TY  - JOUR
AB  - Elevated serum concentrations of glucocorticoids (GCs) result in excessive lipid accumulation in white adipose tissue (WAT) as well as dysfunction of thermogenic brown adipose tissue (BAT), ultimately leading to the development of obesity and metabolic disease. Here, we hypothesized that activation of the sympathetic nervous system either via cold exposure or the use of a selective b3-adrenergic receptor (b3-AR) agonist alleviates the adverse metabolic effects of chronic GC exposure in rodents. To this end, male 10-wk-old C57BL/6NRj mice were treated with corticosterone via drinking water or placebo for 4 wk while being maintained at 29°C (thermoneutrality), 22°C (room temperature), or 13°C (cold temperature); in a follow-up study mice received a selective b3-AR agonist or placebo with and without corticosterone while being maintained at room temperature. Body weight and food intake were monitored throughout the study. Histological and molecular analyses were performed on white and brown adipose depots. Cold exposure not only preserved the thermogenic function of brown adipose tissue but also reversed GC-induced lipid accumulation in white adipose tissue and corrected GC-driven obesity, hyperinsulinemia, and hyperglycemia. The metabolic benefits of cold exposure were associated with enhanced sympathetic activity in adipose tissue, thus potentially linking an increase in sympathetic signaling to the observed metabolic benefits. In line with this concept, chronic administration of a selective b3-AR agonist reproduced the beneficial metabolic effects of cold adaption during exposure to exogenous GCs. This preclinical study demonstrates the potential of b3-AR as a therapeutic target in the management and prevention of GC-induced metabolic disease. NEW & NOTEWORTHY This preclinical study in mice shows that the b3-adrenergic receptor can be a potential therapeutic approach to counteracting glucocorticoid (GC)-induced obesity and metabolic dysfunction. Both cold acclimation and b3-adrenergic receptor stimulation in a mouse model of excess glucocorticoids were adequate in not only preventing obesity, adiposity, and adipose tissue dysfunction but also correcting hyperinsulinemia, hyperleptinemia, and dyslipidemia.
AU  - Gado, M.
AU  - Heinrich, A.*
AU  - Wiedersich, D.*
AU  - Sameith, K.*
AU  - Dahl, A.*
AU  - Alexaki, V.I.*
AU  - Swarbrick, M.M.*
AU  - Baschant, U.*
AU  - Grafe, I.*
AU  - Perakakis, N.
AU  - Bornstein, S.R.
AU  - Rauner, M.*
AU  - Hofbauer, L.C.*
AU  - Henneicke, H.*
C1  - 68542
C2  - 53669
CY  - 6120 Executive Blvd, Suite 600, Rockville, Md, United States
SP  - 514-530
TI  - Activation of β-adrenergic receptor signaling prevents glucocorticoid-induced obesity and adipose tissue dysfunction in male mice.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 324
IS  - 6
PB  - Amer Physiological Soc
PY  - 2023
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - Objective Activation of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) upon cold stimulation leads to substantial increase in energy expenditure to defend body temperature. Increases in energy expenditure after a high caloric food intake, termed diet-induced thermogenesis, are also attributed to BAT. These properties render BAT a potential target to combat diet-induced obesity. However, studies investigating the role of UCP1 to protect against diet-induced obesity are controversial and rely on the phenotyping of a single constitutive UCP1-knockout model. To address this issue, we generated a novel UCP1-knockout model by Cre-mediated deletion of Exon 2 in the UCP1 gene. We studied the effect of constitutive UCP1 knockout on metabolism and the development of diet-induced obesity. Methods UCP1 knockout and wildtype mice were housed at 30°C and fed a control diet for 4-weeks followed by 8-weeks of high-fat diet. Body weight and food intake were monitored continuously over the course of the study and indirect calorimetry was used to determine energy expenditure during both feeding periods. Results Based on Western blot analysis, thermal imaging and noradrenaline test, we confirmed the lack of functional UCP1 in knockout mice. However, body weight gain, food intake and energy expenditure were not affected by deletion of UCP1 gene function during both feeding periods. Conclusion We introduce a novel UCP1-KO mouse enabling the generation of conditional UCP1-knockout mice to scrutinize the contribution of UCP1 to energy metabolism in different cell types or life stages. Our results demonstrate that UCP1 does not protect against diet-induced obesity at thermoneutrality.
AU  - Dieckmann, S.*
AU  - Strohmeyer, A.*
AU  - Willershäuser, M.*
AU  - Maurer, S.F.*
AU  - Wurst, W.
AU  - Marschall, S.
AU  - Hrabě de Angelis, M.
AU  - Kühn, R.
AU  - Worthmann, A.*
AU  - Fuh, M.M.*
AU  - Heeren, J.*
AU  - Pauling, J.K.*
AU  - Klingenspor, M.*
C1  - 63900
C2  - 51631
CY  - 6120 Executive Blvd, Suite 600, Rockville, Md, United States
SP  - E85-E100
TI  - Susceptibility to diet-induced obesity at thermoneutral conditions is independent of UCP1.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 322
IS  - 2
PB  - Amer Physiological Soc
PY  - 2022
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - Glycosylphosphatidylinositol-anchored proteins (GPI-AP) with the complete glycolipid anchor attached have previously been shown to be released from the outer plasma membrane leaflet of rat adipocytes in positive correlation to cell size and blood glucose/insulin levels of the donor rats. Furthermore, they are present in rat and human serum, however, at amounts that are lower in insulin-resistant/obese rats compared with normal ones. These findings prompted further evaluation of the potential of full-length GPI-AP for the prediction and stratification of metabolically deranged states. A comparison of the signatures of horizontal surface acoustic waves that were generated by full-length GPI-AP in the course of their specific capture by and subsequent dissociation from a chip-based sensor between those from rat serum and those reconstituted into lipidic structures strongly argues for expression of full-length GPI-AP in serum in micelle-like complexes in concert with phospholipids, lysophospholipids, and cholesterol. Both the reconstituted and the rat serum complexes were highly sensitive toward mechanical forces, such as vibration. Furthermore, full-length GPI-AP reconstituted into micelle-like complexes represented efficient substrates for cleavage by serum glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD). These findings raised the possibility that the upregulated release of full-length GPI-AP into micelle-like serum complexes from metabolically deranged cells is compensated by elevated GPI-PLD activity. In fact, serum GPI-PLD activity toward full-length GPI-AP in micelle-like complexes, but not in detergent micelles, was positively correlated to early states of insulin resistance and obesity in genetic and diet-induced rat models as well as to the body weight in humans. Moreover, the differences in the degradation of GPI-AP in micelle-like complexes were found to rely in part on the interaction of serum GPI-PLD with an activating serum factor. These data suggest that serum GPI-PLD activity measured with GPI-AP in micelle-like complexes is indicative of enhanced release of full-length GPI-AP from relevant tissues into the circulation as a consequence of early metabolic derangement in rats and humans.
