Objective: Extracellular matrix remodeling is required for adipose expansion under increased caloric intake. In turn, inhibited expandability due to aberrant collagen deposition promotes insulin resistance and progression towards the metabolic syndrome. An emerging role for the small leucine-rich proteoglycan Lumican in metabolically driven nonalcoholic fatty liver disease sparks an interest in further understanding its role in diet-induced obesity and metabolic complications. Methods: Whole body ablation of Lumican (Lum(-/-)) gene and adeno-associated virus-mediated over-expression were used in combination with control or high fat diet to assess energy balance, glucose homeostasis as well as adipose tissue health and remodeling. Results: Lumican was found to be particularly enriched in the stromal cells isolated from murine gonadal white adipose tissue. Likewise murine and human visceral fat showed a robust increase in Lumican as compared to fat from the subcutaneous depot. Lumican null female mice exhibited moderately increased fat mass, decreased insulin sensitivity and increased liver triglycerides in a diet-dependent manner. These changes coincided with inflammation in adipose tissue and no overt effects in adipose expandability, i.e. adipocyte formation and hypertrophy. Lumican over-expression in visceral fat and liver resulted in improved insulin sensitivity and glucose clearance. Conclusions: These data indicate that Lumican may represent a functional link between the extracellular matrix, glucose homeostasis, and features of the metabolic syndrome. (C) 2018 The Authors. Published by Elsevier GmbH.

Obesity and its consequences, such as insulin resistance and metabolic syndrome, is increasing in importance, its prevalence reaching 35% of adults being overweight and 11% obese. The recent discovery of thermogenically active adipose tissue in adult humans, which is able to dissipate excess energy creating heat, has drawn attention to research on brown adipose tissue as well as so called brite adipocytes, that arise in white adipose depots upon cold exposure. A question of interest is whether thermogenically active adipose tissue differs from white fat regarding insulin sensitivity or vice versa depends on functional insulin signalling for development and function. While it had recently been shown that the development of brown fat depends on insulin, however that it maintains sensitivity to β3-adrenergic stimulation in the absence of insulin signaling, the role of insulin in browning of white depots is less clear. We show here that both absence of and resistance to insulin lead to lowered brite state in WAT, but β3-adrenergic stimulation could completely rescue this defect. Further we investigated whether the brite state leads to enhanced insulin sensitivity, which would render browning of WAT an interesting tool for counteracting metabolic consequences of obesity. We showed that indeed brite adipocytes and browned WAT tissues exhibit elevated glucose uptake. However we proved that neither isolated adipocytes differentiated into brite cells nor browned WAT were more insulin sensitive than white. Overall we conclude that while browning is efficient in enhancing systemic glucose clearance, it does not render adipose tissue more insulin sensitive.

ZusammenfassungDie Beziehung zwischen Adipositas und Krebs ist im letzten Jahrzehnt in den Fokus der klinischen und biomedizinischen Forschung geraten. Eingehende epidemiologische Studien und Metaanalysen kamen zu der Schlussfolgerung, dass Adipositas mit einer erhöhten Inzidenz und ungünstigeren Prognose einer Reihe von Krebserkrankungen assoziiert ist. Obwohl Typ-2-Diabetes laut epidemiologischen Befunden auch mit einer erhöhten Inzidenz und Mortalität bestimmter Krebsarten assoziiert ist, kann er an sich nicht als unabhängiger Risikofaktor gelten. Die prinzipielle Rolle der Hyperglykämie, Hyperinsulinämie und der Aktivierung des Insulin/ IGF-1-Signalweges kann jedoch durch epidemiologische Daten, Tiermodelle und in vitro Befunde belegt werden. Zusätzlich werden unter anderem die subakute Inflammation, der ektopische überschuss an Triglyzeriden und freien Fettsäuren und das veränderte Adipokinprofil als plausible molekulare Mechanismen bei der Adipositas-bedingten Krebsentstehung und Progression derzeit erforscht. Die immense Bedeutung der Beziehung zwischen Adipositas und Krebs wird klar im Hinblick auf die steigende Inzidenz von übergewicht und Adipositas, insbesondere im Kindes- und Jugendalter.

Background: Cyclooxygenase-2 (COX-2) over-expression and subsequent prostaglandin E2 (PGE2) production are frequently associated with human non-small-cell lung cancer (NSCLC) and are involved in tumor proliferation, invasion, angiogenesis, and resistance to apoptosis. Here, we report that ciglitazone downregulates PGE2 in NSCLC cells.Methods: PGE2 ELISA assay and COX-2 ELISA assay were performed for measuring PGE2 and COX-2, respectively, in NSCLC. The mRNA level of COX-2 was measured by semi-quantitative RT-PCR. The transient transfection experiments were performed to measure COX-2 and peroxisome proliferator-response element (PPRE) promoter activity in NSCLC. Western blots were unitized to measure PGE synthase (PGES) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) protein expression.Results: COX-2 ELISA assays suggested that ciglitazone-dependent inhibition of PGE2 occurs through the suppression of COX-2. Ciglitazone treatment suppressed COX-2 mRNA expression and COX-2 promoter activity while upregulating PPRE promoter activity. Ciglitazone did not modify the expression of enzymes downstream of COX-2 including PGES and 15-PGDH. Utilization of a dominant-negative PPARγ showed that the suppression of COX-2 and PGE2 by ciglitazone is mediated via non-PPAR pathways.Conclusion: Taken together, our findings suggest that ciglitazone is a negative modulator of COX-2/PGE2 in NSCLC.

De novo glucose production, e.g. gluconeogenesis, by the liver importantly contributes to the maintenance of blood sugar level under stress conditions. Gluconeogenic pathway activity is synergistically induced through glucagon and glucocorticoid hormones acting via distinct transcriptional regulators on the expression of key enzyme genes such as phosphoenolpyruvate carboxykinase (PEPCK). During acute inflammation, interference with hormone signalling and the subsequent suppression of PEPCK expression through pro-inflammatory mediators importantly contributes to the hypoglycaemic phenotype and death in septic patients, the molecular mechanisms of which remain unknown. Therefore, this study aimed to create an experimental system to evaluate the mechanisms of interference between hormonal and inflammatory messengers involved in dysfunctional PEPCK gene expression in vivo.

Strong suppression of de novo glucose production by the liver, e.g. gluconeogenesis, during acute inflammation is one of the major characteristics of the aberrant metabolic state and reason of death in septic patients. Interference with hormone signalling and the subsequent suppression of a key gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), through pro-inflammatory mediators importantly contribute to the hypoglycaemic phenotype in sepsis. However, the molecular mechanisms of aberrant PEPCK gene regulation under these conditions remain unknown.