C6 - Adipokines as modulators of endithelial cell function lipodystrophy and obesity

The impact of adipokines on metabolic and cardiovascular dysfunction and their precise mode of action on the vasculature are incompletely understood. In the next phase of project C6, we aim to explore the role of chemerin and neuregulin 4 on cardiometabolic dysfunction by testing their effects on vascular function and metabolic traits in LDLR^-/-;aP2-nSREBP1c-Tg mice. By focusing on the molecular mechanisms of adipokine actions on the cardiovascular system, the project now integrates local expertise in adipokine and cardiovascular disease research.

Figure 1: Model

Würfel M, Breitfeld J, Gebhard C, Scholz M, Baber R, Riedel-Heller SG, Blüher M, Stumvoll M, Kovacs P, Tönjes A. Interplay between adipose tissue secreted proteins, eating behavior and obesity. Eur J Nutr. 2021 Oct 12.

Weiner J, Roth L, Kranz M, Brust P, Boelen A, Klöting N, Heiker JT, Blüher M, Tönjes A, Pfluger PT, Stumvoll M, Mittag J, Krause K. Leptin counteracts hypothermia in hypothyroidism through its pyrexic effects and by stabilizing serum thyroid hormone levels. Mol Metab. 2021 Oct 2:101348.

Hoffmann A, Ebert T, Hankir MK, Flehmig G, Klöting N, Jessnitzer B, Lössner U, Stumvoll M, Blüher M, Fasshauer M, Tönjes A, Miehle K, Kralisch S. Leptin Improves Parameters of Brown Adipose Tissue Thermogenesis in Lipodystrophic Mice. Nutrients. 2021 Jul 22;13(8):2499.

Epperlein S, Gebhardt C, Rohde K, Chakaroun R, Patt M, Schamarek I, Kralisch S, Heiker JT, Scholz M, Stumvoll M, Kovacs P, Breitfeld J, Tönjes A. The Effect of FGF21 and Its Genetic Variants on Food and Drug Cravings, Adipokines and Metabolic Traits. Biomedicines. 2021 Mar 29;9(4):345.

Behrendt I, Eichner G, Fasshauer M. Association of Antioxidants Use with All-Cause and Cause-Specific Mortality: A Prospective Study of the UK Biobank. Antioxidants (Basel). 2020 Dec 16;9(12):1287.

Kralisch S, Hoffmann A, Estrada-Kunz J, Stumvoll M, Fasshauer M, Tönjes A, Miehle K. Increased Growth Differentiation Factor 15 in Patients with Hypoleptinemia-Associated Lipodystrophy. Int J Mol Sci. 2020 Sep 29;21(19):E7214.

Behrendt I, Fasshauer M, Eichner G. Gluten intake and metabolic health: conflicting findings from the UK Biobank. Eur J Nutr. 2020 Aug 6.

Miehle K, Ebert T, Kralisch S, Hoffmann A, Kratzsch J, Schlögl H, Stumvoll M, Fasshauer M. Serum concentrations of fetuin B in lipodystrophic patients. Cytokine. 2018 Jun;106:165-168.

Püschel J, Miehle K, Müller K, Villringer A, Stumvoll M, Fasshauer M, Schlögl H. Beneficial effects of leptin substitution on impaired eating behavior in lipodystrophy are sustained beyond 150 weeks of treatment. Cytokine. 2019 Jan;113:400-404.

Hoffmann A, Ebert T, Klöting N, Kolb M, Gericke M, Jeromin F, Jessnitzer B, Lössner U, Burkhardt R, Stumvoll M, Fasshauer M, Kralisch S. Leptin decreases circulating inflammatory IL-6 and MCP-1 in mice. Biofactors. 2018 Nov 29.Kralisch S, Hoffmann A, Kratzsch J, Blüher M, Stumvoll M, Fasshauer M, Ebert T. The brown-fat-secreted adipokine neuregulin 4 is decreased in gestational diabetes mellitus. Diabetes Metab. 2017; Epub ahead of print.