AU  - Müller, G.
AU  - Tschöp, M.H.
AU  - Müller, T.D.
C1  - 58595
C2  - 48173
CY  - 9650 Rockville Pike, Bethesda, Md 20814 Usa
SP  - E462-E479
TI  - Upregulated phospholipase D activity toward glycosylphosphatidylinositol-anchored proteins in micelle-like serum complexes in metabolically deranged rats and humans.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 318
IS  - 4
PB  - Amer Physiological Soc
PY  - 2020
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - Little is known about xenometabolites in human metabolism, particularly under exercising conditions. Previously. an exercise-modifiable, likely xenometabolite derivative, cis-3,4-methylene-heptanoylcarnitine, was reported in human plasma. Here, we identified trans-3.4-methylene-heptanoylcarnitine, and its cis-isomer, in plasma and skeletal muscle by liquid chromatography-mass spectrometry. We analyzed the regulation by exercise and the arterialto-venous differences of these cyclopropane ring-containing carnitine esters over the hepatosplanchnic bed and the exercising leg in plasma samples obtained in three separate studies from young. lean and healthy males. Compared with other medium-chain acylcarnitines, the plasma concentrations of the 3.4-methylene-heptanoylcarnitine isomers only marginally increased with exercise. Both isomers showed a more than twofold increase in the skeletal muscle tissue of the exercising leg: this may have been due to the net effect of fatty acid oxidation in the exercising muscle and uptake from blood. The latter idea is supported by a more than twofold increased net uptake in the exercising leg only. Both isomers showed a constant release from the hepatosplanchnic bed, with an increased release of the trans-isomer after exercise. The isomers differ in their plasma concentration, with a four times higher concentration of the cis-isomer regardless of the exercise state. This is the first approach studying kinetics and fluxes of xenolipid isomers from tissues under exercise conditions, supporting the hypothesis that hepatic metabolism of cyclopropane ring-containing fatty acids is one source of these acylcarnitines in plasma. The data also provide clear evidence for an exercise-dependent regulation of xenometabolites, opening perspectives for future studies about the physiological role of this largely unknown class of metabolites.
AU  - Sobhi, H.F.*
AU  - Zhao, X.*
AU  - Plomgaard, P.*
AU  - Hoene, M.*
AU  - Hansen, J.S.*
AU  - Karus, B.*
AU  - Niess, A.M.*
AU  - Häring, H.-U.
AU  - Lehmann, R.
AU  - Adams, S.H.*
AU  - Xu, G.*
AU  - Weigert, C.
C1  - 59055
C2  - 48686
CY  - 9650 Rockville Pike, Bethesda, Md 20814 Usa
SP  - E701-E709
TI  - Identification and regulation of the xenometabolite derivatives cis- and trans-3,4-methylene-heptanoylcarnitine in plasma and skeletal muscle of exercising humans.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 318
IS  - 5
PB  - Amer Physiological Soc
PY  - 2020
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - Dimethylguanidino valeric acid (DMGV) is a marker of fatty liver disease. incident coronary artery disease, cardiovascular mortality, and incident diabetes. Recently. it was reported that circulating DMGV levels correlated positively with consumption of sugary beverages and negatively with intake of fruits and vegetables in three Swedish community-based cohorts. Here, we validate these results in the Framingham Heart Study Third Generation Cohort. Furthermore, in mice, diets rich in sucrose or fat significantly increased plasma DMGV concentrations. DMGV is the product of metabolism of asymmetric dimethylarginine (ADMA) by the hepatic enzyme AGXT2. ADMA can also be metabolized to citrulline by the cytoplasmic enzyme DDAH1. We report that a high-sucrose diet induced conversion of ADMA exclusively into DMGV (supporting the relationship with sugary beverage intake in humans), while a high-fat diet promoted conversion of ADMA to both DMGV and citrulline. On the contrary. replacing dietary native starch with high-fiber-resistant starch increased ADMA concentrations and induced its conversion to citrulline, without altering DMGV concentrations. In a cohort of obese nondiabetic adults, circulating DMGV concentrations increased and ADMA levels decreased in those with either liver or muscle insulin resistance. This was similar to changes in DMGV and ADMA concentrations found in mice fed a high-sucrose diet. Sucrose is a disaccharide of glucose and fructose. Compared with glucose, incubation of hepatocytes with fructose significantly increased DMGV production. Overall, we provide a comprehensive picture of the dietary determinants of DMGV levels and association with insulin resistance.
AU  - Wali, J.A.*
AU  - Koay, Y.C.*
AU  - Chami, J.*
AU  - Wood, C.*
AU  - Corcilius, L.*
AU  - Payne, R.J.*
AU  - Rodionov, R.N.*
AU  - Birkenfeld, A.L.
