M2 Eva Hucklenbruch-Rother, Jörg Dötsch, Gerhard Sengle
Musculoskeletal ECM-induced reprogramming of the metabolic system
Faculty of Medicine, University of Cologne
Kerpener Str. 62, 50937 Cologne
Faculty of Medicine, University of Cologne
Kerpener Str. 62, 50937 Cologne
Prof. Dr. Gerhard Sengle
University Hospital for Pediatrics and Adolescent Medicine
Faculty of Medicine, University of Cologne
Joseph-Stelzmann-Str. 52, 50931 Cologne
Summary
The involvement of the extracellular matrix (ECM) proteins fibrillin and collagen VI in the regulation of body fat is intuitive, since most mutations in the fibrillin (FBN1, FBN2) or collagen VI genes (COL6A1, COL6A2, COL6A3) result in syndromes characterized by a slender habitus with little subcutaneous fat. In 2016, the identification of the C-terminal cleavage product of profibrillin-1, termed asprosin, provided an explanation for the strong genotype-phenotype correlation in patients with FBN1 3’ end mutations. Asprosin is released by the fibrillin-1 producing connective tissue, stimulates rapid hepatic glucose release and activates hunger-promoting neurons in the hypothalamus. Moreover, the C-terminal cleavage product of the collagen VI alpha 3 chain endotrophin was described to affect body weight, body fat and glucose homeostasis. We therefore hypothesize that the musculoskeletal system is involved in metabolic reprogramming by releasing fragments from muscle, cartilage, and bone triggered by connective tissue disease or exercise-induced ECM break down (“biomechanical reprogramming”). To test this hypothesis, we will identify mechanisms of asprosin/ endotrophin production, storage, and release in skeletal muscle, cartilage and bone. Translation into other mouse models and human cohorts of musculoskeletal and metabolic disease will allow assessing the diagnostic, preventive and therapeutic potential of asprosin/ endotrophin.Publications
Elezagic D, Mörgelin M, Hermes G, Hamprecht A, Sengle G, Lau D, Höllriegl S, Wagener R, Paulsson M, Streichert T, Klatt AR 2019 Antimicrobial peptides derived from the cartilage.-specific C-type Lectin Domain Family 3 Member A (CLEC3A) - potential in the prevention and treatment of septic arthritis. Osteoarthritis Cartilage 27(10):1564-1573.
Heumüller SE, Talantikite M, Napoli M, Armengaud J, Mörgelin M, Hartmann U, Sengle G, Paulsson M, Moali C, Wagener R 2019 C-terminal proteolysis of the collagen VI α3 chain by BMP-1 and proprotein convertase(s) releases endotrophin in fragments of different sizes. J Biol Chem 294(37):13769-13780.
Mayorca-Guiliani AE, Willacy O, Madsen CD, Rafaeva M, Heumüller SE, Bock F, Sengle G, Koch M, Imhof T, Zaucke F, Wagener R, Sasaki T, Erler JT, Reuten R 2019 Decellularization and antibody staining of mouse tissues to map native extracellular matrix structures in 3D. Nat Protoc. 14(12):3395-3425.
Schmitz L, Kuglin R, Bae-Gartz I, Janoschek R, Appel S, Mesaros A, Jakovcevski I, Vohlen C, Handwerk M, Ensenauer R, Dötsch J, Hucklenbruch-Rother E 2018 Hippocampal insulin resistance links maternal obesity with impaired neuronal plasticity in adult offspring. Psychoneuroendocrinology 89:46-52.
Bae-Gartz I, Janoschek R, Kloppe CS, Vohlen C, Roels F, Oberthur A, Alejandre Alcazar MA, Lippach G, Muether PS, Dinger K, Ferrari N, Graf C, Dotsch J, Hucklenbruch-Rother E 2016 Running Exercise in Obese Pregnancies Prevents IL-6 Trans-signaling in Male Offspring. Med Sci Sports Exerc 48(5):829-838.
Janoschek R, Bae-Gartz I, Vohlen C, Alcazar MA, Dinger K, Appel S, Dotsch J, Hucklenbruch-Rother E 2016 Dietary intervention in obese dams protects male offspring from WAT induction of TRPV4, adiposity, and hyperinsulinemia. Obesity 24(6):1266-1273.
Sengle G, Carlberg V, Tufa SF, Charbonneau NL, Smaldone S, Carlson EJ, Ramirez F, Keene DR, Sakai LY 2015 Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice. PLoS Genet 11(6):e1005340.
Sengle G, Tufa SF, Sakai LY, Zulliger MA, Keene DR 2013 A correlative method for imaging identical regions of samples by micro-CT, light microscopy, and electron microscopy: imaging adipose tissue in a model system. J Histochem Cytochem 61(4):263-271.
Rother E, Belgardt BF, Tsaousidou E, Hampel B, Waisman A, Myers MG, Jr., Bruning JC 2012 Acute selective ablation of rat insulin promoter-expressing (RIPHER) neurons defines their orexigenic nature. Proc Natl Acad Sci U S A 109(44):18132-1813753.
Rother E, Kuschewski R, Alcazar MA, Oberthuer A, Bae-Gartz I, Vohlen C, Roth B, Dotsch J 2012 Hypothalamic JNK1 and IKKbeta activation and impaired early postnatal glucose metabolism after maternal perinatal high-fat feeding. Endocrinology 153(2):770-781.
Charbonneau NL, Carlson EJ, Tufa S, Sengle G, Manalo EC, Carlberg VM, Ramirez F, Keene DR, Sakai LY 2010 In vivo studies of mutant fibrillin-1 microfibrils. J Biol Chem 285(32):24943-24955.
Plum L, Rother E, Munzberg H, Wunderlich FT, Morgan DA, Hampel B, Shanabrough M, Janoschek R, Konner AC, Alber J, Suzuki A, Krone W, Horvath TL, Rahmouni K, Bruning JC 2007 Enhanced leptin-stimulated Pi3k activation in the CNS promotes white adipose tissue transdifferentiation. Cell metabolism 6(6):431-445.
Gropp E (EHR’s maiden name), Shanabrough M, Borok E, Xu AW, Janoschek R, Buch T, Plum L, Balthasar N, Hampel B, Waisman A, Barsh GS, Horvath TL, Brüning JC 2005 Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci 8(10):1289-91.