Kralisch S, Hoffmann A, Klöting N, Bachmann A, Kratzsch J, Stolzenburg JU, Dietel A, Beige J, Anders M, Bast I, Blüher M, Zhang MZ, Harris RC, Stumvoll M, Fasshauer M, Ebert T. FSTL3 is increased in renal dysfunction. Nephrol Dial Transplant. 2017;32:1637-44.

Miehle K, Ebert T, Kralisch S, Hoffmann A, Kratzsch J, Schlögl H, Stumvoll M, Fasshauer M. Adipocyte and epidermal fatty acid-binding protein serum concentrations in patients with lipodystrophy. Cytokine. 2017;92:20-3.

Miehle K, Ebert T, Kralisch S, Hoffmann A, Kratzsch J, Schlögl H, Stumvoll M, Fasshauer M. Progranulin is increased in human and murine lipodystrophy. Diabetes Res Clin Pract. 2016;120:1-7.

Schlögl H, Müller K, Horstmann A, Miehle K, Püschel J, Villringer A, Pleger B, Stumvoll M, Fasshauer M. Leptin substitution in patients with lipodystrophy: Neural correlates for long-term success in the normalization of eating behavior. Diabetes. 2016;65:172-89.

Miehle K, Ebert T, Kralisch S, Hoffmann A, Kratzsch J, Schlögl H, Stumvoll M, Fasshauer M. Serum concentrations of fibroblast growth factor 21 are elevated in patients with congenital or acquired lipodystrophy. Cytokine. 2016;83:239-44.

Hoffmann A, Manjowk GM, Wagner V, Klöting N, Ebert T, Jessnitzer B, Lössner U, Stukenborg JB, Blüher M, Stumvoll M, Söder O, Svechnikov K, Fasshauer M, Kralisch S. Leptin within the subphysiological to physiological range dose-dependently improves male reproductive function in an obesity mouse model. Endocrinology. 2016;157:2641-8.

Ebert T, Platz M, Kralisch S, Lossner U, Jessnitzer B, Richter J, Blüher M, Stumvoll M, Fasshauer M. Serum levels of copeptin are decreased in gestational diabetes mellitus. Exp Clin Endocrinol Diabetes. 2016;124:257-60.

Schrey S, Wurst U, Ebert T, Kralisch S, Drewlo S, Stepan H, Lössner U, Platz M, Kratzsch J, Stumvoll M, Fasshauer M. The adipokine preadipocyte factor-1 is downregulated in preeclampsia and expressed in placenta. Cytokine. 2015;75:338-43.

Kralisch S, Klöting N, Ebert T, Kern M, Hoffmann A, Krause K, Jessnitzer B, Lossner U, Sommerer I, Stumvoll M, Fasshauer M. Circulating adipocyte fatty acid-binding protein induces insulin resistance in mice in vivo. Obesity (Silver Spring). 2015;23:1007-13.

Ebert T, Kralisch S, Hoffmann A, Bachmann A, Lössner U, Kratzsch J, Blüher M, Stumvoll M, Tönjes A, Faßhauer M. Circulating angiopoietin-like protein 8 is independently associated with fasting plasma glucose and type 2 diabetes mellitus. J Clin Endocrinol Metab. 2014;99:E2510-7.

Blüher M, Klöting N, Wueest S, Schoenle EJ, Schön MR, Dietrich A, Fasshauer M, Stumvoll M, Konrad D. Fas and FasL Expression in Human Adipose Tissue Is Related to Obesity, Insulin Resistance, and Type 2 Diabetes. J Clin Endocrinol Metab. 2014;99:E36-44.

Ebert T, Roth I, Richter J, Tönjes A, Kralisch S, Lossner U, Kratzsch J, Blüher M, Stumvoll M, Fasshauer M. Different associations of adipokines in lean and healthy adults. Horm Metab Res. 2014;46:41-7.

Ebert T, Stepan H, Schrey S, Kralisch S, Hindricks J, Hopf L, Platz M, Lossner U, Jessnitzer B, Drewlo S, Blüher M, Stumvoll M, Fasshauer M. Serum levels of irisin in gestational diabetes mellitus during pregnancy and after delivery. Cytokine. 2014;65:153-8.