AU  - Samocha-Bonet, D.*
AU  - Simpson, S.J.*
AU  - O'Sullivan, J.F.*
C1  - 59977
C2  - 49154
CY  - 9650 Rockville Pike, Bethesda, Md 20814 Usa
SP  - E509-E518
TI  - Nutritional and metabolic regulation of the metabolite dimethylguanidino valeric acid: An early marker of cardiometabolic disease.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 319
IS  - 3
PB  - Amer Physiological Soc
PY  - 2020
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - Mitochondria are dynamic organelles with diverse functions in tissues such as liver and skeletal muscle. To unravel the mitochondrial contribution to tissue-specific physiology, we performed a systematic comparison of the mitochondrial proteome and lipidome of mice and assessed the consequences hereof for respiration. Liver and skeletal muscle mitochondrial protein composition was studied by data-independent ultra-high-performance (UHP)LC-MS/MS-proteomics, and lipid profiles were compared by UIIPLC-MS/MS lipidomics. Mitochondrial function was investigated by high-resolution respirometry in samples from mice and humans. Enzymes of pyruvate oxidation as well as several subunits of complex I, III, and ATP synthase were more abundant in muscle mitochondria. Muscle mitochondria were enriched in cardiolipins associated with higher oxidative phosphorylation capacity and flexibility, in particular CL(18:2)(4) and 22:6-containing cardiolipins. In contrast, protein equipment of liver mitochondria indicated a shuttling of complex I substrates toward gluconeogenesis and ketogenesis and a higher preference for electron transfer via the flavoprotein quinone oxidoreductase pathway. Concordantly, muscle and liver mitochondria showed distinct respiratory substrate preferences. Muscle respired significantly more on the complex I substrates pyruvate and glutamate, whereas in liver maximal respiration was supported by complex II substrate succinate. This was a consistent finding in mouse liver and skeletal muscle mitochondria and human samples. Muscle mitochondria are tailored to produce ATP with a high capacity for complex I-linked substrates. Liver mitochondria are more connected to biosynthetic pathways, preferring fatty acids and succinate for oxidation. The physiologic diversity of mitochondria may help to understand tissue-specific disease pathologies and to develop therapies targeting mitochondrial function.
AU  - Kappler, L.*
AU  - Hoene, M.*
AU  - Hu, C.*
AU  - von Toerne, C.
AU  - Li, J.*
AU  - Bleher, D.*
AU  - Hoffmann, C.*
AU  - Böhm, A.
AU  - Kollipara, L.*
AU  - Zischka, H.
AU  - Königsrainer, A.*
AU  - Häring, H.-U.
AU  - Peter, A.
AU  - Xu, G.*
AU  - Sickmann, A.*
AU  - Hauck, S.M.
AU  - Weigert, C.
AU  - Lehmann, R.
C1  - 56339
C2  - 47008
CY  - 9650 Rockville Pike, Bethesda, Md 20814 Usa
SP  - E374-E387
TI  - Linking bioenergetic function of mitochondria to tissue-specific molecular fingerprints.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 317
IS  - 2
PB  - Amer Physiological Soc
PY  - 2019
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - Bariatric surgery results in marked body weight loss and improves type 2 diabetes in most patients with obesity. The growth differentiation factor 15 (GDF15) has recently emerged as a novel satiety factor. To begin to understand whether GDF15 is involved in mediating the effects of bariatric surgery on body weight and glycemia in humans, we measured plasma GDF15 in patients with obesity ( n = 25) and in patients with obesity and diabetes ( n = 22) before and after Roux-en-Y gastric bypass (RYGB) surgery. GDF15 was increased 1 wk after RYGB compared with before surgery (689 ± 45 vs. 487 ± 28 pg/ml, P < 0.001) and GDF15 remained elevated at 3 mo (554 ± 37 pg/ml, P < 0.05), at 1 yr (566 ± 37 pg/ml, P < 0.05), and at 2.5-4 yr (630 ± 50 pg/ml, P < 0.001) after RYGB surgery. Both age and insulin sensitivity correlated with GDF15 before the surgery ( r = 0.46, P < 0.0001 and r = 0.34, P < 0.001, respectively). These correlations disappeared at 2.5-4 yr following the surgery. Conversely, weight loss magnitude correlated with GDF15, measured 2.5-4 yr postsurgery ( r = 0.21, P < 0.0055). In summary, circulating GDF15 increases and correlates with body weight loss following RYGB surgery.
AU  - Kleinert, M.
AU  - Bojsen-Møller, K.N.*
AU  - Jørgensen, N.B.*
AU  - Svane, M.S.*
AU  - Martinussen, C.*
AU  - Kiens, B.*
AU  - Wojtaszewski, J.F.P.*
AU  - Madsbad, S.*
AU  - Richter, E.A.*
AU  - Clemmensen, C.*
C1  - 55433
C2  - 46349
CY  - 9650 Rockville Pike, Bethesda, Md 20814 Usa
SP  - E615-E621
TI  - Effect of bariatric surgery on plasma GDF15 in humans.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 316
IS  - 4
PB  - Amer Physiological Soc
PY  - 2019
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - To study the possibility that certain components of eukaryotic plasma membranes are released under certain (patho)physiological conditions, a chip-based sensor was developed for the detection of cell surface proteins, which are anchored at the outer leaflet of eukaryotic plasma membranes by a covalently attached glycolipid, exclusively, and might be prone to spontaneous or regulated release on the basis of their amphiphilic character. For this, unprocessed, full-length glycosylphosphatidylinositol-anchored proteins (GPI-AP), together with associated phospholipids, were specifically captured and detected by a chip- and microfluidic channel-based sensor, leading to changes in phase and amplitude of surface acoustic waves (SAW) propagating over the chip surface. Unprocessed GPI-AP in complex with lipids were found to be released from rat adipocyte plasma membranes immobilized on the chip, which was dependent on the flow rate and composition of the buffer stream. The complexes were identified in the incubation medium of primary rat adipocytes, in correlation to the cell size, and in rat as well as human serum. With rats, the measured changes in SAW phase shift, reflecting specific mass/size or amount of the unprocessed GPI-AP in complex with lipids, and SAW amplitude, reflecting their viscoelasticity, enabled the differentiation between the lean and obese (high-fat diet) state, and the normal (Wistar) and hyperinsulinemic (Zucker fatty) as well as hyperinsulinemic hyperglycemic (Zucker diabetic fatty) state. Thus chip-based sensing for complexes of unprocessed GPI-AP and lipids reveals the inherently labile anchorage of GPI-AP at plasma membranes and their susceptibility for release in response to (intrinsic/extrinsic) cues of metabolic relevance and may, therefore, be useful for monitoring of (pre-)diabetic disease states.
AU  - Müller, G.
AU  - Herling, A.W.*
AU  - Stemmer, K.
AU  - Lechner, A.
AU  - Tschöp, M.H.
