B10 - Lipid accumulation mechanisms and their modulation

We will use lipoma to model aberrant lipid accumulation and inhibit target molecules identified in the previous funding period (PIK3CA, PDE3/4/8, MAOA). Further, we will inquire about sequencing data from human lipomas and human obesity databases to identify novel genes involved in adipocyte development and lipid accumulation. We will assess whole-body energy metabolism and characterize differences in adipose tissue between lipoma-bearing and control mice to identify factors involved in adipose tissue remodeling.

Figure: 1A: Schematic overview of the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway which is constitutively active under conditions of phosphatase and tensin homolog (PTEN) haploinsufficiency caused by PTEN germline mutations. 1B: Adipose tissue sections from a lipoma of a patient with PTEN mutation (left) and age-matched control (right). Scale bar = 100 µm 1C: Quantification of adipocyte size in adipose tissue sections of patients with PTEN or PI3K mutations and age-matched controls.

Gjermeni E, Kirstein AS, Kolbig F, Kirchhof M, Bundalian L, Katzmann JL, Laufs U, Blüher M, Garten A, Le Duc D. Obesity-An Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances. Biomolecules. 2021 Sep 29;11(10):1426.

Kirstein AS, Kehr S, Nebe M, Hanschkow M, Barth LAG, Lorenz J, Penke M, Breitfeld J, Le Duc D, Landgraf K, Körner A, Kovacs P, Stadler PF, Kiess W, Garten A. PTEN regulates adipose progenitor cell growth, differentiation, and replicative aging. J Biol Chem. 2021 Jul 14;297(2):100968.

Chen J, … Kiess W, … Körner A, Kovacs P,…, Stumvoll M, …Tönjes A,... , Barroso I. The trans-ancestral genomic architecture of glycemic traits. Nat Genet. 2021 Jun;53(6):840-860.

Kässner F, Kirstein A, Händel N, Schmid GL, Landgraf K, Berthold A, Tannert A, Schaefer M, Wabitsch M, Kiess W, Körner A, Garten A. A New Human Adipocyte Model With PTEN Haploinsufficiency. Adipocyte. 2020 Dec;9(1):290-301.

Le Duc D, Lin CC, Popkova Y, Yang Z, Akhil V, Çakir MV, Grunewald S, Simon JC, Dietz A, Dannenberger D, Garten A, Lemke JR, Schiller J, Blüher M, Nono Nankam PA, Rolle-Kampczyk U, von Bergen M, Kelso J, Schöneberg T. Reduced lipolysis in lipoma phenocopies lipid accumulation in obesity. Int J Obes (Lond). 2020 Nov 24.

Kirstein A, Augustin A, Penke M, Cea M, Körner A, Kies W, Garten A.The Novel Phosphatidylinositol-3-Kinase (PI3K) Inhibitor Alpelisib Effectively Inhibits Growth of PTEN-Haploinsufficient Lipoma Cells. Cancers (Basel). 2019 Oct 17;11(10)

Buhl JP, Garten A, Kratzsch J, Kiess W, Penke M. How Reliable are Commercially Available Glypican4 ELISA Kits? Exp Clin Endocrinol Diabetes. 2020 Oct 16.  

Bohn C, Vogel M, Spielau U, Hilbert C, Kiess W, Körner A. Birth weight increases with birth order despite decreasing maternal pregnancy weight gain. Acta Paediatrica 2020 Sept.

Garten A, Grohmann T, Kluckova K, Lavery GG, Kiess W, Penke M. Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1. Int J Mol Sci. 2019 Aug 19;20(16). pii: E4048.

Sociali G, Grozio A, Caffa I, Schuster S, Becherini P, Damonte P, Sturla L, Fresia C, Passalacqua M, Mazzola F, Raffaelli N, Garten A, Kiess W, Cea M, Nencioni A, Bruzzone S. SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells. FASEB J. 2018 Dec 4:fj201800321R.

Grohmann T, Penke M, Petzold-Quinque S, Schuster S, Richter S, Kiess W, Garten A. Inhibition of NAMPT sensitizes MOLT4 leukemia cells for etoposide treatment through the SIRT2-p53 pathway. Leukemia Res. 2018 Jun,69, 39–46.

Kässner F, Sauer T, Penke M, Richter S, Landgraf K, Körner A, Kiess W, Händel N, Garten A.Simvastatin induces apoptosis in PTEN‑haploinsufficient lipoma cells. Int J Mol Med. 2018 Mar 14.

Penke M, Schuster S, Gorski T, Gebhardt R, Kiess W, Garten A. Oleate ameliorates palmite-induced reduction of NAMPT activity and NAD levels in primary human hepatocytes and hepatocarcinoma cells. Lipids Health Dis. 2017;16:191.

Leipert J, Kässner F, Schuster S, Händel N, Körner A, Kiess W, Garten A. Resveratrol potentiates growth inhibitory effects of rapamycin in PTEN-deficient lipoma cells by suppressing p70S6 kinase activity. Nutr Cancer. 2016;68:342-9.

Wilhelm F, Kässner F, Schmid G, Kratzsch J, Laner A, Wabitsch M, Körner A, Kiess W, Garten A. Phosphatidylinositol 3-kinase (PI3K) signalling regulates insulin-like-growth factor binding protein-2 (IGFBP-2) production in human adipocytes. Growth Horm IGF Res. 2015;25:115-20.

Schmid GL, Kässner F, Uhlig HH, Körner A, Kratzsch J, Händel N, Zepp FP, Kowalzik F, Laner A, Starke S, Wilhelm FK, Schuster S, Viehweger A, Hirsch W, Kiess W, Garten A. Sirolimus treatment of severe PTEN hamartoma tumor syndrome: case report and in vitro studies. Pediatr Res. 2014;75:527-34.