Endocrinology and Metabolism: Projects

​Impaired glucose tolerance is among the most common metabolic disturbances associated with childhood obesity. Both peripheral insulin resistance and impaired beta cell function play roles in this disorder. Later in life, patients often develop Type 2 Diabetes mellitus with severe consequences such as cardiac, renal and neuronal problems.

Obesity is associated with changes in adipocyte function, e.g. altered production of adipocytokines. We hypothesize that there is a link between these altered states of adipocytokine blood levels and impairment of beta cell function. Our aim is therefore to characterize the effects of novel adipocytokines on beta cell viability and function.

Subprojects

• The role of Omentin-1 in ß-cell survival (Melanie Penke)
• Glypican 4 (Joseph Buhl, Melanie Penke)

Glypican-4 ist ein zelloberflächlich vorkommendes Heparansulfatproteoglykan, welches aus einem Proteinkern und angelagerten Heparansulfatketten besteht. Neben einer membranständigen Form existiert auch eine lösliche Form des Glypican-4, welches unter anderem aus dem Fettgewebe  freigesetzt wird. Als relativ neu entdecktes Adipokin spielt es unter anderem in Entwicklungsprozessen und dem Stoffwechsel eine Rolle, ist es schließlich in Wnt- und Insulin-Signalweg eingeschaltet. Serumlevel dieses Proteins korrelieren mit Adipositas und Insulinresistenz. Unser Projekt beschäftigt sich mit dem Einfluss des Glypican-4 auf die Funktion der Beta-Zelle, mit dem Ziel, die grundlegenden Mechanismen der Entstehung von Beta-Zell-Dysfunktion und Typ 2 Diabetes besser zu verstehen.

Glypican-4 is a heparan sulfate proteoglycan linked to the cell membrane and consisting of a protein core with attached heparan sulfate chains. In addition to this membrane-bound form, a soluble form exists, which is released from adipose tissue.  As a newly discovered adipokine, glypican-4 plays a role in developmental processes and metabolism, as it is involved in Wnt- and insulin signaling. Among other things, serum levels of glypican-4 correlate with obesity and insulin resistance.

We want to elucidate the influence of glypican-4 on beta cell function, with the aim to understand the underlying mechanisms of beta cell dysfunction and Type 2 Diabetes in a better way.

​Obesity is associated with aberrant body fat distribution and an impaired adipose tissue function. The factors and pathways involved in the regulation of aberrant adipose tissue accumulation and growth are not fully elucidated. We are using a rare genetic disease called PTEN hamartoma tumor syndrome (PHTS) to better understand underlying mechanisms of adipose tissue overgrowth.

Subprojects

• Molecular causes of the development of lipomatosis in patients with PTEN hamartoma tumor syndrome (Anna Kirstein, Antje Garten)
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• Establishment and characterisation of novel lipoma-derived adipocyte models including 3D lipoma cultures (Anna Kirstein, Antje Garten)
• Organotypic slice cultures as an alternative model for drug testing (Lea Merz)

Mutations in the Phosphatase and tensin homolog (PTEN) gene are one step in the development of several cancers and of lipomas that frequently develop in patients with germline mutation in PTEN. PTEN negatively regulates the PI3K/AKT/mTOR pathway which controls many cellular processes that are important for the formation and progression of cancer. We will establish organotypic tumor tissue slice cultures of lipomas developing in Pten/Rb1 knockout mice to evaluate different inhibitors of the PI3K/AKT/mTOR pathway. This growth factor pathway is aberrantly active in patients with germline mutations in PTEN. Alpelisib is a bioavailable phosphatidylinositol 3-kinase (PI3K) inhibitor which may decrease lipoma proliferation, cell survival and invasiveness and may be therefore a therapeutic option for patients with PTEN-associated unresectable lipomas.

​The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of enzymes involved in cellular energy metabolism, stress resistance and life span. Changes in NAD salvage metabolism are associated with several pathologies, including metabolic disorders and cancer. NAMPT (nicotinamide phosphoribosyltransferase), the key enzyme of the NAD salvage pathway, functions as an intra- and extracellular NAD biosynthetic enzyme that is important for the regulation of NAD-dependent enzymes, such as sirtuins and poly(ADP-ribose) polymerases (PARPs).

Subprojects

• SIRT1 regulates Growth Hormone-mediated expression of  IGF-I (Melanie Penke)
• NAD metabolism in the pathogenesis of non-alcoholic fatty liver disease (Ana Teixeira, Melanie Penke, Antje Garten)

Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in many parts of the world and is characterized by an excess of fat in liver. However, this accumulation promotes the progression of the disease leading to fibrosis, inflammation and steatosis that could culminate in cirrhosis or hepatocellular carcinoma (HCC), and in the worst case leads to death.  In addition, NAFLD is related to insulin resistance and metabolic syndrome, such as T2DM (Christopher et al. 2015, Youngmin at al. 2015).

It is known that NAFLD is more common in men than women, as well as in obese children but the reasons for that are unclear. However, activation of hepatic stellate cells is one of the reasons for disease progression. In vivo studies using mice was observed that hepatic overexpression of SIRT-1 and NAD supplementation protects against hepatic steatosis and alcoholic fatty liver disease (Pfluger et al. 2008, Wang et al. 2018).

As Col-I is a protein present in ECM that is regulated by TGF-β (Transforming Growth Factor Beta), now we are doing in vitro studies using LX2 cells (Hepatic Stellate Cells) to find out if TGF-β expression is increased in livers of “male fast food mice” and if a reduction in NAD levels promotes collagen I production through TGF-β activation. In addition, we want to look for estrogen effect to find out if fibrosis can be arrested by estrogen (reason by female mice are not affected).

This project is important, as we can understand the mechanisms that promote NAFLD progression and find out mechanisms that could impair this progression.

Clinical study: eNAMPT and NAD precursors as novel biomarkers for non-alcoholic fatty liver disease in children and adolescents (collaboration with the LIFE Child cohort Leipzig) (Melanie Penke)