C1  - 55958
C2  - 46710
CY  - 9650 Rockville Pike, Bethesda, Md 20814 Usa
SP  - E212-E233
TI  - Chip-based sensing for release of unprocessed cell surface proteins in vitro and in serum and its (patho)physiological relevance.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 317
IS  - 2
PB  - Amer Physiological Soc
PY  - 2019
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - Intermuscular adipose tissue (IMAT) is negatively related to insulin sensitivity, but a causal role of IMAT in the development of insulin resistance is unknown. IMAT was sampled in humans to test for the ability to induce insulin resistance in vitro and characterize gene expression to unoaver how IMAT may promote skeletal muscle insulin resistance. Human primary muscle cells were incubated with conditioned media from IMAT, visceral (VAT), or subcutaneous adipose tissue (SAT) to evaluate changes in insulin sensitivity. RNAseq analysis was performed on IMAT with gene expression compared with skeletal muscle and SAT, and relationships to insulin sensitivity were determined in men and women spanning a wide range of insulin sensitivity measured by hyperinsulinemic-euglycemic clamp. Conditioned media from IMAT and VAT decreased insulin sensitivity similarly compared with SAT. Multidimensional scaling analysis revealed distinct gene expression patterns in IMAT compared with SAT and muscle. Pathway analysis revealed that IMAT expression of genes in insulin signaling, oxidative phosphorylation, and peroxisomal metabolism related positively to donor insulin sensitivity, whereas expression of macrophage markers, inflammatory cytokines, and secreted extracellular matrix proteins were negatively related to insulin sensitivity. Perilipin 5 gene expression suggested greater IMAT lipolysis in insulin-resistant individuals. Combined, these data show that factors secreted from IMAT modulate muscle insulin sensitivity, possibly via secretion of inflammatory cytokines and extracellular matrix proteins, and by increasing local FFA concentration in humans. These data suggest IMAT may be an important regulator of skeletal muscle insulin sensitivity and could be a novel therapeutic target for skeletal muscle insulin resistance.
AU  - Sachs, S.
AU  - Zarini, S.*
AU  - Kahn, D.E.*
AU  - Harrison, K.A.*
AU  - Perreault, L.*
AU  - Phang, T.*
AU  - Newsom, S.A.*
AU  - Strauss, A.*
AU  - Kerege, A.*
AU  - Schoen, J.A.*
AU  - Bessesen, D.H.*
AU  - Schwarzmayr, T.
AU  - Graf, E.
AU  - Lutter, D.
AU  - Krumsiek, J.
AU  - Hofmann, S.M.
AU  - Bergman, B.C.*
C1  - 55093
C2  - 46259
CY  - 9650 Rockville Pike, Bethesda, Md 20814 Usa
SP  - E866-E879
TI  - Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 316
IS  - 5
PB  - Amer Physiological Soc
PY  - 2019
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - Glucagon secreted from the pancreatic alpha-cells is essential for regulation of blood glucose levels. However, glucagon may play an equally important role in the regulation of amino acid metabolism by promoting ureagenesis. We hypothesized that disruption of glucagon receptor signaling would lead to an increased plasma concentration of amino acids, which in a feedback manner stimulates the secretion of glucagon, eventually associated with compensatory proliferation of the pancreatic alpha-cells. To address this, we performed plasma profiling of glucagon receptor knockout (Gcgr(-/-)) mice and wild-type (WT) littermates using liquid chromatography-mass spectrometry (LC-MS)based metabolomics, and tissue biopsies from the pancreas were analyzed for islet hormones and by histology. A principal component analysis of the plasma metabolome from Gcgr(-/-) and WT littermates indicated amino acids as the primary metabolic component distinguishing the two groups of mice. Apart from their hyperaminoacidemia, Gcgr(-/-) mice display hyperglucagonemia, increased pancreatic content of glucagon and somatostatin (but not insulin), and alpha-cell hyperplasia and hypertrophy compared with WT littermates. Incubating cultured alpha-TC1.9 cells with a mixture of amino acids (Vamin 1%) for 30 min and for up to 48 h led to increased glucagon concentrations (similar to 6-fold) in the media and cell proliferation (similar to 2-fold), respectively. In anesthetized mice, a glucagon receptor-specific antagonist (Novo Nordisk 25-2648, 100 mg/kg) reduced amino acid clearance. Our data support the notion that glucagon secretion and hepatic amino acid metabolism are linked in a close feedback loop, which operates independently of normal variations in glucose metabolism.
AU  - Galsgaard, K.D.*
AU  - Winther-Sørensen, M.*
AU  - Ørskov, C.*
AU  - Kissow, J.*
AU  - Poulsen, S.S.*
AU  - Vilstrup, H.*
AU  - Prehn, C.
AU  - Adamski, J.
AU  - Jepsen, S.L.*
AU  - Hartmann, B.*
AU  - Hunt, J.*
AU  - Charron, M.J.*
AU  - Pedersen, J.H.*
AU  - Wewer Albrechtsen, N.J.*
AU  - Holst, J.J.*
C1  - 52059
C2  - 43662
CY  - Bethesda
SP  - E93-E103
TI  - Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 314
IS  - 1
PB  - Amer Physiological Soc
PY  - 2017
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - The liver is a central regulator of whole body glucose, and lipid homeostasis and hepatokines, like fetuin-A, have been identified as markers and mediators of fatty liver-induced cardiometabolic risk. The closely related protein fetuin-B was shown to be upregulated in the fatty liver and to impact on glucose homeostasis in mice. In the present study we aimed to test the relevance of these findings in humans. In 55 subjects, hepatic mRNA expression of both hepatokines, fetuin-A and fetuin-B, associated positively with liver triglyceride content, whereas only fetuin-A expression associated with the homeostatic model assessment of insulin resistance. In 220 subjects who underwent precise metabolic phenotyping, circulating fetuin-A, but not fetuin-B, associated positively with liver fat content, and negatively with insulin sensitivity, measured during the oral glucose tolerance test (OGTT) and during the euglycemic, hyperinsulinemic clamp. Both circulating fetuin-A and fetuin-B correlated positively with the glucose area under the curve during the OGTT, but after additional adjustment for insulin sensitivity this relationship remained significant only for fetuin-B. In conclusion, despite the fact that the two hepatokines, fetuin-A and fetuin-B, are upregulated in the state of hepatic steatosis in humans, it appears that they differently impact on glucose homeostasis. Our data are in agreement with observations that fetuin-A can alter insulin signaling and that fetuin-B may regulate glucose homeostasis via so far unknown effects, possibly on glucose effectiveness.
