Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-17972 Wissenschaftlicher Artikel Viera, Jonathan Trujillo; El-Merahbi, Rabih; Nieswandt, Bernhard; Stegner, David; Sumara, Grzegorz Phospholipases D1 and D2 Suppress Appetite and Protect against Overweight Obesity is a major risk factor predisposing to the development of peripheral insulin resistance and type 2 diabetes (T2D). Elevated food intake and/or decreased energy expenditure promotes body weight gain and acquisition of adipose tissue. Number of studies implicated phospholipase D (PLD) enzymes and their product, phosphatidic acid (PA), in regulation of signaling cascades controlling energy intake, energy dissipation and metabolic homeostasis. However, the impact of PLD enzymes on regulation of metabolism has not been directly determined so far. In this study we utilized mice deficient for two major PLD isoforms, PLD1 and PLD2, to assess the impact of these enzymes on regulation of metabolic homeostasis. We showed that mice lacking PLD1 or PLD2 consume more food than corresponding control animals. Moreover, mice deficient for PLD2, but not PLD1, present reduced energy expenditure. In addition, deletion of either of the PLD enzymes resulted in development of elevated body weight and increased adipose tissue content in aged animals. Consistent with the fact that elevated content of adipose tissue predisposes to the development of hyperlipidemia and insulin resistance, characteristic for the pre-diabetic state, we observed that Pld1\(^{-/-}\) and Pld2\(^{-/-}\) mice present elevated free fatty acids (FFA) levels and are insulin as well as glucose intolerant. In conclusion, our data suggest that deficiency of PLD1 or PLD2 activity promotes development of overweight and diabetes. 2016 PLoS ONE 11 6 urn:nbn:de:bvb:20-opus-179729 10.1371/journal.pone.0157607 Theodor-Boveri-Institut für Biowissenschaften OPUS4-17056 Wissenschaftlicher Artikel Cai, Kai; El-Merahbi, Rabih; Loeffler, Mona; Mayer, Alexander E.; Sumara, Grzegorz Ndrg1 promotes adipocyte differentiation and sustains their function Adipocytes play a central role in maintaining metabolic homeostasis in the body. Differentiation of adipocyte precursor cells requires the transcriptional activity of peroxisome proliferator-activated receptor-γ (Pparγ) and CCAAT/enhancer binding proteins (C/Ebps). Transcriptional activity is regulated by signaling modules activated by a plethora of hormones and nutrients. Mechanistic target of rapamacin complexes (mTORC) 1 and 2 are central for the coordination of hormonal and nutritional inputs in cells and are essential for adipogenesis. Serum glucocorticoid kinase 1 (Sgk1)-dependent phosphorylation of N-Myc downstream-regulated gene 1 (Ndrg1) is a hallmark of mTORC2 activation in cells. Moreover, Pparγ activation promotes Ndrg1 expression. However, the impact of Ndrg1 on adipocyte differentiation and function has not yet been defined. Here, we show that Ndrg1 expression and its Sgk1-dependent phosphorylation are induced during adipogenesis. Consistently, we demonstrate that Ndrg1 promotes adipocyte differentiation and function by inducing Pparγ expression. Additionally, our results indicate that Ndrg1 is required for C/Ebpα phosphorylation. Moreover, we found that Ndrg1 phosphorylation by Sgk1 promotes adipocyte formation. Taken together, we show that induction of Ndrg1 expression by Pparγ and its phosphorylation by Sgk1 kinase are required for the acquisition of adipocyte characteristics by precursor cells. 2017 Scientific Reports 7 7191 urn:nbn:de:bvb:20-opus-170565 10.1038/s41598-017-07497-x Rudolf-Virchow-Zentrum OPUS4-17609 unpublished Löffler, Mona C.; Mayer, Alexander E.; Trujillo Viera, Jonathan; Loza Valdes, Angel; El-Merahib, Rabih; Ade, Carsten P.; Karwen, Till; Schmitz, Werner; Slotta, Anja; Erk, Manuela; Janaki-Raman, Sudha; Matesanz, Nuria; Torres, Jorge L.; Marcos, Miguel; Sabio, Guadalupe; Eilers, Martin; Schulze, Almut; Sumara, Grzegorz Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others, activates G-protein coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown. Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP-activated protein kinase (AMPK)-dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet-induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the β3-adrenergic receptor (ADRB3) in a CCAAT/enhancerbinding protein (C/EBP)-α and δ-dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis. Thus, loss of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications. 2018 The EMBO Journal urn:nbn:de:bvb:20-opus-176093 Theodor-Boveri-Institut für Biowissenschaften OPUS4-25002 Wissenschaftlicher Artikel Mayer, Alexander E.; Löffler, Mona C.; Loza Valdés, Angel E.; Schmitz, Werner; El-Merahbi, Rabih; Trujillo-Viera, Jonathan; Erk, Manuela; Zhang, Thianzhou; Braun, Ursula; Heikenwalder, Mathias; Leitges, Michael; Schulze, Almut; Sumara, Grzegorz The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity. accepted manuscript 2019 Science Signaling urn:nbn:de:bvb:20-opus-250025 10.1126/scisignal.aav9150 Theodor-Boveri-Institut für Biowissenschaften OPUS4-23901 Wissenschaftlicher Artikel Trujillo-Viera, Jonathan; El-Merahbi, Rabih; Schmidt, Vanessa; Karwen, Till; Loza-Valdes, Angel; Strohmeyer, Akim; Reuter, Saskia; Noh, Minhee; Wit, Magdalena; Hawro, Izabela; Mocek, Sabine; Fey, Christina; Mayer, Alexander E.; Löffler, Mona C.; Wilhelmi, Ilka; Metzger, Marco; Ishikawa, Eri; Yamasaki, Sho; Rau, Monika; Geier, Andreas; Hankir, Mohammed; Seyfried, Florian; Klingenspor, Martin; Sumara, Grzegorz Protein Kinase D2 drives chylomicron-mediated lipid transport in the intestine and promotes obesity Lipids are the most energy-dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron-mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high-fat diet-induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity. 2021 EMBO Molecular Medicine 13 5 urn:nbn:de:bvb:20-opus-239018 10.15252/emmm.202013548 Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)