 receptors, serum IGF-1 concentrations should decrease via negative feedback.
In a crossover study, insulin glargine or NPH insulin, respectively, were used in identical doses as basal insulins in treatment periods of 3 weeks.
Overall glycaemic control was not different between the treatment regimens. In contrast to the hypothesis, serum IGF-1 concentrations were higher during insulin glargine treatment compared with NPH insulin in patients with Type 1 diabetes (177 +/- 18 vs. 159 +/- 18 microg/l, P < 0.02, n = 17, age 28 +/- 2 years). The effect on IGF-1 was most pronounced in male patients with Type 1 diabetes (174 +/- 11 vs. 146 +/- 10 microg/l, P < 0.02, n = 10), but was not significant in patients with Type 2 diabetes (92 +/- 9 vs. 86 +/- 8 microg/l, NS, n = 25, age 66 +/- 2 years).
In contrast to our hypothesis, serum IGF-1 did not decrease, but rose during insulin glargine treatment, suggesting an absence of relevant IGF-1-like activity of glargine at the level of the pituitary. Improved plasma glucose at dawn during glargine treatment may intensify growth hormone surges and increase IGF-1 synthesis. Significant increases were seen in younger patients, compatible with the higher activity of the GH-IGF-1 axis in this age group.
Diabetic Medicine 07/2006; 23(7):814-7. · 3.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The safest place to store lipids is the white adipose tissue, but its storage capacity may become saturated resulting in excess of fat "overspilled" to non-adipose tissues. This overspill of fat occurs in apparently opposite pathological states such as lipodistrophy or obesity. When the excess of energy is redirected towards peripheral organs, their initial response is to facilitate the storage of the surplus in the form of triacylglycerol, but the limited triacylglycerol buffer capacity becomes saturated soon. Under these conditions excess of lipids enter alternative non-oxidative pathways that result in production of toxic reactive lipid species that induce organ-specific toxic responses leading to apoptosis. Reactive lipids can accumulate in non-adipose tissues of metabolically relevant organs such as pancreatic beta-cells, liver, heart and skeletal muscle leading to lipotoxicity, a process that contributes substantially to the pathophysiology of insulin resistance, type 2 diabetes, steatotic liver disease and heart failure. The effects of this lipotoxic insult can be minimised by several strategies: (a) decreased incorporation of energy, (b) a less orthodox approach such as increased adipose tissue expandability and/or (c) increased oxidation of fat in peripheral organs. Aging should be considered as physiological degenerative process potentially accelerated by concomitant lipotoxic insults. Conversely, the process of aging can sensitise cells to effects of lipid toxicity.
Ageing Research Reviews 06/2006; 5(2):144-64. · 7.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity is one of the major health problems in developed countries. More than 35% of adults in Germany are considered to be overweight (BMI 25-29.9 kg/m(2)) and approximately 15-20% to be obese (BMI >30 kg/m(2)). Overweight and obesity result from chronic disruption of energy balance. Recent progress in understanding of appetite control and energy expenditure has elucidated a complex integrated system of energy homoeostasis. Although changes in nutritional habits and reduction of physical activity are the main characteristics leading to the strong increase in obesity, it is now recognized that obesity is not only caused by a lack of will power, but can be a consequence of metabolic defects. As obesity results from a genetic make-up favoring weight gain in an "obesigenic" environment the elucidation of the underlying molecular mechanisms might be translated in novel therapeutic options in the future.
Der Internist 03/2006; 47(2):120-9. · 0.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Preoperative localization of parathyroid adenomas (PA) can shorten operation time and improve curative rate; it becomes especially important in minimally invasive surgical techniques. AIM of this study was to investigate whether positron emission tomography (PET) with 3-,4-dihydroxy-6- (18) F-fluorophenylalanine ( (18) F-DOPA), which showed very promising results in other neuroendocrine tumours, also helps to localize PA.
Eight patients with proven primary hyperparathyroidism were studied preoperatively with PET. Seven also underwent scintigraphy with (99m) Tc-MIBI and ultrasonography of the neck. All patients were operated and the histological finding was used as a gold standard.
All eight patients had a histologically proven PA. None of the PA showed any detectable uptake of (18) F-DOPA. However, ultrasonography detected 5/7 PA, scintigraphy detected 3/7 PA.
These results suggest that PET with (18) F-DOPA is not useful in the detection of PA in patients with primary hyperparathyroidism.