AU  - Peter, A.
AU  - Kovarova, M.*
AU  - Staiger, H.
AU  - Machann, J.
AU  - Schick, F.*
AU  - Königsrainer, A.*
AU  - Koenigsrainer, I.*
AU  - Schleicher, E.D.*
AU  - Fritsche, A.
AU  - Häring, H.-U.
AU  - Stefan, N.
C1  - 52823
C2  - 44186
CY  - Bethesda
SP  - E266-E273
TI  - The hepatokines fetuin-A and fetuin-B are upregulated in the state of hepatic steatosis and may differently impact on glucose homeostasis in humans.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 314
IS  - 3
PB  - Amer Physiological Soc
PY  - 2017
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - CONTEXT: Metabolomic profiling of obese individuals revealed altered concentrations of many metabolites, especially branched-chain amino acids (BCAA), possibly linked to altered adipose tissue BCAA catabolism. OBJECTIVE: We tested the hypothesis that some features of this metabolite signature relate closely to visceral obesity and concomitant alterations in cardiometabolic risk factors. We also postulated that alterations in BCAA-catabolizing enzymes are predominant in visceral adipose tissue. METHODS: Fifty-nine women (BMI 20-41 kg/m(2)) undergoing gynecologic surgery were recruited and characterized for overall and regional adiposity, blood metabolite levels using targeted metabolomics and cardiometabolic risk factors. Adipose samples (visceral and subcutaneous) were obtained and used for gene expression and western blot analyses. RESULTS: Obese women had significantly higher circulating BCAA and Kynurenine/Tryptophan (KYN/Trp) ratio than lean or overweight women (p<0.01). Principal component analysis confirmed that factors related to AA and the KYN/Trp ratio were positively associated with BMI, fat mass, visceral or subcutaneous adipose tissue area and subcutaneous adipocyte size (p≤0.05). AA-related factor was positively associated with HOMA-IR (p≤0.01). Factors reflecting glycerophospholipids and sphingolipids levels were mostly associated with altered blood lipid concentrations (p≤0.05). Glutamate level was the strongest independent predictor of visceral adipose tissue area (r=0.46, p<0.001). Obese women had lower expression and protein levels of BCAA-catabolizing enzymes in visceral adipose tissue compared to overweight or lean women (p≤0.05). CONCLUSIONS: Among metabolites altered in obesity, plasma concentrations of BCAA and the KYN/Trp ratio are closely related to increased adiposity. Alterations in expression and protein levels of BCAA-catabolizing enzymes are predominant in visceral adipose tissue.
AU  - Boulet, M.M.*
AU  - Chevrier, G.*
AU  - Grenier-Larouche, T.*
AU  - Pelletier, M.P.*
AU  - Nadeau, M.*
AU  - Scarpa, J.
AU  - Prehn, C.
AU  - Marette, A.*
AU  - Adamski, J.
AU  - Tchernof, A.*
C1  - 46764
C2  - 37791
SP  - E736-E746
TI  - Alterations of plasma metabolite profiles related to adipose tissue distribution and cardiometabolic risk.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 309
IS  - 8
PY  - 2015
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - In humans and rodents, risk of metabolic syndrome is sexually dimorphic, with an increased incidence in males. Additionally, the protective role of female gonadal hormones is ostensible, as prevalence of type 2 diabetes mellitus (T2DM) increases after menopause. Here, we investigated the influence of estrogen (E2) on the onset of T2DM in female New Zealand obese (NZO) mice. Diabetes prevalence (defined as blood glucose levels >16.6 mmol/l) of NZO females on high-fat diet (60 kcal% fat) in week 22 was 43%. This was markedly dependent on liver fat content in week 10, as detected by computed tomography. Only mice with a liver fat content >9% in week 10 plus glucose levels >10 mmol/l in week 9 developed hyperglycemia by week 22. In addition, at 11 wk, diacylglycerols were elevated in livers of diabetes-prone mice compared with controls. Hepatic expression profiles obtained from diabetes-prone and -resistant mice at 11 wk revealed increased abundance of two transcripts in diabetes-prone mice: Mogat1, which catalyzes the synthesis of diacylglycerols from monoacylglycerol and fatty acyl-CoA, and the fatty acid transporter Cd36. E2 treatment of diabetes-prone mice for 10 wk prevented any further increase in liver fat content and reduced diacylglycerols and the abundance of Mogat1 and Cd36, leading to a reduction of diabetes prevalence and an improved glucose tolerance compared with untreated mice. Our data indicate that early elevation of hepatic Cd36 and Mogat1 associates with increased production and accumulation of triglycerides and diacylglycerols, presumably resulting in reduced hepatic insulin sensitivity and leading to later onset of T2DM.
AU  - Lubura, M.*
AU  - Hesse, D.*
AU  - Kraemer, M.*
AU  - Hallahan, N.*
AU  - Schupp, M.*
AU  - von Loeffelholz, C.*
AU  - Kriebel, J.
AU  - Rudovich, N.N.*
AU  - Pfeiffer, A.*
AU  - John, C.*
AU  - Scheja, L.*
AU  - Heeren, J.*
AU  - Koliaki, C.*
AU  - Roden, M.*
AU  - Schuermann, A.*
C1  - 47637
C2  - 39464
SP  - E968-E980
TI  - Diabetes prevalence in NZO females depends on estrogen action on liver fat content.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 309
IS  - 12
PY  - 2015
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - Glucocorticoids are well known to affect T cell migration, leading to a redistribution of the cells from blood to the bone marrow, accompanied by a concurrent suppression of lymph node homing. Despite numerous studies in this context, with most of them employing synthetic glucocorticoids in nonphysiological doses, the mechanisms of this redistribution are not well understood. Here, we investigated in healthy men the impact of cortisol at physiological concentrations on the expression of different migration molecules on eight T cell subpopulations in vivo and in vitro. Hydrocortisone (cortisol, 22 mg) infused during nocturnal rest when endogenous cortisol levels are low, compared with placebo, differentially reduced numbers of T cell subsets, with naive CD4(+) and CD8(+) subsets exhibiting the strongest reduction. Hydrocortisone in vivo and in vitro increased CXCR4 expression, which presumably mediates the recruitment of T cells to the bone marrow. Expression of the lymph node homing receptor CD62L on total CD3(+) and CD8(+) T cells appeared reduced following hydrocortisone infusion. However, this was due to a selective extravasation of CD62L(+) T cell subsets, as hydrocortisone affected neither CD62L expression on a subpopulation level nor CD62L expression in vitro. Corresponding results in the opposite direction were observed after blocking of endogenous cortisol synthesis by metyrapone. CCR7, another lymph node homing receptor, was also unaffected by hydrocortisone in vitro. Thus, cortisol seems to redirect T cells to the bone marrow by upregulating their CXCR4 expression, whereas its inhibiting effect on T cell homing to lymph nodes is apparently regulated independently of the expression of classical homing receptors.