Ebert T, Focke D, Petroff D, Wurst U, Richter J, Bachmann A, Lössner U, Kralisch S, Kratzsch J, Beige J, Bast I, Anders M, Blüher M, Stumvoll M, Fasshauer M. Serum levels of the myokine irisin in relation to metabolic and renal function. Eur J Endocrinol. 2014;170:501-6.

Hindricks J, Ebert T, Bachmann A, Kralisch S, Lössner U, Kratzsch J, Stolzenburg JU, Dietel A, Beige J, Anders M, Bast I, Blüher M, Stumvoll M, Fasshauer M. Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction. Clin Endocrinol. 2014;80:918-24.

Ebert T, Hindricks J, Kralisch S, Lößner U, Jeßnitzer B, Richter J, Blüher M, Stumvoll M, Fasshauer M. Serum levels of fractalkine are associated with markers of insulin resistance in gestational diabetes mellitus. Diabet Med. 2014;31:1014-7.

Kralisch S, Ebert T, Lossner U, Jesnitzer B, Stumvoll M, Fasshauer M. Adipocyte fatty acid binding protein is released from adipocytes by a non-conventional mechanism. Int J Obes (Lond). 2014;38:1251-4.

Fasshauer M, Blüher M, Stumvoll M. Adipokines in gestational diabetes. Lancet Diabetes Endocrinol. 2014;2:488-99.

Tönjes A, Kralisch S, Lossner U, Kovacs P, Bluher M, Stumvoll M, Fasshauer M. Metabolic and genetic predictors of circulating adipocyte fatty acid-binding protein. Int J Obes (Lond). 2012;36:766-73.

Miehle K, Stumvoll M, Fasshauer M. Lipodystrophy. Mechanisms, clinical presentation, therapy. Internist. 2011;52:362-70.

Sommer G, Kralisch S, Kloting N, Kamprad M, Schrock K, Kratzsch J, Tönjes A, Lossner U, Bluher M, Stumvoll M, Fasshauer M. Visfatin Is a Positive Regulator of MCP-1 in Human Adipocytes In Vitro and in Mice In Vivo. Obesity (Silver Spring). 2010;18:1486-92.

Pfau D, Bachmann A, Lossner U, Kratzsch J, Bluher M, Stumvoll M, Fasshauer M. Serum levels of the adipokine chemerin in relation to renal function. Diabetes Care. 2010;33:171-3.

Kralisch S, Sommer G, Stangl V, Kohler U, Kratzsch J, Stepan H, Faber R, Schubert A, Lossner U, Vietzke A, Bluher M, Stumvoll M, Fasshauer M. Secretory Products from Human Adipocytes Impair Endothelial Function via Nuclear Factor k B. Atherosclerosis. 2008;196:523-31.

Kloting N, Graham TE, Berndt J, Kralisch S, Kovacs P, Wason CJ, Fasshauer M, Schon MR, Stumvoll M, Blüher M, Kahn BB. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab. 2007;6:79-87.

PROJECT TEAM

Project Leader

Prof. Dr. Anke Tönjes

Project Leader

Prof. Dr. Ulrich Laufs

Group leader

PD Dr. Jes-Niels Boeckel

Doctoral Researcher

Sascha Rittig

Office address:	MBFZ A020
Phone (lab or office): E-mail:	+49 341 97-25812 sascha.rittig@medizin.uni-leipzig.de
PhD project description:	Sascha Rittig has been studying medicine at Leipzig University since 2015. Alongside his studies, he gained practical experience in anesthesiology and intensive care medicine, fascinating in cardiovascular physiology. Preclinical studies also aroused his interest in basic research, so he joined the cardiology research laboratory of Prof. Ulrich Laufs and PD Dr. Jes-Niels Boeckel. His research focuses on the mechanisms linking trimethylamine N-oxide (a metabolite produced by the gut microbiota partly in response to meat consumption) to poor cardiometabolic health.

Doctoral Researcher

Jasmin Kneuer

Office address:	MBFZ A020, Johannisallee 30
Phone (lab or office): E-mail:	+49 341 97-25813 jasmin.kneuer@medizin.uni-leipzig.de
PhD project description:	High resolution analysis of leptin treatment on atherosclerosis progression in a model of murine lypodystrophy using spatial transcriptomics.