C6 - Role of leptin in brain morphology and vascular function—studies in human and rodent lipodystrophy

Both adipokine dysregulation in lipodystrophy (LD) and in obesity are a consequence of adipose tissue dysfunction and are associated with metabolic and vascular disease. In recent years, dysregulation of the adipokines leptin, adiponectin, and adipocyte fatty acid-binding protein (AFABP) has been linked to adverse outcomes in obesity. However, the relative impact of these adipokines on metabolic and vascular dysfunction in LD is unclear. Therefore, lipodystrophic and atherosclerosis-prone mouse models are treated with recombinant leptin, an oral adiponectin receptor agonist (AdipoRon), and an oral AFABP inhibitor (BMS309403) both alone and in combination within the proposed project. The effect of these adipokine-based treatment modalities on metabolic disease, as well as atheroscle­rotic lesion area and composition, is elucidated in these animals. Furthermore, the impact of leptin, AdipoRon, and BMS309403 on recruitment and inflammatory activation of macro­phages is studied. In addition, the influence of leptin on vascular function, as well as brain morphology and function, is assessed over two years in LD patients treated at the Leptin Treatment Center Leipzig and compared to non-leptin-treated LD controls.

Figure 1: Model 

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


Püschel J, Miehle K, Müller K, Villringer AStumvoll MFasshauer 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.


Slutsky N, Vatarescu M, Haim Y, Goldstein N, Kirshtein B, Harman-Boehm I, Gepner Y, Shai I, Bashan N,Blüher M,Rudich A. Decreased adiponectin links elevated adipose tissue autophagy with adipocyte endocrine dysfunction in obesity.Int J Obes (Lond). 2016;40:912-20.


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.


Tonjes 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, Tonjes 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.


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