AU  - Besedovsky, L.*
AU  - Linz, B.*
AU  - Dimitrov, S.*
AU  - Groch, S.*
AU  - Born, J.
AU  - Lange, T.*
C1  - 31820
C2  - 34792
CY  - Bethesda
SP  - E1322-E1329
TI  - Cortisol increases CXCR4 expression but does not affect CD62L and CCR7 levels on specific T cell subsets in humans.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 306
IS  - 11
PB  - Amer Physiological Soc
PY  - 2014
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - UCP1-Tg mice with ectopic expression of uncoupling protein1(UCP1) in skeletal muscle (SM) are a model of improved substrate metabolism and increased longevity. Analysis of myokine expression showed an induction of fibroblast growth factor 21 (FGF21) in SM, resulting in approximately fivefold elevated circulating FGF21 in UCP1-Tg mice. Despite a reduced muscle mass, UCP1-Tg mice showed no evidence for a myopathy or muscle autophagy deficiency but an activation of integrated stress response (ISR; eIF2 alpha/ATF4) in SM. Targeting mitochondrial function in vitro by treating C2C12 myoblasts with the uncoupler FCCP resulted in a dose-dependent activation of ISR, which was associated with increased expression of FGF21, which was also observed by treatment with respiratory chain inhibitors antimycin A and myxothiazol. The cofactor required for FGF21 action, beta- klotho, was expressed in white adipose tissue (WAT) of UCP1-Tg mice, which showed an increased browning of WAT similar to what occurred in altered adipocyte morphology, increased brown adipocyte markers (UCP1, CIDEA), lipolysis (HSL phosphorylation), and respiratory capacity. Importantly, treatment of primary white adipocytes with serum of transgenic mice resulted in increased UCP1 expression. Additionally, UCP1-Tg mice showed reduced body length through the suppressed IGF-I-GH axis and decreased bone mass. We conclude that the induction of FGF21 as a myokine is coupled to disturbance of mitochondrial function and ISR activation in SM. FGF21 released from SM has endocrine effects leading to increased browning of WAT and can explain the healthy metabolic phenotype of UCP1-Tg mice. These results confirm muscle as an important endocrine regulator of whole body metabolism.
AU  - Keipert, S.
AU  - Ost, M.*
AU  - Johann, K.*
AU  - Imber, F.*
AU  - Jastroch, M.
AU  - van Schothorst, E.M.*
AU  - Keijer, J.*
AU  - Klaus, S.*
C1  - 31057
C2  - 33597
CY  - Bethesda
SP  - E469-E482
TI  - Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 306
IS  - 5
PB  - Amer Physiological Soc
PY  - 2014
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - Moderate low-carbohydrate/high-fat (LC-HF) diets are widely used to induce weight loss in overweight subjects, whereas extreme ketogenic LC-HF diets are used to treat neurological disorders like pediatric epilepsy. Usage of LC-HF diets for improvement of glucose metabolism is highly controversial; some studies suggest that LC-HF diets ameliorate glucose tolerance, whereas other investigations could not identify positive effects of these diets or reported impaired insulin sensitivity. Here, we investigate the effects of LC-HF diets on glucose and insulin metabolism in a well-characterized animal model. Male rats were fed isoenergetic or hypocaloric amounts of standard control diet, a high-protein "Atkins-style" LC-HF diet, or a low-protein, ketogenic, LC-HF diet. Both LC-HF diets induced lower fasting glucose and insulin levels associated with lower pancreatic β-cell volumes. However, dynamic challenge tests (oral and intraperitoneal glucose tolerance tests, insulin-tolerance tests, and hyperinsulinemic euglycemic clamps) revealed that LC-HF pair-fed rats exhibited impaired glucose tolerance and impaired hepatic and peripheral tissue insulin sensitivity, the latter potentially being mediated by elevated intramyocellular lipids. Adjusting visceral fat mass in LC-HF groups to that of controls by reducing the intake of LC-HF diets to 80% of the pair-fed groups did not prevent glucose intolerance. Taken together, these data show that lack of dietary carbohydrates leads to glucose intolerance and insulin resistance in rats despite causing a reduction in fasting glucose and insulin concentrations. Our results argue against a beneficial effect of LC-HF diets on glucose and insulin metabolism, at least under physiological conditions. Therefore, use of LC-HF diets for weight loss or other therapeutic purposes should be balanced against potentially harmful metabolic side effects.
AU  - Bielohuby, M.*
AU  - Sisley, S.*
AU  - Sandoval, D.A.*
AU  - Herbach, N.*
AU  - Zengin, A.*
AU  - Fischereder, M.*
AU  - Menhofer, D.*
AU  - Stoehr, B.J.*
AU  - Stemmer, K.
AU  - Wanke, R.*
AU  - Tschöp, M.H.
AU  - Seeley, R.J.*
AU  - Bidlingmaier, M.*
C1  - 28194
C2  - 33006
SP  - E1059-E1070
TI  - Impaired glucose tolerance in rats fed low-carbohydrate, high-fat diets.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 305
IS  - 9
PB  - Amer. Physiological Soc.
PY  - 2013
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - In studies emphasizing antiobesogenic and anti-inflammatory effects of long-chain n-3 polyunsaturated fatty acids (LC-n-3 PUFA), diets with very high fat content, not well-defined fat quality, and extreme n-6/n-3 PUFA ratios have been applied frequently. Additionally, comparative analyses of visceral adipose tissues (VAT) were neglected. Considering the link of visceral obesity to insulin resistance or inflammatory bowel diseases, we hypothesized that VAT, especially mesenteric adipose tissue (MAT), may exhibit differential responsiveness to diets through modulation of metabolic and inflammatory processes. Here, we aimed to assess dietary LC-n-3 PUFA effects on MAT and epididymal adipose tissue (EAT) and on MAT-adjacent liver and intestine in diet-induced obese mice fed defined soybean/palm oil-based diets. High-fat (HF) and LC-n-3 PUFA-enriched high-fat diet (HF/n-3) contained moderately high fat with unbalanced and balanced n-6/n-3 PUFA ratios, respectively. Body composition/organ analyses, glucose tolerance test, measurements of insulin, lipids, mRNA and protein expression, and immunohistochemistry were applied. Compared with HF, HF/n-3 mice showed reduced fat mass, smaller adipocytes in MAT than EAT, improved insulin level, and lower hepatic triacylglycerol and plasma NEFA levels, consistent with liver and brown fat gene expression. Gene expression arrays pointed to immune cell activation in MAT and alleviation of intestinal endothelial cell activation. Validations demonstrated simultaneously upregulated pro- (TNF alpha, MCP-1) and anti-inflammatory (IL-10) cytokines and M1/M2-macrophage markers in VAT and reduced CD4/CD8 alpha expression in MAT and spleen. Our data revealed differential responsiveness to diets for VAT through preferentially metabolic alterations in MAT and inflammatory processes in EAT. LC-n-3 PUFA effects were pro- and anti-inflammatory and disclose T cell-immunosuppressive potential.
AU  - Ludwig, T.*
AU  - Worsch, S.*
AU  - Heikenwälder, M.
AU  - Daniel, H.*
AU  - Hauner, H.*
AU  - Bader, B.L.*
C1  - 25750
C2  - 31911
SP  - E1140-E1156
TI  - Metabolic and immunomodulatory effects of n-3 fatty acids are different in mesenteric and epididymal adipose tissue of diet-induced obese mice.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 304
IS  - 11
PB  - Amer. Physiological Soc.
PY  - 2013
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - The identity of specific serine phosphorylation residues of insulin receptor substrate (IRS)-2 and their impact on insulin signal transduction are largely unknown. Ser 675 and Ser 907 of mouse IRS-2 are adjacent to PI3 kinase or Grb2 binding domains, respectively. Using monoclonal phospho-site specific antibodies we demonstrated the phosphorylation of both serines after stimulation of Fao hepatoma cells with insulin, anisomycin, or phorbol esters. Phosphorylation of both sites was a late and prolonged event during insulin treatment and was also detected in liver tissue of insulin-treated as well as refed mice. Inhibition and si-RNA mediated knockdown of ERK1/2 indicated that the insulin-induced phosphorylation of Ser 907 was ERK-dependent. Phosphorylation of Ser 907 did not influence the insulin-induced association of IRS-2 with Grb2, but phosphorylation of the adjacent Tyr 911 was proven to be crucial in HEK 293 cells expressing IRS-2 Ala mutants. The insulin-induced phosphorylation of Ser 675 was prevented by inhibition and siRNA mediated knock-down of mTOR, but not of p70 S6K1. Mutation of Ser 675 to Ala did not affect downstream insulin signaling, but increased the half life of the protein, suggesting an involvement of phospho-Ser 675 in an accelerated degradation of IRS-2. Moreover, the insulin-induced degradation of IRS-2 was blocked by inhibition of mTOR. We conclude that the two novel insulin-dependent serine phosphorylation sites of IRS-2 were not involved in the regulation of the adjacent PI3 kinase and Grb2 binding domains but might be implicated in the ERK and mTOR-mediated negative feedback control.
AU  - Fritsche, L.*
AU  - Neukamm, S.S.*
AU  - Lehmann, R.*
AU  - Kremmer, E.
AU  - Hennige, A.M.*
AU  - Hunder-Gugel, A.*
AU  - Schenk, M.*
AU  - Häring, H.-U.*
AU  - Schleicher, E.D.*
AU  - Weigert, C.*
C1  - 4919
C2  - 27863
SP  - E824-E836
TI  - Insulin-induced serine phosphorylation of irs-2 via erk1/2 and mtor: Studies on the function of ser 675 and ser 907.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 300
IS  - 5
PB  - American Physiological Society, Bethesda MD
PY  - 2011
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - Several mutant mouse models for human diseases such as diabetes mellitus have been generated in the large-scale Munich ENU (N-ethyl-N-nitrosourea) mouse mutagenesis project. The aim of this study was to identify the causal mutation of one of these strains and to characterize the resulting diabetic phenotype. Mutants exhibit a T to G transversion mutation at nt 629 in the glucokinase (Gck) gene, leading to an amino acid exchange from methionine to arginine at position 210. Adult Munich Gck(M210R) mutant mice demonstrated a significant reduction of hepatic glucokinase enzyme activity but equal glucokinase mRNA and protein abundances. While homozygous mutant mice exhibited growth retardation and died soon after birth in consequence of severe hyperglycemia, heterozygous mutant mice displayed only slightly elevated blood glucose levels, present from birth, with development of disturbed glucose tolerance and glucose-induced insulin secretion. Additionally, insulin sensitivity and fasting serum insulin levels were slightly reduced in male mutant mice from an age of 90 days onward. While beta-cell mass was unaltered in neonate heterozygous and homozygous mutant mice, the total islet and beta-cell volumes and the total volume of isolated beta-cells were significantly decreased in 210-day-old male, but not female heterozygous mutant mice despite undetectable apoptosis. These findings indicate that reduced total islet and beta-cell volumes of male mutants might emerge from disturbed postnatal islet neogenesis. Considering the lack of knowledge about the pathomorphology of maturity-onset diabetes of the young type 2 (MODY 2), this glucokinase mutant model of reduced total islet and total beta-cell volume provides the opportunity to elucidate the impact of a defective glucokinase on development and maintenance of beta-cell mass and its relevance in MODY 2 patients.
AU  - van Bürck, L.*
AU  - Blutke, A.*
AU  - Kautz, S.*
AU  - Rathkolb, B.*
AU  - Klaften, M.
AU  - Wagner, S.
AU  - Kemter, E.*
AU  - Hrabě de Angelis, M.
AU  - Wolf, E.*
AU  - Aigner, B.*
AU  - Wanke, R.*
AU  - Herbach, N.*
C1  - 1662
C2  - 27173
SP  - E512-E523
TI  - Phenotypic and pathomorphological characteristics of a novel mutant mouse model for maturity-onset diabetes of the young type 2 (MODY 2).
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 298
IS  - 3
PB  - American Physiological Society
PY  - 2010
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - More than 150 million people suffer from diabetes mellitus worldwide, and this number is expected to rise substantially within the next decades. Despite its high prevalence, the pathogenesis of diabetes mellitus is not completely understood. Therefore, appropriate experimental models are essential tools to gain more insight into the genetics and pathogenesis of the disease. Here, we describe the current efforts to establish novel diabetes models derived from unbiased, phenotype-driven, large-scale N-ethyl-N-nitrosourea (ENU) mouse mutagenesis projects started a decade ago using hyperglycemia as a high-throughput screen parameter. Mouse lines were established according to their hyperglycemia phenotype over several generations, thereby revealing a mutation as cause for the aberrant phenotype. Chromosomal assignment of the causative mutation and subsequent candidate gene analysis led to the detection of the mutations that resulted in novel alleles of genes already known to be involved in glucose homeostasis, like glucokinase, insulin 2, and insulin receptor. Additional ENU-induced hyperglycemia lines are under genetic analysis. Improvements in screen for diabetic animals are implemented to detect more subtle phenotypes. Moreover, diet challenge assays are being employed to uncover interactions between genetic and environmental factors in the pathogenesis of diabetes mellitus. The new mouse mutants recovered in phenotype-driven ENU mouse mutagenesis projects complement the available models generated by targeted mutagenesis of candidate genes, all together providing the large resource of models required for a systematic dissection of the pathogenesis of diabetes mellitus.
AU  - Aigner, B.*
AU  - Rathkolb, B.*
AU  - Herbach, N.*
AU  - Hrabě de Angelis, M.
AU  - Wanke, R.*
AU  - Wolf, E.*
C1  - 4031
C2  - 25147
SP  - 232-240
TI  - Diabetes models by screen for hyperglycemia in phenotype-driven ENU mouse mutagenesis projects.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 294
IS  - 2
PB  - APS
PY  - 2008
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - PCOS is known to be associated with an increased risk of T2DM and has been proposed to share a common genetic background with T2DM. Recent studies suggest that the Calpain-10 gene (CAPN10) is an interesting candidate gene for PCOS susceptibility. However, contradictory results were reported concerning the contribution of certain CAPN10 variants, especially of UCSNP-44, to genetic predisposition to T2DM, hirsutism, and PCOS. By means of MALDI-TOF MS technique, we genotyped an expanded single nucleotide polymorphism panel, including the CAPN10 UCSNP-44, -43, -56, ins/del-19, -110, -58, -63, and -22 in a sample of 146 German PCOS women and 606 population-based controls. Statistical analysis revealed an association between UCSNP-56 and susceptibility to PCOS with an odds ratio (OR) of 2.91 (95% CI=1.51-5.61) for women carrying an AA genotype compared with GG. As expected, the 22-genotype of the ins/del-19 variant, which is in high linkage disequilibrium (r2=0.98) with UCSNP-56, was also significantly associated (OR=2.98, 95% CI=1.55-5.73). None of the additionally tested variants alone showed any significant association with PCOS. A meta-analysis including our study (altogether 623 PCOS cases and 1,224 controls) also showed significant association only with ins/del-19. The most common haplotype TGG3AGCA was significantly associated with a lower risk for PCOS (OR=0.487, P=0.0057). In contrast, the TGA2AGCA haplotype was associated with an increased risk for PCOS (OR=3.557, P=0.0011). By investigating a broad panel of CAPN10 variants, our results pointed to an allele dose-dependent association of UCSNP-56 and ins/del-19 with PCOS.
AU  - Vollmert, C.
AU  - Hahn, S.*
AU  - Lamina, C.
AU  - Huth, C.
AU  - Kolz, M.
AU  - Schöpfer-Wendels, A.
AU  - Mann, K.*
AU  - Bongardt, F*
AU  - Mueller, J.C.*
AU  - Kronenberg, F.
AU  - Wichmann, H.-E.
AU  - Herder, C.*
AU  - Holle, R.
AU  - Löwel, H.
AU  - Illig, T.
AU  - Janssen, O.E*
AU  - KORA Study Group (Wichmann, H.-E.
AU  - Holle, R.
AU  - John, J.
AU  - Illig, T.
AU  - Meisinger, C.)
C1  - 5193
C2  - 24441
SP  - E836-E844
TI  - Calpain-10 variants and haplotypes are associated with polycystic ovary syndrome in Caucasians.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 292
IS  - 3
PB  - APS
PY  - 2007
SN  - 0193-1849
ER  - 

TY  - JOUR
AB  - Excessive synthesis and release of proinflammatory cytokines during endotoxemia causes severe pathophysiological derangements and organ failure. Because the lysosomotropic agent chloroquine has been effective in the treatment of diseases associated with increased secretion of proinflammatory cytokines such as malaria or rheumatoid arthritis, this study evaluates the potential effect of chloroquine on endotoxin-induced cytokinemia using human whole blood from healthy volunteers. Chloroquine revealed a dose-dependent inhibitory effect on endotoxin-induced secretion of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 that was associated with reduced cytokine mRNA expression. Moreover, ammonia and methylamine, which react as weak bases like chloroquine, reduced synthesis and secretion of proinflammatory cytokines. These data indicate a potent anti-inflammatory effect of chloroquine on endotoxin-induced synthesis of proinflammatory cytokines that may be due to its weak base effect. Thus chloroquine may be of therapeutic benefit not only, during chronic inflammation but also in diseases that are related to bacteria-induced inflammation.
AU  - Karres, I.*
AU  - Kremer, J.-P.
AU  - Dietl, I.*
AU  - Steckholzer, U.*
AU  - Jochum, M.*
AU  - Ertel, W.*
C1  - 24117
C2  - 31442
SP  - R1058-R1064
TI  - Chloroquine inhibits proinflammatory cytokine release into human whole blood.
JO  - Am. J. Physiol. Endocrinol. Metab.
VL  - 274
IS  - 4
PB  - Amer. Physiological Soc.
PY  - 1998
SN  - 0193-1849
ER  -